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He P, Qiao R, Liu C, Zhang W, Li H, He F. Neuroprotective Mechanisms of Baicalin in Ischemia Stroke. ACS Chem Neurosci 2025. [PMID: 40402033 DOI: 10.1021/acschemneuro.4c00842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2025] Open
Abstract
Ischemic stroke (IS) remains one of the leading global causes of mortality and disability, imposing a substantial socioeconomic burden on families and healthcare systems. Despite recognition as a critical global health challenge, therapeutic interventions for cerebral ischemia remain severely limited. The current standard treatment for acute ischemic stroke is intravenous thrombolysis using a tissue plasminogen activator (tPA). However, its narrow therapeutic window and elevated risk of hemorrhagic complications restrict thrombolytic therapy to a minority of eligible patients. Baicalin, a bioactive flavonoid derived from Scutellaria baicalensis roots, exhibits neuroprotective properties across diverse neurological conditions, including ischemic and hemorrhagic brain injury. Its neuroprotective mechanisms are multifactorial, encompassing antioxidant activity, antiapoptotic, and antiinflammatory effects, upregulation of neurotrophic factors, mitochondrial protection, and vasodilation of peripheral vasculature. The breadth of baicalin's neuroprotective actions highlights its potential as a promising therapeutic candidate for ischemic stroke. This review synthesizes current evidence on baicalin's neuroprotective effects and molecular mechanisms in ischemic stroke, emphasizing its potential as a novel therapeutic strategy.
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Affiliation(s)
- Peng He
- Pharmacy College, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
- Hunan Key Laboratory of Druggability and Preparation Modification for Traditional Chinese Medicine, Changsha, Hunan 410208, China
| | - Ru Qiao
- Pharmacy College, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
- Hunan Key Laboratory of Druggability and Preparation Modification for Traditional Chinese Medicine, Changsha, Hunan 410208, China
| | - Can Liu
- Pharmacy College, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
- Hunan Key Laboratory of Druggability and Preparation Modification for Traditional Chinese Medicine, Changsha, Hunan 410208, China
| | - Weilong Zhang
- Pharmacy College, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
- Hunan Key Laboratory of Druggability and Preparation Modification for Traditional Chinese Medicine, Changsha, Hunan 410208, China
| | - Haiying Li
- The First Affiliated Hospital of Hunan University of Traditional Chinese Medicine, Changsha, Hunan 410007, China
| | - Fuyuan He
- Pharmacy College, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
- Hunan Key Laboratory of Druggability and Preparation Modification for Traditional Chinese Medicine, Changsha, Hunan 410208, China
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Zeng D, Basilio AV, Pichay LA, Ateshian GA, Hansen OS, Romanov A, Morrison B. Experimental Measurement and Mathematical Quantification of Fixed-Charged Density in Rat and Pig Brain Tissue. Ann Biomed Eng 2025; 53:813-824. [PMID: 39702733 DOI: 10.1007/s10439-024-03666-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 12/02/2024] [Indexed: 12/21/2024]
Abstract
Cerebral edema is associated with poor prognosis because brain swelling within the rigid skull raises intracranial pressure, exacerbating secondary injuries following traumatic brain injury. Brain swelling can be characterized by triphasic biomechanics, which models brain tissue as a mixture of a deformable porous solid matrix with a negative fixed-charged density (FCD), water, and monovalent counterions. When brain cells die, the intracellular FCD is exposed, attracting cations into the cells. The increase in intracellular solute concentration generates osmotic pressure via the Gibbs-Donnan effect, driving water into cells and causing swelling. This study quantifies the FCD of rat and pig brain tissue by measuring the pressure generated by tissue within a confined volume as cells died. Rat brain tissue generated an averaged swelling pressure of 52.92 ± 20.40 mmHg (mean ± one standard deviation). Variations were observed between pig cortical white matter (7.14 ± 4.79 mmHg) and cortical gray matter (33.86 ± 11.89 mmHg). The corresponding FCD values were 42.54 ± 8.14 mEq/L for rat brain tissue, and 15.18 ± 5.38 mEq/L and 34.22 ± 6.31 mEq/L for pig cortical white and gray matter, respectively. Treating the rat brain tissue with DNAse, heparinase I, heparinase III, and chondroitinase ABC to degrade FCD significantly reduced swelling pressure. Good agreement between the experimental and numerically simulated responses supported the role of the FCD in cerebral edema formation. The reported FCD values can improve the biofidelity of computational models to predict post-traumatic cerebral edema, aiding the improvement of safety systems.
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Affiliation(s)
- Delin Zeng
- Department of Biomedical Engineering, Columbia University, 351 Engineering Terrace MC 8904, 1210 Amsterdam Avenue, New York, NY, 10027, USA
| | - Andrew V Basilio
- Department of Biomedical Engineering, Columbia University, 351 Engineering Terrace MC 8904, 1210 Amsterdam Avenue, New York, NY, 10027, USA
| | - Leanne A Pichay
- Department of Biomedical Engineering, Columbia University, 351 Engineering Terrace MC 8904, 1210 Amsterdam Avenue, New York, NY, 10027, USA
| | - Gerard A Ateshian
- Department of Biomedical Engineering, Columbia University, 351 Engineering Terrace MC 8904, 1210 Amsterdam Avenue, New York, NY, 10027, USA
- Department of Mechanical Engineering, Columbia University, 220 S. W. Mudd Building, 500 West 120th Street, New York, NY, 10027, USA
| | - Olivia S Hansen
- Department of Biomedical Engineering, Columbia University, 351 Engineering Terrace MC 8904, 1210 Amsterdam Avenue, New York, NY, 10027, USA
| | - Alexander Romanov
- Institute of Comparative Medicine, Columbia University, 650 West 168th Street, BB 1912B, New York, NY, 10032, USA
| | - Barclay Morrison
- Department of Biomedical Engineering, Columbia University, 351 Engineering Terrace MC 8904, 1210 Amsterdam Avenue, New York, NY, 10027, USA.
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Meng T, Zhang Y, Ye Y, Li H, He Y. Bioinformatics insights into mitochondrial and immune gene regulation in Alzheimer's disease. Eur J Med Res 2025; 30:89. [PMID: 39920860 PMCID: PMC11806906 DOI: 10.1186/s40001-025-02297-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 01/13/2025] [Indexed: 02/09/2025] Open
Abstract
BACKGROUND There is growing evidence that the pathogenesis of Alzheimer's disease is closely linked to the resident innate immune cells of the central nervous system, including microglia and astrocytes. Mitochondrial dysfunction in microglia has also been reported to play an essential role in the pathogenesis of AD and other neurological diseases. Therefore, finding the mitochondrial and immune-related gene (MIRG) signatures in AD can be significant in diagnosing and treating AD. METHODS In this study, the intersection of the differentially expressed genes (DEGs) from the GSE109887 cohort, immune-related genes (IRGs) obtained from WGCNA analysis, and mitochondria-related genes (MRGs) was taken to identify mitochondria-immune-related genes (MIRGs). Then, using machine learning algorithms, biomarkers with good diagnostic value were selected, and a nomogram was constructed. Subsequently, we further analyzed the signaling pathways and potential biological mechanisms of the biomarkers through gene set enrichment analysis, prediction of transcription factors (TFs), miRNAs, and drug prediction. RESULTS Using machine learning algorithms, five biomarkers (TSPO, HIGD1A, NDUFAB1, NT5DC3, and MRPS30) were successfully identified, and a nomogram model with strong diagnostic ability and accuracy (AUC > 0.9) was constructed. In addition, single-gene enrichment analysis revealed that NDUFAB1 was significantly enriched in pathways associated with diseases, such as Alzheimer's and Parkinson's, providing valuable insights for future clinical research on Alzheimer's in the context of mitochondrial-immune interactions. Interestingly, brain tissue pathology showed neuronal atrophy and demyelination in AD mice, along with a reduction in Nissl bodies. Furthermore, the escape latency of AD mice was significantly longer than that of the control group. After platform removal, there was a notable increase in the path complexity and time required to reach the target quadrant, suggesting a reduction in spatial memory capacity in AD mice. Moreover, qRT-PCR validation confirmed that the mRNA expression of the five biomarkers was consistent with bioinformatics results. In AD mice, TSPO expression was increased, while HIGD1A, NDUFAB1, NT5DC3, and MRPS30 expressions were decreased. However, peripheral blood samples did not show expression of HIGD1A or MRPS30. These findings provide new insights for research on Alzheimer's disease in the context of mitochondrial-immune interactions, further exploring the pathogenesis of Alzheimer's disease and offering new perspectives for the clinical development of novel drugs. CONCLUSIONS Five mitochondrial and immune biomarkers, i.e., TSPO, HIGD1A, NDUFAB1, NT5DC3, and MRPS30, with diagnostic value in Alzheimer's disease, were screened by machine-learning algorithmic models, which will be a guide for future clinical research of Alzheimer's disease in the mitochondria-immunity-related direction.
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Affiliation(s)
- Tian Meng
- Yunnan Yunke Institute of Biotechnology, No. 871 Longquan Rd, Kunming, 650500, China
| | - Yazhou Zhang
- Department of Geriatrics, The Second People's Hospital of Kunming, No. 338Guangming Rd, Kunming, 650233, Yunnan, China
| | - Yuan Ye
- Department of Geriatrics, The Second People's Hospital of Kunming, No. 338Guangming Rd, Kunming, 650233, Yunnan, China
| | - Hui Li
- Yunnan Labreal Biotechnology Co., LTD, No. 871 Longquan Rd, Kunming, 650500, China
| | - Yongsheng He
- Yunnan Yunke Institute of Biotechnology, No. 871 Longquan Rd, Kunming, 650500, China.
- Yunnan Labreal Biotechnology Co., LTD, No. 871 Longquan Rd, Kunming, 650500, China.
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Koyama Y, Hamada Y, Fukui Y, Hosogi N, Fujimoto R, Hishinuma S, Ogawa Y, Takahashi K, Izumi Y, Michinaga S. Endothelin-1 increases Na +-K +-2Cl - cotransporter-1 expression in cultured astrocytes and in traumatic brain injury model: An involvement of HIF1α activation. Glia 2024; 72:2231-2246. [PMID: 39166289 DOI: 10.1002/glia.24609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 08/07/2024] [Accepted: 08/09/2024] [Indexed: 08/22/2024]
Abstract
Na+-K+-2Cl- cotransporter-1 (NKCC1) is present in brain cells, including astrocytes. The expression of astrocytic NKCC1 increases in the acute phase of traumatic brain injury (TBI), which induces brain edema. Endothelin-1 (ET-1) is a factor that induces brain edema and regulates the expression of several pathology-related genes in astrocytes. In the present study, we investigated the effect of ET-1 on NKCC1 expression in astrocytes. ET-1 (100 nM)-treated cultured astrocytes showed increased NKCC1 mRNA and protein levels. The effect of ET-1 on NKCC1 expression in cultured astrocytes was reduced by BQ788 (1 μM), an ETB antagonist, but not by FR139317 (1 μM), an ETA antagonist. The involvement of ET-1 in NKCC1 expression in TBI was examined using a fluid percussion injury (FPI) mouse model that replicates the pathology of TBI with high reproducibility. Administration of BQ788 (15 nmol/day) decreased FPI-induced expressions of NKCC1 mRNA and protein, accompanied with a reduction of astrocytic activation. FPI-induced brain edema was attenuated by BQ788 and NKCC1 inhibitors (azosemide and bumetanide). ET-1-treated cultured astrocytes showed increased mRNA and protein expression of hypoxia-inducible factor-1α (HIF1α). Immunohistochemical observations of mouse cerebrum after FPI showed co-localization of HIF1α with GFAP-positive astrocytes. Increased HIF1α expression in the TBI model was reversed by BQ788. FM19G11 (an HIF inhibitor, 1 μM) and HIF1α siRNA suppressed ET-induced increase in NKCC1 expression in cultured astrocytes. These results indicate that ET-1 increases NKCC1 expression in astrocytes through the activation of HIF1α.
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Affiliation(s)
- Yutaka Koyama
- Laboratory of Pharmacology, Kobe Pharmaceutical University, Kobe, Japan
| | - Yasuhiro Hamada
- Laboratory of Pharmacology, Kobe Pharmaceutical University, Kobe, Japan
| | - Yura Fukui
- Laboratory of Pharmacology, Kobe Pharmaceutical University, Kobe, Japan
| | - Nami Hosogi
- Laboratory of Pharmacology, Kobe Pharmaceutical University, Kobe, Japan
| | - Rina Fujimoto
- Laboratory of Pharmacology, Kobe Pharmaceutical University, Kobe, Japan
| | - Shigeru Hishinuma
- Department of Pharmacodynamics, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan
| | - Yasuhiro Ogawa
- Department of Pharmacodynamics, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan
| | - Kenta Takahashi
- Department of Pharmacodynamics, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan
| | - Yasuhiko Izumi
- Laboratory of Pharmacology, Kobe Pharmaceutical University, Kobe, Japan
| | - Shotaro Michinaga
- Department of Pharmacodynamics, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan
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Sengking J, Mahakkanukrauh P. The underlying mechanism of calcium toxicity-induced autophagic cell death and lysosomal degradation in early stage of cerebral ischemia. Anat Cell Biol 2024; 57:155-162. [PMID: 38680098 PMCID: PMC11184419 DOI: 10.5115/acb.24.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 02/21/2024] [Accepted: 03/11/2024] [Indexed: 05/01/2024] Open
Abstract
Cerebral ischemia is the important cause of worldwide disability and mortality, that is one of the obstruction of blood vessels supplying to the brain. In early stage, glutamate excitotoxicity and high level of intracellular calcium (Ca2+) are the major processes which can promote many downstream signaling involving in neuronal death and brain tissue damaging. Moreover, autophagy, the reusing of damaged cell organelles, is affected in early ischemia. Under ischemic conditions, autophagy plays an important role to maintain energy of the brain and its function. In the other hand, over intracellular Ca2+ accumulation triggers excessive autophagic process and lysosomal degradation leading to autophagic process impairment which finally induce neuronal death. This article reviews the association between intracellular Ca2+ and autophagic process in acute stage of ischemic stroke.
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Affiliation(s)
- Jirakhamon Sengking
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Pasuk Mahakkanukrauh
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Excellence in Osteology Research and Training Center (ORTC), Chaing Mai University, Chiang Mai, Thailand
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Löscher W, Gramer M, Römermann K. Heterogeneous brain distribution of bumetanide following systemic administration in rats. Biopharm Drug Dispos 2024; 45:138-148. [PMID: 38823029 DOI: 10.1002/bdd.2390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 04/19/2024] [Accepted: 05/16/2024] [Indexed: 06/03/2024]
Abstract
Bumetanide is used widely as a tool and off-label treatment to inhibit the Na-K-2Cl cotransporter NKCC1 in the brain and thereby to normalize intra-neuronal chloride levels in several brain disorders. However, following systemic administration, bumetanide only poorly penetrates into the brain parenchyma and does not reach levels sufficient to inhibit NKCC1. The low brain penetration is a consequence of both the high ionization rate and plasma protein binding, which restrict brain entry by passive diffusion, and of brain efflux transport. In previous studies, bumetanide was determined in the whole brain or a few brain regions, such as the hippocampus. However, the blood-brain barrier and its efflux transporters are heterogeneous across brain regions, so it cannot be excluded that bumetanide reaches sufficiently high brain levels for NKCC1 inhibition in some discrete brain areas. Here, bumetanide was determined in 14 brain regions following i.v. administration of 10 mg/kg in rats. Because bumetanide is much more rapidly eliminated by rats than humans, its metabolism was reduced by pretreatment with piperonyl butoxide. Significant, up to 5-fold differences in regional bumetanide levels were determined with the highest levels in the midbrain and olfactory bulb and the lowest levels in the striatum and amygdala. Brain:plasma ratios ranged between 0.004 (amygdala) and 0.022 (olfactory bulb). Regional brain levels were significantly correlated with local cerebral blood flow. However, regional bumetanide levels were far below the IC50 (2.4 μM) determined previously for rat NKCC1. Thus, these data further substantiate that the reported effects of bumetanide in rodent models of brain disorders are not related to NKCC1 inhibition in the brain.
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Affiliation(s)
- Wolfgang Löscher
- Translational Neuropharmacology Laboratory, NIFE, Department of Experimental Otology of the ENT Clinics, Hannover Medical School, Hannover, Germany
- Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany
- Center for Systems Neuroscience Hannover, Hannover, Germany
| | - Martina Gramer
- Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Kerstin Römermann
- Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany
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Nascimento AA, Pereira-Figueiredo D, Borges-Martins VP, Kubrusly RC, Calaza KC. GABAergic system and chloride cotransporters as potential therapeutic targets to mitigate cell death in ischemia. J Neurosci Res 2024; 102:e25355. [PMID: 38808645 DOI: 10.1002/jnr.25355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 04/17/2024] [Accepted: 05/06/2024] [Indexed: 05/30/2024]
Abstract
Gamma aminobutyric acid (GABA) is a critical inhibitory neurotransmitter in the central nervous system that plays a vital role in modulating neuronal excitability. Dysregulation of GABAergic signaling, particularly involving the cotransporters NKCC1 and KCC2, has been implicated in various pathologies, including epilepsy, schizophrenia, autism spectrum disorder, Down syndrome, and ischemia. NKCC1 facilitates chloride influx, whereas KCC2 mediates chloride efflux via potassium gradient. Altered expression and function of these cotransporters have been associated with excitotoxicity, inflammation, and cellular death in ischemic events characterized by reduced cerebral blood flow, leading to compromised tissue metabolism and subsequent cell death. NKCC1 inhibition has emerged as a potential therapeutic approach to attenuate intracellular chloride accumulation and mitigate neuronal damage during ischemic events. Similarly, targeting KCC2, which regulates chloride efflux, holds promise for improving outcomes and reducing neuronal damage under ischemic conditions. This review emphasizes the critical roles of GABA, NKCC1, and KCC2 in ischemic pathologies and their potential as therapeutic targets. Inhibiting or modulating the activity of these cotransporters represents a promising strategy for reducing neuronal damage, preventing excitotoxicity, and improving neurological outcomes following ischemic events. Furthermore, exploring the interactions between natural compounds and NKCC1/KCC2 provides additional avenues for potential therapeutic interventions for ischemic injury.
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Affiliation(s)
- A A Nascimento
- Neurobiology of the Retina Laboratory, Department of Neurobiology and Graduate Program of Neurosciences, Institute of Biology, Fluminense Federal University, Niterói, Brazil
| | - D Pereira-Figueiredo
- Graduate Program in Biomedical Sciences (Physiology and Pharmacology), Fluminense Federal University, Niterói, Brazil
| | - V P Borges-Martins
- Laboratory of Neuropharmacology, Department of Physiology and Pharmacology, Biomedical Institute, Fluminense Federal University, Niterói, Brazil
| | - R C Kubrusly
- Laboratory of Neuropharmacology, Department of Physiology and Pharmacology, Biomedical Institute, Fluminense Federal University, Niterói, Brazil
| | - K C Calaza
- Neurobiology of the Retina Laboratory, Department of Neurobiology and Graduate Program of Neurosciences, Institute of Biology, Fluminense Federal University, Niterói, Brazil
- Graduate Program in Biomedical Sciences (Physiology and Pharmacology), Fluminense Federal University, Niterói, Brazil
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Nadzri AN, Nik Mohamed NA, Payne SJ, Mohamed Mokhtarudin MJ. Poroelastic modelling of brain tissue swelling and decompressive craniectomy treatment in ischaemic stroke. Comput Methods Biomech Biomed Engin 2024:1-11. [PMID: 38461460 DOI: 10.1080/10255842.2024.2326972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 03/01/2024] [Indexed: 03/12/2024]
Abstract
Brain oedema or tissue swelling that develops after ischaemic stroke can cause detrimental effects, including brain herniation and increased intracranial pressure (ICP). These effects can be reduced by performing a decompressive craniectomy (DC) operation, in which a portion of the skull is removed to allow swollen brain tissue to expand outside the skull. In this study, a poroelastic model is used to investigate the effect of brain ischaemic infarct size and location on the severity of brain tissue swelling. Furthermore, the model will also be used to evaluate the effectiveness of DC surgery as a treatment for brain tissue swelling after ischaemia. The poroelastic model consists of two equations: one describing the elasticity of the brain tissue and the other describing the changes in the interstitial tissue pressure. The model is applied on an idealized brain geometry, and it is found that infarcts with radius larger than approximately 14 mm and located near the lateral ventricle produce worse brain midline shift, measured through lateral ventricle compression. Furthermore, the model is also able to show the positive effect of DC treatment in reducing the brain midline shift by allowing part of the brain tissue to expand through the skull opening. However, the model does not show a decrease in the interstitial pressure during DC treatment. Further improvement and validation could enhance the capability of the proposed poroelastic model in predicting the occurrence of brain tissue swelling and DC treatment post ischaemia.
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Affiliation(s)
- Aina Najwa Nadzri
- Faculty of Manufacturing and Mechatronics Engineering Technology, Universiti Malaysia Pahang, Pekan, Pahang, Malaysia
| | - Nik Abdullah Nik Mohamed
- Faculty of Engineering, Technology and Built Environment, UCSI University Kuala Lumpur, Kuala Lumpur, Malaysia
| | - Stephen J Payne
- Institute of Applied Mechanics, National Taiwan University, Taipei, Taiwan
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Kim HR, Martina M. Bidirectional Regulation of GABA A Reversal Potential in the Adult Brain: Physiological and Pathological Implications. Life (Basel) 2024; 14:143. [PMID: 38276272 PMCID: PMC10817304 DOI: 10.3390/life14010143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/16/2024] [Accepted: 01/17/2024] [Indexed: 01/27/2024] Open
Abstract
In physiological conditions, the intracellular chloride concentration is much lower than the extracellular. As GABAA channels are permeable to anions, the reversal potential of GABAA is very close to that of Cl-, which is the most abundant free anion in the intra- and extracellular spaces. Intracellular chloride is regulated by the activity ratio of NKCC1 and KCC2, two chloride-cation cotransporters that import and export Cl-, respectively. Due to the closeness between GABAA reversal potential and the value of the resting membrane potential in most neurons, small changes in intracellular chloride have a major functional impact, which makes GABAA a uniquely flexible signaling system. In most neurons of the adult brain, the GABAA reversal potential is slightly more negative than the resting membrane potential, which makes GABAA hyperpolarizing. Alterations in GABAA reversal potential are a common feature in numerous conditions as they are the consequence of an imbalance in the NKCC1-KCC2 activity ratio. In most conditions (including Alzheimer's disease, schizophrenia, and Down's syndrome), GABAA becomes depolarizing, which causes network desynchronization and behavioral impairment. In other conditions (neonatal inflammation and neuropathic pain), however, GABAA reversal potential becomes hypernegative, which affects behavior through a potent circuit deactivation.
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Affiliation(s)
- Haram R. Kim
- Department of Neuroscience, Feinberg School of Medicine, Northwestern University, 300 E. Superior, Chicago, IL 60611, USA;
| | - Marco Martina
- Department of Neuroscience, Feinberg School of Medicine, Northwestern University, 300 E. Superior, Chicago, IL 60611, USA;
- Department of Psychiatry, Feinberg School of Medicine, Northwestern University, 300 E. Superior, Chicago, IL 60611, USA
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Gao HM, Chen H, Cui GY, Hu JX. Damage mechanism and therapy progress of the blood-brain barrier after ischemic stroke. Cell Biosci 2023; 13:196. [PMID: 37915036 PMCID: PMC10619327 DOI: 10.1186/s13578-023-01126-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Accepted: 09/04/2023] [Indexed: 11/03/2023] Open
Abstract
The blood-brain barrier (BBB) serves as a defensive line protecting the central nervous system, while also maintaining micro-environment homeostasis and inhibiting harmful materials from the peripheral blood. However, the BBB's unique physiological functions and properties make drug delivery challenging for patients with central nervous system diseases. In this article, we briefly describe the cell structure basis and mechanism of action of the BBB, as well as related functional proteins involved. Additionally, we discuss the various mechanisms of BBB damage following the onset of an ischemic stroke, and lastly, we mention several therapeutic strategies accounting for impairment mechanisms. We hope to provide innovative ideas for drug delivery research via the BBB.
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Affiliation(s)
- Hui-Min Gao
- Institute of Stroke Research, Xuzhou Medical University, Jiangsu, China
| | - Hao Chen
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Jiangsu, China
| | - Gui-Yun Cui
- Institute of Stroke Research, Xuzhou Medical University, Jiangsu, China
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Jiangsu, China
| | - Jin-Xia Hu
- Institute of Stroke Research, Xuzhou Medical University, Jiangsu, China.
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Jiangsu, China.
- School of Chemical Engineering and Technology, China University of Mining and Technology, Xuzhou, 221116, China.
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Kung TFC, Wilkinson CM, Liddle LJ, Colbourne F. A systematic review and meta-analysis on the efficacy of glibenclamide in animal models of intracerebral hemorrhage. PLoS One 2023; 18:e0292033. [PMID: 37756302 PMCID: PMC10529582 DOI: 10.1371/journal.pone.0292033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023] Open
Abstract
Intracerebral hemorrhage (ICH) is a devastating stroke with many mechanisms of injury. Edema worsens outcome and can lead to mortality after ICH. Glibenclamide (GLC), a sulfonylurea 1- transient receptor potential melastatin 4 (Sur1-Trpm4) channel blocker, has been shown to attenuate edema in ischemic stroke models, raising the possibility of benefit in ICH. This meta-analysis synthesizes current pre-clinical (rodent) literature regarding the efficacy of post-ICH GLC administration (vs. vehicle controls) on behaviour (i.e., neurological deficit, motor, and memory outcomes), edema, hematoma volume, and injury volume. Six studies (5 in rats and 1 in mice) were included in our meta-analysis (PROSPERO registration = CRD42021283614). GLC significantly improved behaviour (standardized mean difference (SMD) = -0.63, [-1.16, -0.09], n = 70-74) and reduced edema (SMD = -0.91, [-1.64, -0.18], n = 70), but did not affect hematoma volume (SMD = 0.0788, [-0.5631, 0.7207], n = 18-20), or injury volume (SMD = 0.2892, [-0.4950, 1.0734], n = 24). However, these results should be interpreted cautiously. Findings were conflicted with 2 negative and 4 positive reports, and Egger regressions indicated missing negative edema data (p = 0.0001), and possible missing negative behavioural data (p = 0.0766). Experimental quality assessed via the SYRCLE and CAMARADES checklists was concerning, as most studies demonstrated high risks of bias. Studies were generally low-powered (e.g., average n = 14.4 for behaviour), and future studies should employ sample sizes of 41 to detect our observed effect size in behaviour and 33 to detect our observed effect in edema. Overall, missing negative studies, low study quality, high risk of bias, and incomplete attention to key recommendations (e.g., investigating female, aged, and co-morbid animals) suggest that further high-powered confirmatory studies are needed before conclusive statements about GLC's efficacy in ICH can be made, and before further clinical trials are performed.
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Affiliation(s)
- Tiffany F. C. Kung
- Department of Psychology, University of Alberta, Edmonton, Alberta, Canada
| | | | - Lane J. Liddle
- Department of Psychology, University of Alberta, Edmonton, Alberta, Canada
| | - Frederick Colbourne
- Department of Psychology, University of Alberta, Edmonton, Alberta, Canada
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada
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Ong J, Tarver W, Brunstetter T, Mader TH, Gibson CR, Mason SS, Lee A. Spaceflight associated neuro-ocular syndrome: proposed pathogenesis, terrestrial analogues, and emerging countermeasures. Br J Ophthalmol 2023; 107:895-900. [PMID: 36690421 PMCID: PMC10359702 DOI: 10.1136/bjo-2022-322892] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 12/11/2022] [Indexed: 01/25/2023]
Abstract
Spaceflight associated neuro-ocular syndrome (SANS) refers to a distinct constellation of ocular, neurological and neuroimaging findings observed in astronauts during and following long duration spaceflight. These ocular findings, to include optic disc oedema, posterior globe flattening, chorioretinal folds and hyperopic shifts, were first described by NASA in 2011. SANS is a potential risk to astronaut health and will likely require mitigation prior to planetary travel with prolonged exposures to microgravity. While the exact pathogenesis of SANS is not completely understood, several hypotheses have been proposed to explain this neuro-ocular phenomenon. In this paper, we briefly discuss the current hypotheses and contributing factors underlying SANS pathophysiology as well as analogues used to study SANS on Earth. We also review emerging potential countermeasures for SANS including lower body negative pressure, nutritional supplementation and translaminar pressure gradient modulation. Ongoing investigation within these fields will likely be instrumental in preparing and protecting astronaut vision for future spaceflight missions including deep space exploration.
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Affiliation(s)
- Joshua Ong
- Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | | | | | | | - C Robert Gibson
- KBR, NASA Space Medicine Operations Division, Houston, Texas, USA
- South Shore Eye Center, League City, Texas, USA
| | | | - Andrew Lee
- Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas, USA
- Center for Space Medicine, Baylor College of Medicine, Houston, Texas, USA
- The Houston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas, USA
- Departments of Ophthalmology, Neurology, and Neurosurgery, Weill Cornell Medicine, New York, New York, USA
- Department of Ophthalmology, University of Texas Medical Branch, Galveston, Texas, USA
- University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Texas A&M College of Medicine, Bryan, Texas, USA
- Department of Ophthalmology, The University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA
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13
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Maharajni P, Caretti V, Moro MA, McCullough LD. Role of the Meningeal Lymphatics in Stroke. Stroke 2023; 54:1670-1673. [PMID: 37216448 PMCID: PMC10204316 DOI: 10.1161/strokeaha.123.043424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Affiliation(s)
- Perla Maharajni
- Department of Neurology, McGovern Medical School, UTHealth Houston, Houston, TX, 77030
| | - Viola Caretti
- Department of Neurology, McGovern Medical School, UTHealth Houston, Houston, TX, 77030
- Department of Pediatrics, Section of Pediatric Neurology and Developmental Neuroscience, Baylor College of Medicine, 6621 Fannin St., Houston, TX 77030, USA
| | - Maria A. Moro
- Centro Nacional de Investigaciones Cardiovasculares Carlos III Neurovascular, Melchor Fernández Almagro 3, Madrid 28029, Spain
| | - Louise D. McCullough
- Department of Neurology, McGovern Medical School, UTHealth Houston, Houston, TX, 77030
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14
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Seblani M, Decherchi P, Brezun JM. Edema after CNS Trauma: A Focus on Spinal Cord Injury. Int J Mol Sci 2023; 24:ijms24087159. [PMID: 37108324 PMCID: PMC10138956 DOI: 10.3390/ijms24087159] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 04/09/2023] [Accepted: 04/11/2023] [Indexed: 04/29/2023] Open
Abstract
Edema after spinal cord injury (SCI) is one of the first observations after the primary injury and lasts for few days after trauma. It has serious consequences on the affected tissue and can aggravate the initial devastating condition. To date, the mechanisms of the water content increase after SCI are not fully understood. Edema formation results in a combination of interdependent factors related to mechanical damage after the initial trauma progressing, along with the subacute and acute phases of the secondary lesion. These factors include mechanical disruption and subsequent inflammatory permeabilization of the blood spinal cord barrier, increase in the capillary permeability, deregulation in the hydrostatic pressure, electrolyte-imbalanced membranes and water uptake in the cells. Previous research has attempted to characterize edema formation by focusing mainly on brain swelling. The purpose of this review is to summarize the current understanding of the differences in edema formation in the spinal cord and brain, and to highlight the importance of elucidating the specific mechanisms of edema formation after SCI. Additionally, it outlines findings on the spatiotemporal evolution of edema after spinal cord lesion and provides a general overview of prospective treatment strategies by focusing on insights to prevent edema formation after SCI.
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Affiliation(s)
- Mostafa Seblani
- Aix Marseille Univ, CNRS, ISM, UMR 7287, Institut des Sciences du Mouvement: Etienne-Jules MAREY, Equipe «Plasticité des Systèmes Nerveux et Musculaire» (PSNM), Parc Scientifique et Technologique de Luminy, CC910-163, Avenue de Luminy, F-13288 Marseille, CEDEX 09, France
| | - Patrick Decherchi
- Aix Marseille Univ, CNRS, ISM, UMR 7287, Institut des Sciences du Mouvement: Etienne-Jules MAREY, Equipe «Plasticité des Systèmes Nerveux et Musculaire» (PSNM), Parc Scientifique et Technologique de Luminy, CC910-163, Avenue de Luminy, F-13288 Marseille, CEDEX 09, France
| | - Jean-Michel Brezun
- Aix Marseille Univ, CNRS, ISM, UMR 7287, Institut des Sciences du Mouvement: Etienne-Jules MAREY, Equipe «Plasticité des Systèmes Nerveux et Musculaire» (PSNM), Parc Scientifique et Technologique de Luminy, CC910-163, Avenue de Luminy, F-13288 Marseille, CEDEX 09, France
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15
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Zadka Y, Doron O, Rosenthal G, Barnea O. Mechanisms of reduced cerebral blood flow in cerebral edema and elevated intracranial pressure. J Appl Physiol (1985) 2023; 134:444-454. [PMID: 36603049 DOI: 10.1152/japplphysiol.00287.2022] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
A mechanism of elevated intracranial pressure (ICP) in cerebral edema and its effects on cerebral blood flow (CBF) are presented in this paper. To study and demonstrate these effects, a mathematical model of intracranial hydrodynamics was developed. The model simulates the intracranial hydrodynamics and the changes that occur when cerebral edema predominates. To account for an edema pathology, the model includes resistances to cerebrospinal fluid (CSF) and interstitial fluid (ISF) flows within the parenchyma. The resistances change as the intercellular space becomes smaller due to swelling of brain cells. The model demonstrates the effect of changes in these resistances on ICP and venous resistance to blood flow by accounting for the key interactions between pressure, volume, and flow in the intracranial compartments in pathophysiological conditions. The model represents normal intracranial physiology as well as pathological conditions. Simulating cerebral edema with increased resistance to cerebral ISF flow resulted in elevated ICP, increased brain volume, markedly reduced ventricular volume, and decreased CBF as observed in the neurointensive care patients. The model indicates that in high ICP values, alternation of the arterial-arteriolar resistance to flow minimally affects CBF, whereas at low ICP they have a much greater effect on CBF. The model demonstrates and elucidates intracranial mechanisms related to elevated ICP.NEW & NOTEWORTHY Study goal was to elucidate the role of "bulk flow" of ISF through brain parenchyma. A model was developed to simulate fluid shifts in brain edema, ICP elevation, and their effect on CBF. Bulk flow resistance affected by edema elevates ICP and reduces CBF. Bulk flow affects transmural pressure and volume distribution in brain compartments. Changes in bulk flow resistance result in increase of venous resistance to flow and decrease in CBF.
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Affiliation(s)
- Yuliya Zadka
- Department of Biomedical Engineering, Tel Aviv University, Tel Aviv, Israel
| | - Omer Doron
- Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts
| | - Guy Rosenthal
- Department of Neurosurgery, Hadassah University Medical Center, Jerusalem, Israel
| | - Ofer Barnea
- Department of Biomedical Engineering, Tel Aviv University, Tel Aviv, Israel
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16
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Abstract
Dementias encompass a range of debilitating neurologic conditions. Here, we summarize the neuropathology of common forms of dementia, focusing on Alzheimer disease (AD) and related dementias. AD is part of a spectrum of neurodegenerative diseases that consists of various protein inclusions (ie, proteinopathies) but other brain abnormalities are also related to dementia. Beta-amyloid and tau aggregates are hallmarks of AD. Other tissue substrates include Lewy bodies, TDP-43 inclusions, vascular brain lesions, and mixed pathologies. This review highlights the complexity of neurodegenerative and other disease substrates and summarizes topography of these lesions and concepts of mixed brain pathologies, resistance, and resilience.
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Affiliation(s)
- Rupal I Mehta
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA; Department of Pathology, Rush University Medical Center, 1750 West Harrison Street, Chicago, IL 60612, USA.
| | - Julie A Schneider
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA; Department of Pathology, Rush University Medical Center, 1750 West Harrison Street, Chicago, IL 60612, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA
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17
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Lam P, Newland J, Faull RLM, Kwakowsky A. Cation-Chloride Cotransporters KCC2 and NKCC1 as Therapeutic Targets in Neurological and Neuropsychiatric Disorders. Molecules 2023; 28:1344. [PMID: 36771011 PMCID: PMC9920462 DOI: 10.3390/molecules28031344] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 01/21/2023] [Accepted: 01/25/2023] [Indexed: 02/04/2023] Open
Abstract
Neurological diseases including Alzheimer's, Huntington's disease, Parkinson's disease, Down syndrome and epilepsy, and neuropsychiatric disorders such as schizophrenia, are conditions that affect not only individuals but societies on a global scale. Current therapies offer a means for small symptomatic relief, but recently there has been increasing demand for therapeutic alternatives. The γ-aminobutyric acid (GABA)ergic signaling system has been investigated for developing new therapies as it has been noted that any dysfunction or changes to this system can contribute to disease progression. Expression of the K-Cl-2 (KCC2) and N-K-C1-1 (NKCC1) cation-chloride cotransporters (CCCs) has recently been linked to the disruption of GABAergic activity by affecting the polarity of GABAA receptor signaling. KCC2 and NKCC1 play a part in multiple neurological and neuropsychiatric disorders, making them a target of interest for potential therapies. This review explores current research suggesting the pathophysiological role and therapeutic importance of KCC2 and NKCC1 in neuropsychiatric and neurological disorders.
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Affiliation(s)
- Patricia Lam
- Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
| | - Julia Newland
- Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
| | - Richard L. M. Faull
- Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
| | - Andrea Kwakowsky
- Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
- Pharmacology and Therapeutics, School of Medicine, Galway Neuroscience Centre, University of Galway, H91 W5P7 Galway, Ireland
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18
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Lithium Biological Action Mechanisms after Ischemic Stroke. Life (Basel) 2022; 12:life12111680. [DOI: 10.3390/life12111680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 10/18/2022] [Accepted: 10/19/2022] [Indexed: 11/05/2022] Open
Abstract
Lithium is a source of great scientific interest because although it has such a simple structure, relatively easy-to-analyze chemistry, and well-established physical properties, the plethora of effects on biological systems—which influence numerous cellular and molecular processes through not entirely explained mechanisms of action—generate a mystery that modern science is still trying to decipher. Lithium has multiple effects on neurotransmitter-mediated receptor signaling, ion transport, signaling cascades, hormonal regulation, circadian rhythm, and gene expression. The biochemical mechanisms of lithium action appear to be multifactorial and interrelated with the functioning of several enzymes, hormones, vitamins, and growth and transformation factors. The widespread and chaotic marketing of lithium salts in potions and mineral waters, always at inadequate concentrations for various diseases, has contributed to the general disillusionment with empirical medical hypotheses about the therapeutic role of lithium. Lithium salts were first used therapeutically in 1850 to relieve the symptoms of gout, rheumatism, and kidney stones. In 1949, Cade was credited with discovering the sedative effect of lithium salts in the state of manic agitation, but frequent cases of intoxication accompanied the therapy. In the 1960s, lithium was shown to prevent manic and also depressive recurrences. This prophylactic effect was first demonstrated in an open-label study using the “mirror” method and was later (after 1970) confirmed by several placebo-controlled double-blind studies. Lithium prophylaxis was similarly effective in bipolar and also unipolar patients. In 1967, the therapeutic value of lithemia was determined, included in the range of 0.5–1.5 mEq/L. Recently, new therapeutic perspectives on lithium are connected with improved neurological outcomes after ischemic stroke. The effects of lithium on the development and maintenance of neuroprotection can be divided into two categories: short-term effects and long-term effects. Unfortunately, the existing studies do not fully explain the lithium biological action mechanisms after ischemic stroke.
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19
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Eitelmann S, Stephan J, Everaerts K, Durry S, Pape N, Gerkau NJ, Rose CR. Changes in Astroglial K + upon Brief Periods of Energy Deprivation in the Mouse Neocortex. Int J Mol Sci 2022; 23:ijms23094836. [PMID: 35563238 PMCID: PMC9102782 DOI: 10.3390/ijms23094836] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 04/21/2022] [Accepted: 04/24/2022] [Indexed: 11/16/2022] Open
Abstract
Malfunction of astrocytic K+ regulation contributes to the breakdown of extracellular K+ homeostasis during ischemia and spreading depolarization events. Studying astroglial K+ changes is, however, hampered by a lack of suitable techniques. Here, we combined results from fluorescence imaging, ion-selective microelectrodes, and patch-clamp recordings in murine neocortical slices with the calculation of astrocytic [K+]. Brief chemical ischemia caused a reversible ATP reduction and a transient depolarization of astrocytes. Moreover, astrocytic [Na+] increased by 24 mM and extracellular [Na+] decreased. Extracellular [K+] increased, followed by an undershoot during recovery. Feeding these data into the Goldman-Hodgkin-Katz equation revealed a baseline astroglial [K+] of 146 mM, an initial K+ loss by 43 mM upon chemical ischemia, and a transient K+ overshoot of 16 mM during recovery. It also disclosed a biphasic mismatch in astrocytic Na+/K+ balance, which was initially ameliorated, but later aggravated by accompanying changes in pH and bicarbonate, respectively. Altogether, our study predicts a loss of K+ from astrocytes upon chemical ischemia followed by a net gain. The overshooting K+ uptake will promote low extracellular K+ during recovery, likely exerting a neuroprotective effect. The resulting late cation/anion imbalance requires additional efflux of cations and/or influx of anions, the latter eventually driving delayed astrocyte swelling.
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20
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Wang J, Liu R, Hasan MN, Fischer S, Chen Y, Como M, Fiesler VM, Bhuiyan MIH, Dong S, Li E, Kahle KT, Zhang J, Deng X, Subramanya AR, Begum G, Yin Y, Sun D. Role of SPAK-NKCC1 signaling cascade in the choroid plexus blood-CSF barrier damage after stroke. J Neuroinflammation 2022; 19:91. [PMID: 35413993 PMCID: PMC9006540 DOI: 10.1186/s12974-022-02456-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 03/29/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The mechanisms underlying dysfunction of choroid plexus (ChP) blood-cerebrospinal fluid (CSF) barrier and lymphocyte invasion in neuroinflammatory responses to stroke are not well understood. In this study, we investigated whether stroke damaged the blood-CSF barrier integrity due to dysregulation of major ChP ion transport system, Na+-K+-Cl- cotransporter 1 (NKCC1), and regulatory Ste20-related proline-alanine-rich kinase (SPAK). METHODS Sham or ischemic stroke was induced in C57Bl/6J mice. Changes on the SPAK-NKCC1 complex and tight junction proteins (TJs) in the ChP were quantified by immunofluorescence staining and immunoblotting. Immune cell infiltration in the ChP was assessed by flow cytometry and immunostaining. Cultured ChP epithelium cells (CPECs) and cortical neurons were used to evaluate H2O2-mediated oxidative stress in stimulating the SPAK-NKCC1 complex and cellular damage. In vivo or in vitro pharmacological blockade of the ChP SPAK-NKCC1 cascade with SPAK inhibitor ZT-1a or NKCC1 inhibitor bumetanide were examined. RESULTS Ischemic stroke stimulated activation of the CPECs apical membrane SPAK-NKCC1 complex, NF-κB, and MMP9, which was associated with loss of the blood-CSF barrier integrity and increased immune cell infiltration into the ChP. Oxidative stress directly activated the SPAK-NKCC1 pathway and resulted in apoptosis, neurodegeneration, and NKCC1-mediated ion influx. Pharmacological blockade of the SPAK-NKCC1 pathway protected the ChP barrier integrity, attenuated ChP immune cell infiltration or neuronal death. CONCLUSION Stroke-induced pathological stimulation of the SPAK-NKCC1 cascade caused CPECs damage and disruption of TJs at the blood-CSF barrier. The ChP SPAK-NKCC1 complex emerged as a therapeutic target for attenuating ChP dysfunction and lymphocyte invasion after stroke.
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Affiliation(s)
- Jun Wang
- Department of Neurology, The Second Hospital of Dalian Medical University, Dalian, 116027, Liaoning, China
- Department of Neurology, University of Pittsburgh, 7016 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA, 15260, USA
| | - Ruijia Liu
- Department of Neurology, University of Pittsburgh, 7016 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA, 15260, USA
| | - Md Nabiul Hasan
- Department of Neurology, University of Pittsburgh, 7016 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA, 15260, USA
- Research Service, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA
| | - Sydney Fischer
- Department of Neurology, University of Pittsburgh, 7016 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA, 15260, USA
| | - Yang Chen
- Department of Neurology, The Second Hospital of Dalian Medical University, Dalian, 116027, Liaoning, China
- Department of Neurology, University of Pittsburgh, 7016 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA, 15260, USA
| | - Matt Como
- Pennsylvania State University, State College, PA, USA
| | - Victoria M Fiesler
- Department of Neurology, University of Pittsburgh, 7016 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA, 15260, USA
| | - Mohammad Iqbal H Bhuiyan
- Department of Neurology, University of Pittsburgh, 7016 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA, 15260, USA
- Research Service, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA
| | - Shuying Dong
- Department of Neurology, University of Pittsburgh, 7016 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA, 15260, USA
| | - Eric Li
- Department of Neurology, University of Pittsburgh, 7016 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA, 15260, USA
| | - Kristopher T Kahle
- Department of Neurosurgery, The Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jinwei Zhang
- Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Hatherly Laboratory, Exeter, EX4 4PS, UK
| | - Xianming Deng
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Arohan R Subramanya
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Research Service, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA
| | - Gulnaz Begum
- Department of Neurology, University of Pittsburgh, 7016 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA, 15260, USA
- Research Service, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA
| | - Yan Yin
- Department of Neurology, The Second Hospital of Dalian Medical University, Dalian, 116027, Liaoning, China.
| | - Dandan Sun
- Department of Neurology, University of Pittsburgh, 7016 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA, 15260, USA.
- Research Service, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA.
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21
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Alwjwaj M, Kadir RRA, Bayraktutan U. Outgrowth endothelial progenitor cells restore cerebral barrier function following ischaemic damage: the impact of NOX2 inhibition. Eur J Neurosci 2022; 55:1658-1670. [PMID: 35179812 DOI: 10.1111/ejn.15627] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 02/08/2022] [Accepted: 02/15/2022] [Indexed: 11/29/2022]
Abstract
Disruption of blood-brain barrier (BBB), formed mainly by human brain microvascular endothelial cells (HBMECs), constitutes the major cause of mortality following ischaemic stroke. This study investigates whether OECs (outgrowth endothelial cells) can restore BBB integrity and function following ischaemic damage, and how inhibition of NOX2, a main source of vascular oxidative stress, affects the characteristics of BBB established with OECs and HBMECs in ischaemic settings. In vitro models of human BBB were constructed by co-culture of pericytes and astrocytes with either OECs or HBMECs before exposure to oxygen-glucose deprivation (OGD) alone or followed by reperfusion (OGD+R) in the absence or presence of NOX2 inhibitor, gp91ds-tat. The function and integrity of BBB were assessed by measurements of paracellular flux of sodium fluorescein (NaF) and transendothelial electrical resistance (TEER), respectively. Treatment with OECs during OGD+R effectively restored BBB integrity and function. Compared to HBMECs, OECs possessed lower NADPH oxidase activity, superoxide anion levels, and had greater total antioxidant capacity during OGD and OGD+R. Inhibition of NADPH oxidase during OGD and OGD+R restored the integrity and function of BBB established by HBMECs. This was evidenced by reductions in NADPH oxidase activity and superoxide anion levels. In contrast, treatment with gp91ds-tat aggravated ischaemic injury-induced BBB damage constructed by OECs. In conclusion, OECs are more resistant to ischaemic conditions and can effectively repair cerebral barrier following ischaemic damage. Suppression of oxidative stress through specific targeting of NOX2 requires close attention while using OECs as therapeutics.
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Affiliation(s)
- Mansour Alwjwaj
- Academic Unit of Mental Health and Clinical Neuroscience, School of Medicine, Nottingham, UK
| | - Rais Reskiawan A Kadir
- Academic Unit of Mental Health and Clinical Neuroscience, School of Medicine, Nottingham, UK
| | - Ulvi Bayraktutan
- Academic Unit of Mental Health and Clinical Neuroscience, School of Medicine, Nottingham, UK
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22
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Meyer J, Gerkau NJ, Kafitz KW, Patting M, Jolmes F, Henneberger C, Rose CR. Rapid Fluorescence Lifetime Imaging Reveals That TRPV4 Channels Promote Dysregulation of Neuronal Na + in Ischemia. J Neurosci 2022; 42:552-566. [PMID: 34872928 PMCID: PMC8805620 DOI: 10.1523/jneurosci.0819-21.2021] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 10/28/2021] [Accepted: 11/17/2021] [Indexed: 11/21/2022] Open
Abstract
Fluorescence imaging is an indispensable method for analysis of diverse cellular and molecular processes, enabling, for example, detection of ions, second messengers, or metabolites. Intensity-based approaches, however, are prone to artifacts introduced by changes in fluorophore concentrations. This drawback can be overcome by fluorescence lifetime imaging (FLIM) based on time-correlated single-photon counting. FLIM often necessitates long photon collection times, resulting in strong temporal binning of dynamic processes. Recently, rapidFLIM was introduced, exploiting ultra-low dead-time photodetectors together with rapid electronics. Here, we demonstrate the applicability of rapidFLIM, combined with new and improved correction schemes, for spatiotemporal fluorescence lifetime imaging of low-emission fluorophores in a biological system. Using tissue slices of hippocampi of mice of either sex, loaded with the Na+ indicator ING2, we show that improved rapidFLIM enables quantitative, dynamic imaging of neuronal Na+ signals at a full-frame temporal resolution of 0.5 Hz. Induction of transient chemical ischemia resulted in unexpectedly large Na+ influx, accompanied by considerable cell swelling. Both Na+ loading and cell swelling were dampened on inhibition of TRPV4 channels. Together, rapidFLIM enabled the spatiotemporal visualization and quantification of neuronal Na+ transients at unprecedented speed and independent from changes in cell volume. Moreover, our experiments identified TRPV4 channels as hitherto unappreciated contributors to neuronal Na+ loading on metabolic failure, suggesting this pathway as a possible target to ameliorate excitotoxic damage. Finally, rapidFLIM will allow faster and more sensitive detection of a wide range of dynamic signals with other FLIM probes, most notably those with intrinsic low-photon emission.SIGNIFICANCE STATEMENT FLIM is an indispensable method for analysis of cellular processes. FLIM often necessitates long photon collection periods, requiring the sacrifice of temporal resolution at the expense of spatial information. Here, we demonstrate the applicability of the recently introduced rapidFLIM for quantitative, dynamic imaging with low-emission fluorophores in brain slices. RapidFLIM, combined with improved correction schemes, enabled intensity-independent recording of neuronal Na+ transients at unprecedented full-frame rates of 0.5 Hz. It also allowed quantitative imaging independent from changes in cell volume, revealing a surprisingly strong and hitherto uncovered contribution of TRPV4 channels to Na+ loading on energy failure. Collectively, our study thus provides a novel, unexpected insight into the mechanisms that are responsible for Na+ changes on energy depletion.
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Affiliation(s)
- Jan Meyer
- Institute of Neurobiology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - Niklas J Gerkau
- Institute of Neurobiology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - Karl W Kafitz
- Institute of Neurobiology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | | | | | - Christian Henneberger
- Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, 53127 Bonn, Germany
- German Center for Neurodegenerative Diseases, 53175 Bonn, Germany
- UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, England
| | - Christine R Rose
- Institute of Neurobiology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
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23
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Zhang X, Huang P, Zhang R. Evaluation and Prediction of Post-stroke Cerebral Edema Based on Neuroimaging. Front Neurol 2022; 12:763018. [PMID: 35087464 PMCID: PMC8786707 DOI: 10.3389/fneur.2021.763018] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 12/06/2021] [Indexed: 11/13/2022] Open
Abstract
Cerebral edema is a common complication of acute ischemic stroke that leads to poorer functional outcomes and substantially increases the mortality rate. Given that its negative effects can be reduced by more intensive monitoring and evidence-based interventions, the early identification of patients with a high risk of severe edema is crucial. Neuroimaging is essential for the assessment and prediction of edema. Simple markers, such as midline shift and hypodensity volume on computed tomography, have been used to evaluate edema in clinical trials; however, advanced techniques can be applied to examine the underlying mechanisms. In this study, we aimed to review current imaging tools in the assessment and prediction of cerebral edema to provide guidance for using these methods in clinical practice.
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Affiliation(s)
| | | | - Ruiting Zhang
- Department of Radiology, School of Medicine, The Second Affiliated Hospital of Zhejiang University, Hangzhou, China
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Löscher W, Kaila K. CNS pharmacology of NKCC1 inhibitors. Neuropharmacology 2021; 205:108910. [PMID: 34883135 DOI: 10.1016/j.neuropharm.2021.108910] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 11/25/2021] [Accepted: 11/26/2021] [Indexed: 12/21/2022]
Abstract
The Na-K-2Cl cotransporter NKCC1 and the neuron-specific K-Cl cotransporter KCC2 are considered attractive CNS drug targets because altered neuronal chloride regulation and consequent effects on GABAergic signaling have been implicated in numerous CNS disorders. While KCC2 modulators are not yet clinically available, the loop diuretic bumetanide has been used off-label in attempts to treat brain disorders and as a tool for NKCC1 inhibition in preclinical models. Bumetanide is known to have anticonvulsant and neuroprotective effects under some pathophysiological conditions. However, as shown in several species from neonates to adults (mice, rats, dogs, and by extrapolation in humans), at the low clinical doses of bumetanide approved for diuresis, this drug has negligible access into the CNS, reaching levels that are much lower than what is needed to inhibit NKCC1 in cells within the brain parenchyma. Several drug discovery strategies have been initiated over the last ∼15 years to develop brain-permeant compounds that, ideally, should be selective for NKCC1 to eliminate the diuresis mediated by inhibition of renal NKCC2. The strategies employed to improve the pharmacokinetic and pharmacodynamic properties of NKCC1 blockers include evaluation of other clinically approved loop diuretics; development of lipophilic prodrugs of bumetanide; development of side-chain derivatives of bumetanide; and unbiased high-throughput screening approaches of drug discovery based on large chemical compound libraries. The main outcomes are that (1), non-acidic loop diuretics such as azosemide and torasemide may have advantages as NKCC1 inhibitors vs. bumetanide; (2), bumetanide prodrugs lead to significantly higher brain levels than the parent drug and have lower diuretic activity; (3), the novel bumetanide side-chain derivatives do not exhibit any functionally relevant improvement of CNS accessibility or NKCC1 selectivity vs. bumetanide; (4) novel compounds discovered by high-throughput screening may resolve some of the inherent problems of bumetanide, but as yet this has not been achieved. Thus, further research is needed to optimize the design of brain-permeant NKCC1 inhibitors. In parallel, a major challenge is to identify the mechanisms whereby various NKCC1-expressing cellular targets of these drugs within (e.g., neurons, oligodendrocytes or astrocytes) and outside the brain parenchyma (e.g., the blood-brain barrier, the choroid plexus, and the endocrine system), as well as molecular off-target effects, might contribute to their reported therapeutic and adverse effects.
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Affiliation(s)
- Wolfgang Löscher
- Dept. of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany; Center for Systems Neuroscience Hannover, Germany.
| | - Kai Kaila
- Molecular and Integrative Biosciences and Neuroscience Center (HiLIFE), University of Helsinki, Finland
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25
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Suzuki R, Sato M, Ogura M, Murofushi Y, Abe Y, Kamei K. Unilateral motor weakness with kidney failure: Answers. Pediatr Nephrol 2021; 36:4131-4134. [PMID: 34499255 DOI: 10.1007/s00467-021-05187-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 06/03/2021] [Indexed: 11/29/2022]
Affiliation(s)
- Ryutaro Suzuki
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan
| | - Mai Sato
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan
| | - Masao Ogura
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan
| | - Yuka Murofushi
- Division of Neurology, National Center for Child Health and Development, Tokyo, Japan
| | - Yuichi Abe
- Division of Neurology, National Center for Child Health and Development, Tokyo, Japan
| | - Koichi Kamei
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.
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26
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Palzur E, Edelman D, Sakas R, Soustiel JF. Etifoxine Restores Mitochondrial Oxidative Phosphorylation and Improves Cognitive Recovery Following Traumatic Brain Injury. Int J Mol Sci 2021; 22:12881. [PMID: 34884686 PMCID: PMC8657969 DOI: 10.3390/ijms222312881] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/22/2021] [Accepted: 11/23/2021] [Indexed: 12/05/2022] Open
Abstract
The opening of the mitochondrial permeability transition pore (mPTP) has emerged as a pivotal event following traumatic brain injury (TBI). Evidence showing the impact of the translocator protein (TSPO) over mPTP activity has prompted several studies exploring the effect of TSPO ligands, including etifoxine, on the outcome of traumatic brain injury (TBI). Mitochondrial respiration was assessed by respirometry in isolated rat brain mitochondria (RBM) by measurements of oxidative phosphorylation capacity (OXPHOS). The addition of calcium to RBM was used to induce mitochondrial injury and resulted in significant OXPHOS reduction that could be reversed by preincubation of RBM with etifoxine. Sensorimotor and cognitive functions were assessed following controlled cortical impact and compared in vehicle and etifoxine-treated animals. There was no difference between the vehicle and etifoxine groups for sensorimotor functions as assessed by rotarod. In contrast, etifoxine resulted in a significant improvement of cognitive functions expressed by faster recovery in Morris water maze testing. The present findings show a significant neuroprotective effect of etifoxine in TBI through restoration of oxidative phosphorylation capacity associated with improved behavioral and cognitive outcomes. Since etifoxine is a registered drug used in common clinical practice, implementation in a phase II study may represent a reasonable step forward.
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Affiliation(s)
- Eilam Palzur
- Eliachar Research Laboratory, Galilee Medical Center, Nahariya 2210001, Israel; (E.P.); (R.S.)
| | - Doron Edelman
- Galilee Medical Center, Department of Neurosurgery, Nahariya 2210001, Israel;
| | - Reem Sakas
- Eliachar Research Laboratory, Galilee Medical Center, Nahariya 2210001, Israel; (E.P.); (R.S.)
| | - Jean Francois Soustiel
- Eliachar Research Laboratory, Galilee Medical Center, Nahariya 2210001, Israel; (E.P.); (R.S.)
- Galilee Medical Center, Department of Neurosurgery, Nahariya 2210001, Israel;
- Azrieli Faculty of Medicine, University of Bar Ilan, Zafed 1311502, Israel
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27
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Molecular Mechanisms of Neuroimmune Crosstalk in the Pathogenesis of Stroke. Int J Mol Sci 2021; 22:ijms22179486. [PMID: 34502395 PMCID: PMC8431165 DOI: 10.3390/ijms22179486] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/26/2021] [Accepted: 08/28/2021] [Indexed: 12/21/2022] Open
Abstract
Stroke disrupts the homeostatic balance within the brain and is associated with a significant accumulation of necrotic cellular debris, fluid, and peripheral immune cells in the central nervous system (CNS). Additionally, cells, antigens, and other factors exit the brain into the periphery via damaged blood–brain barrier cells, glymphatic transport mechanisms, and lymphatic vessels, which dramatically influence the systemic immune response and lead to complex neuroimmune communication. As a result, the immunological response after stroke is a highly dynamic event that involves communication between multiple organ systems and cell types, with significant consequences on not only the initial stroke tissue injury but long-term recovery in the CNS. In this review, we discuss the complex immunological and physiological interactions that occur after stroke with a focus on how the peripheral immune system and CNS communicate to regulate post-stroke brain homeostasis. First, we discuss the post-stroke immune cascade across different contexts as well as homeostatic regulation within the brain. Then, we focus on the lymphatic vessels surrounding the brain and their ability to coordinate both immune response and fluid homeostasis within the brain after stroke. Finally, we discuss how therapeutic manipulation of peripheral systems may provide new mechanisms to treat stroke injury.
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28
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Zhou X, Li Y, Lenahan C, Ou Y, Wang M, He Y. Glymphatic System in the Central Nervous System, a Novel Therapeutic Direction Against Brain Edema After Stroke. Front Aging Neurosci 2021; 13:698036. [PMID: 34421575 PMCID: PMC8372556 DOI: 10.3389/fnagi.2021.698036] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 07/12/2021] [Indexed: 11/13/2022] Open
Abstract
Stroke is the destruction of brain function and structure, and is caused by either cerebrovascular obstruction or rupture. It is a disease associated with high mortality and disability worldwide. Brain edema after stroke is an important factor affecting neurologic function recovery. The glymphatic system is a recently discovered cerebrospinal fluid (CSF) transport system. Through the perivascular space and aquaporin 4 (AQP4) on astrocytes, it promotes the exchange of CSF and interstitial fluid (ISF), clears brain metabolic waste, and maintains the stability of the internal environment within the brain. Excessive accumulation of fluid in the brain tissue causes cerebral edema, but the glymphatic system plays an important role in the process of both intake and removal of fluid within the brain. The changes in the glymphatic system after stroke may be an important contributor to brain edema. Understanding and targeting the molecular mechanisms and the role of the glymphatic system in the formation and regression of brain edema after stroke could promote the exclusion of fluids in the brain tissue and promote the recovery of neurological function in stroke patients. In this review, we will discuss the physiology of the glymphatic system, as well as the related mechanisms and therapeutic targets involved in the formation of brain edema after stroke, which could provide a new direction for research against brain edema after stroke.
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Affiliation(s)
- Xiangyue Zhou
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Youwei Li
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cameron Lenahan
- Burrell College of Osteopathic Medicine, Las Cruces, NM, United States
| | - Yibo Ou
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Minghuan Wang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yue He
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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29
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Kim EH, Kim ES, Shin D, Kim D, Choi S, Shin YJ, Kim KA, Noh D, Caglayan AB, Rajanikant G, Majid A, Bae ON. Carnosine Protects against Cerebral Ischemic Injury by Inhibiting Matrix-Metalloproteinases. Int J Mol Sci 2021; 22:7495. [PMID: 34299128 PMCID: PMC8306548 DOI: 10.3390/ijms22147495] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/02/2021] [Accepted: 07/11/2021] [Indexed: 12/11/2022] Open
Abstract
Stroke is one of the leading causes of death and disability worldwide. However, treatment options for ischemic stroke remain limited. Matrix-metalloproteinases (MMPs) contribute to brain damage during ischemic strokes by disrupting the blood-brain barrier (BBB) and causing brain edemas. Carnosine, an endogenous dipeptide, was found by us and others to be protective against ischemic brain injury. In this study, we investigated whether carnosine influences MMP activity. Brain MMP levels and activity were measured by gelatin zymography after permanent occlusion of the middle cerebral artery (pMCAO) in rats and in vitro enzyme assays. Carnosine significantly reduced infarct volume and edema. Gelatin zymography and in vitro enzyme assays showed that carnosine inhibited brain MMPs. We showed that carnosine inhibited both MMP-2 and MMP-9 activity by chelating zinc. Carnosine also reduced the ischemia-mediated degradation of the tight junction proteins that comprise the BBB. In summary, our findings show that carnosine inhibits MMP activity by chelating zinc, an essential MMP co-factor, resulting in the reduction of edema and brain injury. We believe that our findings shed new light on the neuroprotective mechanism of carnosine against ischemic brain damage.
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Affiliation(s)
- Eun-Hye Kim
- College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea; (E.-H.K.); (E.-S.K.); (D.S.); (D.K.); (S.C.); (Y.-J.S.); (K.-A.K.); (D.N.)
| | - Eun-Sun Kim
- College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea; (E.-H.K.); (E.-S.K.); (D.S.); (D.K.); (S.C.); (Y.-J.S.); (K.-A.K.); (D.N.)
| | - Donggeun Shin
- College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea; (E.-H.K.); (E.-S.K.); (D.S.); (D.K.); (S.C.); (Y.-J.S.); (K.-A.K.); (D.N.)
| | - Donghyun Kim
- College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea; (E.-H.K.); (E.-S.K.); (D.S.); (D.K.); (S.C.); (Y.-J.S.); (K.-A.K.); (D.N.)
| | - Sungbin Choi
- College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea; (E.-H.K.); (E.-S.K.); (D.S.); (D.K.); (S.C.); (Y.-J.S.); (K.-A.K.); (D.N.)
| | - Young-Jun Shin
- College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea; (E.-H.K.); (E.-S.K.); (D.S.); (D.K.); (S.C.); (Y.-J.S.); (K.-A.K.); (D.N.)
| | - Kyeong-A Kim
- College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea; (E.-H.K.); (E.-S.K.); (D.S.); (D.K.); (S.C.); (Y.-J.S.); (K.-A.K.); (D.N.)
| | - Dabi Noh
- College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea; (E.-H.K.); (E.-S.K.); (D.S.); (D.K.); (S.C.); (Y.-J.S.); (K.-A.K.); (D.N.)
| | - Ahmet B. Caglayan
- Department of Physiology, Faculty of Medicine, Istanbul Medipol University, 34810 Istanbul, Turkey;
| | - G.K. Rajanikant
- School of Biotechnology, National Institute of Technology Calicut, Calicut 673601, India;
| | - Arshad Majid
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2TN, UK
| | - Ok-Nam Bae
- College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea; (E.-H.K.); (E.-S.K.); (D.S.); (D.K.); (S.C.); (Y.-J.S.); (K.-A.K.); (D.N.)
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30
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Cui Y, Hou Y, Zhang H, Liu Y, Mao K, Nie H, Ding Y. Regulation of Electrolyte Permeability by Herbal Monomers in Edematous Disorders. Curr Pharm Des 2021; 27:833-839. [PMID: 32940173 DOI: 10.2174/1381612826666200917144655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 08/10/2020] [Indexed: 11/22/2022]
Abstract
Edema is a gradual accumulation of fluid in the interstitial tissues or luminal cavities, which is regulated by ion transport pathways and reflects dysfunction of fluid and salt homeostasis. Increasing evidence suggests that some herbal monomers significantly reduce organ/tissue edema. In this review, we briefly summarized the electrolyte permeability involved in pathomechanisms of organ edema, and the benefits of herbal monomers on ionic transport machinery, including Na+-K+-ATPase, Na+ and Cl- channels, Na+-K+-2Cl- co-transporter, etc. Pharmaceutical relevance is implicated in developing advanced strategies to mitigate edematous disorders. In conclusion, the natural herbal monomers regulate electrolyte permeability in many edematous disorders, and further basic and clinical studies are needed.
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Affiliation(s)
- Yong Cui
- Department of Anesthesiology, the First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yapeng Hou
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Honglei Zhang
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Yanhong Liu
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Kejun Mao
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Hongguang Nie
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Yan Ding
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, China
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31
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Chen J, Wang L, Xu H, Wang Y, Liang Q. The lymphatic drainage system of the CNS plays a role in lymphatic drainage, immunity, and neuroinflammation in stroke. J Leukoc Biol 2021; 110:283-291. [PMID: 33884651 DOI: 10.1002/jlb.5mr0321-632r] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Revised: 03/19/2021] [Accepted: 03/26/2021] [Indexed: 12/31/2022] Open
Abstract
The lymphatic drainage system of the central nervous system (CNS) plays an important role in maintaining interstitial fluid balance and regulating immune responses and immune surveillance. The impaired lymphatic drainage system of the CNS might be involved in the onset and progression of various neurodegenerative diseases, neuroinflammation, and cerebrovascular diseases. A significant immune response and brain edema are observed after stroke, resulting from disrupted homeostasis in the brain. Thus, understanding the lymphatic drainage system of the CNS in stroke may lead to the development of new approaches for therapeutic interventions in the future. Here, we review recent evidence implicating the lymphatic drainage system of the CNS in stroke.
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Affiliation(s)
- Jinman Chen
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Key Laboratory of theory and therapy of muscles and bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), Shanghai, China
| | - Linmei Wang
- Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hao Xu
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Key Laboratory of theory and therapy of muscles and bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), Shanghai, China
| | - Yongjun Wang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Key Laboratory of theory and therapy of muscles and bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), Shanghai, China
| | - Qianqian Liang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Key Laboratory of theory and therapy of muscles and bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), Shanghai, China
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32
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Pergakis M, Badjatia N, Simard JM. An update on the pharmacological management and prevention of cerebral edema: current therapeutic strategies. Expert Opin Pharmacother 2021; 22:1025-1037. [PMID: 33467932 DOI: 10.1080/14656566.2021.1876663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Introduction: Cerebral edema is a common complication of multiple neurological diseases and is a strong predictor of outcome, especially in traumatic brain injury and large hemispheric infarction.Areas Covered: Traditional and current treatments of cerebral edema include treatment with osmotherapy or decompressive craniectomy at the time of clinical deterioration. The authors discuss preclinical and clinical models of a variety of neurological disease states that have identified receptors, ion transporters, and channels involved in the development of cerebral edema as well as modulation of these receptors with promising agents.Expert opinion: Further study is needed on the safety and efficacy of the agents discussed. IV glibenclamide has shown promise in preclinical and clinical trials of cerebral edema in large hemispheric infarct and traumatic brain injury. Consideration of underlying pathophysiology and pharmacodynamics is vital, as the synergistic use of agents has the potential to drastically mitigate cerebral edema and secondary brain injury thusly transforming our treatment paradigms.
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Affiliation(s)
- Melissa Pergakis
- Program in Trauma Department of Neurology University of Maryland School of Medicine,Baltimore MD USA
| | - Neeraj Badjatia
- Program in Trauma Department of Neurology University of Maryland School of Medicine,Baltimore MD USA
| | - J Marc Simard
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA
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33
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Josiah SS, Meor Azlan NF, Zhang J. Targeting the WNK-SPAK/OSR1 Pathway and Cation-Chloride Cotransporters for the Therapy of Stroke. Int J Mol Sci 2021; 22:1232. [PMID: 33513812 PMCID: PMC7865768 DOI: 10.3390/ijms22031232] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/22/2021] [Accepted: 01/24/2021] [Indexed: 02/05/2023] Open
Abstract
Stroke is one of the major culprits responsible for morbidity and mortality worldwide, and the currently available pharmacological strategies to combat this global disease are scanty. Cation-chloride cotransporters (CCCs) are expressed in several tissues (including neurons) and extensively contribute to the maintenance of numerous physiological functions including chloride homeostasis. Previous studies have implicated two CCCs, the Na+-K+-Cl- and K+-Cl- cotransporters (NKCCs and KCCs) in stroke episodes along with their upstream regulators, the with-no-lysine kinase (WNKs) family and STE20/SPS1-related proline/alanine rich kinase (SPAK) or oxidative stress response kinase (OSR1) via a signaling pathway. As the WNK-SPAK/OSR1 pathway reciprocally regulates NKCC and KCC, a growing body of evidence implicates over-activation and altered expression of NKCC1 in stroke pathology whilst stimulation of KCC3 during and even after a stroke event is neuroprotective. Both inhibition of NKCC1 and activation of KCC3 exert neuroprotection through reduction in intracellular chloride levels and thus could be a novel therapeutic strategy. Hence, this review summarizes the current understanding of functional regulations of the CCCs implicated in stroke with particular focus on NKCC1, KCC3, and WNK-SPAK/OSR1 signaling and discusses the current and potential pharmacological treatments for stroke.
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Affiliation(s)
| | | | - Jinwei Zhang
- Hatherly Laboratories, Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Exeter EX4 4PS, UK; (S.S.J.); (N.F.M.A.)
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34
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Hampel P, Römermann K, Gailus B, Johne M, Gericke B, Kaczmarek E, Löscher W. Effects of the NKCC1 inhibitors bumetanide, azosemide, and torasemide alone or in combination with phenobarbital on seizure threshold in epileptic and nonepileptic mice. Neuropharmacology 2021; 185:108449. [PMID: 33450274 DOI: 10.1016/j.neuropharm.2021.108449] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 12/07/2020] [Accepted: 12/22/2020] [Indexed: 12/31/2022]
Abstract
The sodium-potassium-chloride (Na-K-Cl) cotransporter NKCC1 is found in the plasma membrane of a wide variety of cell types, including neurons, glia and endothelial cells in the brain. Increased expression of neuronal NKCC1 has been implicated in several brain disorders, including neonatal seizures and epilepsy. The loop diuretic and NKCC inhibitor bumetanide has been evaluated as an antiseizure agent alone or together with approved antiseizure drugs such as phenobarbital (PB) in pre-clinical and clinical studies with varying results. The equivocal efficacy of bumetanide may be a result of its poor brain penetration. We recently reported that the loop diuretic azosemide is more potent to inhibit NKCC1 than bumetanide. In contrast to bumetanide, azosemide is not acidic, which should favor its brain penetration. Thus, azosemide may be a promising alternative to bumetanide for treatment of brain disorders such as epilepsy. In the present study, we determined the effect of azosemide and bumetanide on seizure threshold in adult epileptic mice. A structurally related non-acidic loop diuretic, torasemide, which also blocks NKCC1, was included in the experiments. The drug effects were assessed by determing the maximal electroshock seizure threshold (MEST) in epileptic vs. nonepileptic mice. Epilepsy was induced by pilocarpine, which was shown to produce long-lasting increases in NKCC1 in the hippocampus, whereas MEST did not alter NKCC1 mRNA in this region. None of the three loop diuretics increased MEST or the effect of PB on MEST in nonepileptic mice. In epileptic mice, all three diuretics significantly increased PB's seizure threshold increasing efficacy, but the effect was variable upon repeated MEST determinations and not correlated with the drugs' diuretic potency. These data may indicate that inhibition of NKCC1 by loop diuretics is not an effective means of increasing seizure threshold in adult epilepsy.
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Affiliation(s)
- Philip Hampel
- Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany.
| | - Kerstin Römermann
- Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany
| | - Björn Gailus
- Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany
| | - Marie Johne
- Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany
| | - Birthe Gericke
- Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany
| | - Edith Kaczmarek
- Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany
| | - Wolfgang Löscher
- Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany
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35
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Cellular and Molecular Mechanisms of R/S-Roscovitine and CDKs Related Inhibition under Both Focal and Global Cerebral Ischemia: A Focus on Neurovascular Unit and Immune Cells. Cells 2021; 10:cells10010104. [PMID: 33429982 PMCID: PMC7827530 DOI: 10.3390/cells10010104] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/29/2020] [Accepted: 01/05/2021] [Indexed: 12/29/2022] Open
Abstract
Ischemic stroke is the second leading cause of death worldwide. Following ischemic stroke, Neurovascular Unit (NVU) inflammation and peripheral leucocytes infiltration are major contributors to the extension of brain lesions. For a long time restricted to neurons, the 10 past years have shown the emergence of an increasing number of studies focusing on the role of Cyclin-Dependent Kinases (CDKs) on the other cells of NVU, as well as on the leucocytes. The most widely used CDKs inhibitor, (R)-roscovitine, and its (S) isomer both decreased brain lesions in models of global and focal cerebral ischemia. We previously showed that (S)-roscovitine acted, at least, by modulating NVU response to ischemia. Interestingly, roscovitine was shown to decrease leucocytes-mediated inflammation in several inflammatory models. Specific inhibition of roscovitine majors target CDK 1, 2, 5, 7, and 9 showed that these CDKs played key roles in inflammatory processes of NVU cells and leucocytes after brain lesions, including ischemic stroke. The data summarized here support the investigation of roscovitine as a potential therapeutic agent for the treatment of ischemic stroke, and provide an overview of CDK 1, 2, 5, 7, and 9 functions in brain cells and leucocytes during cerebral ischemia.
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Garneau AP, Slimani S, Fiola MJ, Tremblay LE, Isenring P. Multiple Facets and Roles of Na+-K+-Cl−Cotransport: Mechanisms and Therapeutic Implications. Physiology (Bethesda) 2020; 35:415-429. [DOI: 10.1152/physiol.00012.2020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
The Na+-K+-Cl−cotransporters play key physiological and pathophysiological roles by regulating the membrane potential of many cell types and the movement of fluid across a variety of epithelial or endothelial structures. As such, they should soon become invaluable targets for the treatment of various disorders including pain, epilepsy, brain edema, and hypertension. This review highlights the nature of these roles, the mechanisms at play, and the unresolved issues in the field.
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Affiliation(s)
- A. P. Garneau
- Department of Medicine, Nephrology Research Group, Laval University, Québec, Canada; and
- Cardiometabolic Axis, School of Kinesiology and Physical Activity Sciences, University of Montréal, Montréal, Canada
| | - S. Slimani
- Department of Medicine, Nephrology Research Group, Laval University, Québec, Canada; and
| | - M. J. Fiola
- Department of Medicine, Nephrology Research Group, Laval University, Québec, Canada; and
| | - L. E. Tremblay
- Department of Medicine, Nephrology Research Group, Laval University, Québec, Canada; and
| | - P. Isenring
- Department of Medicine, Nephrology Research Group, Laval University, Québec, Canada; and
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Rathore P, Arora I, Rastogi S, Akhtar M, Singh S, Samim M. Collagen Nanoparticle-Mediated Brain Silymarin Delivery: An Approach for Treating Cerebral Ischemia and Reperfusion-Induced Brain Injury. Front Neurosci 2020; 14:538404. [PMID: 33192240 PMCID: PMC7649428 DOI: 10.3389/fnins.2020.538404] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 08/25/2020] [Indexed: 12/12/2022] Open
Abstract
Silymarin is a bioactive constituent isolated from milk thistle (Silybum marinum). Since its discovery, silymarin has been considered a gold standard drug in treating ailments related to the liver, resulting from alcohol consumption and viral hepatitis. This hepatoprotective nature of silymarin arises out of antioxidative and tissue-regenerating properties of silymarin. However, several recent studies have established the neuroprotective link of silymarin, too. Thus, the current investigation was aimed at exploring the neuroprotective effect of nanosilymarin (silymarin encapsulated inside collagen-based polymeric nanoparticulate drug delivery system). The study aimed at bringing out the role of nanoparticles in enhancing the therapeutic effect of silymarin against neuronal injury, originating out of oxidative-stress-related brain damages in focal cerebral ischemia. Collagen-based micellar nanoparticles were prepared and stabilized using 3-ethyl carbodiimide-hydrochloride (EDC-Hcl) and malondialdehyde (MDA) as crosslinkers. Nanoparticles were characterized using dynamic light scattering (DLS), transmission electron microscopy (TEM), and Fourier transform infrared (FT-IR) spectroscopy techniques, and the size of nanoparticles was found to be around 48 nm. Male albino Wistar rats were pretreated with three different doses of nanosilymarin of 10, 100, and 1,000 μg/kg b.wt and a dose of free silymarin of 100 mg/kg b.wt intraperitoneally (i.p.) for 7 days. Focal cerebral ischemia was induced using the middle cerebral artery occlusion (MCAO) model on the eighth day for 1 h followed by 24 h reperfusion. The animals were then evaluated for neurobehavioral, infarct analysis, biochemical, histopathological, and immunohistochemical studies. All the above parameters showed remarkable improvement in nanosilymarin-treated groups in comparison to the silymarin-treated group. Nanoparticle encapsulation of drug enhanced neuroprotection by increasing drug bioavailability and targeting. Thus, the present study concluded with satisfactory results, showing the critical role played by nanoparticles in improving the neuroprotection at very low drug doses.
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Affiliation(s)
- Pankaj Rathore
- Department of Chemistry, School of Chemical & Life Sciences, Jamia Hamdard, New Delhi, India
| | - Indu Arora
- Department of Biomedical Sciences, Shaheed Rajguru College, University of Delhi, New Delhi, India
| | - Shweta Rastogi
- Department of Chemistry, Hansraj College, University of Delhi, New Delhi, India
| | - Mohd Akhtar
- Department of Pharmacology, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, India
| | - Shruti Singh
- Department of Botany, School of Chemical & Life Sciences, Jamia Hamdard, New Delhi, India
| | - Mohammed Samim
- Department of Chemistry, School of Chemical & Life Sciences, Jamia Hamdard, New Delhi, India
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Kwon JI, Heo H, Ham SJ, Chae YJ, Lee DW, Kim ST, Min J, Sung YS, Kim KW, Choi Y, Woo DC, Woo CW. Aryl hydrocarbon receptor antagonism before reperfusion attenuates cerebral ischaemia/reperfusion injury in rats. Sci Rep 2020; 10:14906. [PMID: 32913241 PMCID: PMC7483549 DOI: 10.1038/s41598-020-72023-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 08/24/2020] [Indexed: 12/15/2022] Open
Abstract
Aryl hydrocarbon receptor (AhR) antagonism can mitigate cellular damage associated with cerebral ischaemia and reperfusion (I/R) injury. This study investigated the neuroprotective effects of AhR antagonist administration before reperfusion in a rat stroke model and influence of the timing of AhR antagonist administration on its neuroprotective effects. Magnetic resonance imaging (MRI) was performed at baseline, immediately after, and 3, 8, and 24 h after ischaemia in the sham, control (I/R injury), TMF10 (trimethoxyflavone [TMF] administered 10 min post-ischaemia), and TMF50 (TMF administered 50 min post-ischaemia) groups. The TMF treatment groups had significantly fewer infarcts than the control group. At 24 h, the relative apparent diffusion coefficient values of the ischaemic core and peri-infarct region were significantly higher and relative T2 values were significantly lower in the TMF10 groups than in the control group. The TMF treatment groups showed significantly fewer terminal deoxynucleotidyl transferase dUTP nick-end labelling positive (+) cells (%) in the peri-infarct region than the control group. This study demonstrated that TMF treatment 10 or 50 min after ischaemia alleviated brain damage. Furthermore, the timing of AhR antagonist administration affected the inhibition of cellular or vasogenic oedema formation caused by a transient ischaemic stroke.
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Affiliation(s)
- Jae-Im Kwon
- Asan Institute for Life Sciences, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Hwon Heo
- Asan Institute for Life Sciences, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Su Jeong Ham
- Asan Institute for Life Sciences, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Yeon Ji Chae
- Asan Institute for Life Sciences, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Do-Wan Lee
- Asan Institute for Life Sciences, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Sang Tae Kim
- Convergence Medicine Research Center, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Joongkee Min
- Asan Institute for Life Sciences, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Yu Sub Sung
- Clinical Research Center, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Kyung Won Kim
- Department of Radiology, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Yoonseok Choi
- Medical Research Institute, Gangneung Asan Hospital, 38, Bangdong-gil, Sacheon-myeon, Gangneung-si, Gangwon-do, Republic of Korea
| | - Dong Cheol Woo
- Convergence Medicine Research Center, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.
| | - Chul-Woong Woo
- Convergence Medicine Research Center, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.
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Akita T, Fukuda A. Intracellular Cl - dysregulation causing and caused by pathogenic neuronal activity. Pflugers Arch 2020; 472:977-987. [PMID: 32300887 DOI: 10.1007/s00424-020-02375-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 03/23/2020] [Accepted: 03/27/2020] [Indexed: 02/06/2023]
Abstract
The intracellular Cl- concentration ([Cl-]i) is tightly regulated in brain neurons for stabilizing brain performance. The [Cl-]i in mature neurons is determined by the balance between the rate of Cl- extrusion mainly mediated by the neuron-specific type 2 K+-Cl- cotransporter (KCC2) and the rate of Cl- entry through various Cl- channels including GABAA receptors during neuronal activity. Disturbance of the balance causes instability of brain circuit performance and may lead to epileptic seizures. In the first part of this review, we discuss how genetic alterations in KCC2 in humans cause infantile migrating focal seizures, based on our previous report and others. Depolarization of the membrane potential increases the driving force for Cl- entry into neurons. Thus, the duration of action potential spike generation and the frequency of excitatory synaptic inputs are the crucial factors for determining the total amount of Cl- entry and the equilibrium [Cl-]i in neurons. Moreover, there is also a significant interdependence between the neuronal activity and the KCC2 expression. In the second part, we discuss plausible mechanisms by which excessive neuronal activity due to excitotoxic brain insults or other epilepsy-associated gene mutations may cause the Cl- imbalance in neurons and lead to epileptic discharges over the brain, using the schematic "unifying foci" model based on literature.
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Affiliation(s)
- Tenpei Akita
- Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan.
| | - Atsuo Fukuda
- Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan
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Wang QS, Ding HG, Chen SL, Liu XQ, Deng YY, Jiang WQ, Li Y, Huang LQ, Han YL, Wen MY, Wang MQ, Zeng HK. Hypertonic saline mediates the NLRP3/IL-1β signaling axis in microglia to alleviate ischemic blood-brain barrier permeability by downregulating astrocyte-derived VEGF in rats. CNS Neurosci Ther 2020; 26:1045-1057. [PMID: 32529750 PMCID: PMC7539845 DOI: 10.1111/cns.13427] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 05/18/2020] [Accepted: 05/21/2020] [Indexed: 02/06/2023] Open
Abstract
Introduction The aim of this study was to explore whether the antibrain edema of hypertonic saline (HS) is associated with alleviating ischemic blood‐brain barrier (BBB) permeability by downregulating astrocyte‐derived vascular endothelial growth factor (VEGF), which is mediated by microglia‐derived NOD‐like receptor protein 3 (NLRP3) inflammasome. Methods The infarct volume and BBB permeability were detected. The protein expression level of VEGF in astrocytes in a transient focal brain ischemia model of rats was evaluated after 10% HS treatment. Changes in the NLRP3 inflammasome, IL‐1β protein expression, and the interleukin‐1 receptor (IL1R1)/pNF‐кBp65/VEGF signaling pathway were determined in astrocytes. Results HS alleviated the BBB permeability, reduced the infarct volume, and downregulated the expression of VEGF in astrocytes. HS downregulates IL‐1β expression by inhibiting the activation of the NLRP3 inflammasome in microglia and then downregulates VEGF expression by inhibiting the phosphorylation of NF‐кBp65 mediated by IL‐1β in astrocytes. Conclusions HS alleviated the BBB permeability, reduced the infarct volume, and downregulated the expression of VEGF in astrocytes. HS downregulated IL‐1β expression via inhibiting the activation of the NLRP3 inflammasome in microglia and then downregulated VEGF expression through inhibiting the phosphorylation of NF‐кBp65 mediated by IL‐1β in astrocytes.
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Affiliation(s)
- Qiao-Sheng Wang
- Department of Critical Care Medicine, The First Affiliated Hospital, University of South China, Hengyang, China.,Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Hong-Guang Ding
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Sheng-Long Chen
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xin-Qiang Liu
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yi-Yu Deng
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Wen-Qiang Jiang
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Ya Li
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,School of Medicine, South China University of Technology, Guangzhou, China
| | - Lin-Qiang Huang
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yong-Li Han
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Miao-Yun Wen
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Mei-Qiu Wang
- Department of Critical Care Medicine, The First Affiliated Hospital, University of South China, Hengyang, China
| | - Hong-Ke Zeng
- Department of Critical Care Medicine, The First Affiliated Hospital, University of South China, Hengyang, China.,Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
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Chen L, Ding Y, Hou Y, Liu Y, Nie H. Regulation of Cl- Electrolyte Permeability in Epithelia by Active Traditional Chinese Medicine Monomers for Diarrhea. Curr Drug Targets 2020; 21:902-909. [PMID: 32364074 DOI: 10.2174/1389450121666200504073635] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 02/25/2020] [Accepted: 02/28/2020] [Indexed: 11/22/2022]
Abstract
The epithelial layer, lining the inner surface of the mammalian alveolar, kidney, brain and colon, is a typical electrolyte transporting tissue. Large quantities of salt and fluid are actively moved from the mucosal side toward the blood vessel. Transepithelial salt re-absorption in epithelial tissues plays an important role in maintaining fluid homeostasis. In absorptive epithelium, fluid and salt flux is controlled by the machinery mainly composed of epithelial sodium channel, cystic fibrosis transmembrane conductance regulator, Na+-K+-2Cl- cotransporter, Na+/H+ exchanger, and Na+/K+-ATPase. Dysregulation of salt permeability across epithelium contributes to the pathogenesis of organ edema. In numerous ion transporters, epithelial Cl- transportation plays an important role in water secretion across epithelial tissues and regulation of body fluid content. Many traditional Chinese medicines treat diarrhea by regulating the Cl- electrolyte transport. We systematically summarized the recent progress regarding the traditional Chinese medicine on Cl- electrolyte transport in the intestinal epithelial tissues. The pharmaceutical relevance of developing advanced strategies to mitigate edematous disorders is also implicated. In conclusion, the crosstalk between Cl- electrolyte transport and active traditional Chinese medicine monomers may lead to the development of new strategies for diarrhea by manipulating the function and expression of ion channels.
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Affiliation(s)
- Lei Chen
- China Medical University, Shenyang, China
| | - Yan Ding
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Yapeng Hou
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Yanhong Liu
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Hongguang Nie
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, China
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Taherian M, Norenberg MD, Panickar KS, Shamaladevi N, Ahmad A, Rahman P, Jayakumar AR. Additive Effect of Resveratrol on Astrocyte Swelling Post-exposure to Ammonia, Ischemia and Trauma In Vitro. Neurochem Res 2020; 45:1156-1167. [PMID: 32166573 DOI: 10.1007/s11064-020-02997-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 12/12/2019] [Accepted: 02/22/2020] [Indexed: 12/16/2022]
Abstract
Swelling of astrocytes represents a major component of the brain edema associated with many neurological conditions, including acute hepatic encephalopathy (AHE), traumatic brain injury (TBI) and ischemia. It has previously been reported that exposure of cultured astrocytes to ammonia (a factor strongly implicated in the pathogenesis of AHE), oxygen/glucose deprivation, or to direct mechanical trauma results in an increase in cell swelling. Since dietary polyphenols have been shown to exert a protective effect against cell injury, we examined whether resveratrol (RSV, 3,5,4'-trihydroxy-trans-stilbene, a stilbenoid phenol), has a protective effect on astrocyte swelling following its exposure to ammonia, oxygen-glucose deprivation (OGD), or trauma in vitro. Ammonia increased astrocyte swelling, and pre- or post-treatment of astrocytes with 10 and 25 µM RSV displayed an additive effect, while 5 µM did not prevent the effect of ammonia. However, pre-treatment of astrocytes with 25 µM RSV slightly, but significantly, reduced the trauma-induced astrocyte swelling at earlier time points (3 h), while post-treatment had no significant effect on the trauma-induced cell swelling at the 3 h time point. Instead, pre- or post-treatment of astrocytes with 25 µM RSV had an additive effect on trauma-induced astrocyte swelling. Further, pre- or post-treatment of astrocytes with 5 or 10 µM RSV had no significant effect on trauma-induced astrocyte swelling. When 5 or 10 µM RSV were added prior to, or during the process of OGD, as well as post-OGD, it caused a slight, but not statistically significant decline in cell swelling. However, when 25 µM RSV was added during the process of OGD, as well as after the cells were returned to normal condition (90 min period), such treatment showed an additive effect on the OGD-induced astrocyte swelling. Noteworthy, a higher concentration of RSV (25 µM) exhibited an additive effect on levels of phosphorylated forms of ERK1/2, and p38MAPK, as well as an increased activity of the Na+-K+-Cl- co-transporter-1 (NKCC1), factors known to induce astrocytes swelling, when the cells were treated with ammonia or after trauma or ischemia. Further, inhibition of ERK1/2, and p38MAPK diminished the RSV-induced exacerbation of cell swelling post-ammonia, trauma and OGD treatment. These findings strongly suggest that treatment of cultured astrocytes with RSV enhanced the ammonia, ischemia and trauma-induced cell swelling, likely through the exacerbation of intercellular signaling kinases and ion transporters. Accordingly, caution should be exercised when using RSV for the treatment of these neurological conditions, especially when brain edema is also suspected.
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Affiliation(s)
- Mehran Taherian
- General Medical Research, Neuropathology Section, R&D Service, Veterans Affairs Medical Center, Miami, FL, 33125, USA
| | - Michael D Norenberg
- Department of Pathology, University of Miami School of Medicine, Miami, FL, USA
- Department of Biochemistry & Molecular Biology, University of Miami School of Medicine, Miami, FL, USA
- Department of Neurology and Neurological Surgery, University of Miami School of Medicine, Miami, FL, USA
| | - Kiran S Panickar
- General Medical Research, Neuropathology Section, R&D Service, Veterans Affairs Medical Center, Miami, FL, 33125, USA
| | | | - Anis Ahmad
- Department of Radiation Oncology, Sylvester Cancer Center, University of Miami School of Medicine, Miami, FL, USA
| | - Purbasha Rahman
- General Medical Research, Neuropathology Section, R&D Service, Veterans Affairs Medical Center, Miami, FL, 33125, USA
- Department of Microbiology and Immunology, University of Miami, Coral Cables, Miami, FL, USA
| | - Arumugam R Jayakumar
- General Medical Research, Neuropathology Section, R&D Service, Veterans Affairs Medical Center, Miami, FL, 33125, USA.
- South Florida VA Foundation for Research and Education Inc, Veterans Affairs Medical Center, Miami, FL, 33125, USA.
- General Medical Research, Neuropathology Section, R&D Service, Veterans Affairs Medical Center, 1201 NW 16th St, Res-151, Room 314, Miami, FL, USA.
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Galdamez LA, Brunstetter TJ, Lee AG, Tarver WJ. Origins of Cerebral Edema: Implications for Spaceflight-Associated Neuro-Ocular Syndrome. J Neuroophthalmol 2020; 40:84-91. [DOI: 10.1097/wno.0000000000000852] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Zhang J, Bhuiyan MIH, Zhang T, Karimy JK, Wu Z, Fiesler VM, Zhang J, Huang H, Hasan MN, Skrzypiec AE, Mucha M, Duran D, Huang W, Pawlak R, Foley LM, Hitchens TK, Minnigh MB, Poloyac SM, Alper SL, Molyneaux BJ, Trevelyan AJ, Kahle KT, Sun D, Deng X. Modulation of brain cation-Cl - cotransport via the SPAK kinase inhibitor ZT-1a. Nat Commun 2020; 11:78. [PMID: 31911626 PMCID: PMC6946680 DOI: 10.1038/s41467-019-13851-6] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 11/27/2019] [Indexed: 02/08/2023] Open
Abstract
The SLC12A cation-Cl- cotransporters (CCC), including NKCC1 and the KCCs, are important determinants of brain ionic homeostasis. SPAK kinase (STK39) is the CCC master regulator, which stimulates NKCC1 ionic influx and inhibits KCC-mediated efflux via phosphorylation at conserved, shared motifs. Upregulation of SPAK-dependent CCC phosphorylation has been implicated in several neurological diseases. Using a scaffold-hybrid strategy, we develop a novel potent and selective SPAK inhibitor, 5-chloro-N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxybenzamide ("ZT-1a"). ZT-1a inhibits NKCC1 and stimulates KCCs by decreasing their SPAK-dependent phosphorylation. Intracerebroventricular delivery of ZT-1a decreases inflammation-induced CCC phosphorylation in the choroid plexus and reduces cerebrospinal fluid (CSF) hypersecretion in a model of post-hemorrhagic hydrocephalus. Systemically administered ZT-1a reduces ischemia-induced CCC phosphorylation, attenuates cerebral edema, protects against brain damage, and improves outcomes in a model of stroke. These results suggest ZT-1a or related compounds may be effective CCC modulators with therapeutic potential for brain disorders associated with impaired ionic homeostasis.
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Affiliation(s)
- Jinwei Zhang
- Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Hatherly Laboratories, Exeter, EX4 4PS, UK.
- Xiamen Cardiovascular Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, 361004, China.
| | - Mohammad Iqbal H Bhuiyan
- Department of Neurology and Pittsburgh Institute For Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Ting Zhang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
| | - Jason K Karimy
- Departments of Neurosurgery, Pediatrics, and Cellular & Molecular Physiology; Interdepartmental Neuroscience Program; and Centers for Mendelian Genomics, Yale School of Medicine, New Haven, CT, 06511, USA
| | - Zhijuan Wu
- Newcastle University Business School, Newcastle University, Newcastle upon Tyne, NE1 4SE, UK
| | - Victoria M Fiesler
- Department of Neurology and Pittsburgh Institute For Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Jingfang Zhang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
| | - Huachen Huang
- Department of Neurology and Pittsburgh Institute For Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Md Nabiul Hasan
- Department of Neurology and Pittsburgh Institute For Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Anna E Skrzypiec
- Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Hatherly Laboratories, Exeter, EX4 4PS, UK
| | - Mariusz Mucha
- Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Hatherly Laboratories, Exeter, EX4 4PS, UK
| | - Daniel Duran
- Departments of Neurosurgery, Pediatrics, and Cellular & Molecular Physiology; Interdepartmental Neuroscience Program; and Centers for Mendelian Genomics, Yale School of Medicine, New Haven, CT, 06511, USA
| | - Wei Huang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
| | - Robert Pawlak
- Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Hatherly Laboratories, Exeter, EX4 4PS, UK
| | - Lesley M Foley
- Animal Imaging Center, University of Pittsburgh, Pittsburgh, PA, 15203, USA
| | - T Kevin Hitchens
- Animal Imaging Center, University of Pittsburgh, Pittsburgh, PA, 15203, USA
- Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Margaret B Minnigh
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Samuel M Poloyac
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Seth L Alper
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA
| | - Bradley J Molyneaux
- Department of Neurology and Pittsburgh Institute For Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, 15213, USA
- Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Andrew J Trevelyan
- Institute of Neuroscience, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK
| | - Kristopher T Kahle
- Departments of Neurosurgery, Pediatrics, and Cellular & Molecular Physiology; Interdepartmental Neuroscience Program; and Centers for Mendelian Genomics, Yale School of Medicine, New Haven, CT, 06511, USA.
| | - Dandan Sun
- Department of Neurology and Pittsburgh Institute For Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
- Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, PA, 15213, USA.
| | - Xianming Deng
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China.
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45
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Auer T, Schreppel P, Erker T, Schwarzer C. Impaired chloride homeostasis in epilepsy: Molecular basis, impact on treatment, and current treatment approaches. Pharmacol Ther 2020; 205:107422. [DOI: 10.1016/j.pharmthera.2019.107422] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 10/07/2019] [Indexed: 12/14/2022]
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46
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Bing Y, Garcia-Gonzalez D, Voets N, Jérusalem A. Medical imaging based in silico head model for ischaemic stroke simulation. J Mech Behav Biomed Mater 2020; 101:103442. [DOI: 10.1016/j.jmbbm.2019.103442] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 09/03/2019] [Accepted: 09/18/2019] [Indexed: 12/15/2022]
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47
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Deng G, Ma C, Zhao H, Zhang S, Liu J, Liu F, Chen Z, Chen AT, Yang X, Avery J, Zou P, Du F, Lim KP, Holden D, Li S, Carson RE, Huang Y, Chen Q, Kimberly WT, Simard JM, Sheth KN, Zhou J. Anti-edema and antioxidant combination therapy for ischemic stroke via glyburide-loaded betulinic acid nanoparticles. Theranostics 2019; 9:6991-7002. [PMID: 31660082 PMCID: PMC6815966 DOI: 10.7150/thno.35791] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 07/30/2019] [Indexed: 12/19/2022] Open
Abstract
Stroke is a deadly disease without effective pharmacotherapies, which is due to two major reasons. First, most therapeutics cannot efficiently penetrate the brain. Second, single agent pharmacotherapy may be insufficient and effective treatment of stroke requires targeting multiple complementary targets. Here, we set to develop single component, multifunctional nanoparticles (NPs) for targeted delivery of glyburide to the brain for stroke treatment. Methods: To characterize the brain penetrability, we radiolabeled glyburide, intravenously administered it to stroke- bearing mice, and determined its accumulation in the brain using positron emission tomography-computed tomography (PET/CT). To identify functional nanomaterials to improve drug delivery to the brain, we developed a chemical extraction approach and tested it for isolation of nanomaterials from E. ulmoides, a medicinal herb. To assess the therapeutic benefits, we synthesized glyburide-loaded NPs and evaluated them in stroke- bearing mice. Results: We found that glyburide has a limited ability to penetrate the ischemic brain. We identified betulinic acid (BA) capable of forming NPs, which, after intravenous administration, efficiently penetrate the brain and significantly reduce ischemia-induced infarction as an antioxidant agent. We demonstrated that BA NPs enhance delivery of glyburide, leading to therapeutic benefits significantly greater than those achieved by either glyburide or BA NPs. Conclusion: This study suggests a new direction to identify functional nanomaterials and a simple approach to achieving anti-edema and antioxidant combination therapy. The resulting glyburide- loaded BA NPs may be translated into clinical applications to improve clinical management of stroke.
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Affiliation(s)
- Gang Deng
- Department of Neurosurgery, Yale University, New Haven, CT, 06510, USA
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Chao Ma
- Department of Neurosurgery, Yale University, New Haven, CT, 06510, USA
- College of Biological Sciences and Biotechnology, Beijing Forestry University, Beijing 100083, China
| | - Haitian Zhao
- Department of Neurosurgery, Yale University, New Haven, CT, 06510, USA
- School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin 150090, China
| | - Shenqi Zhang
- Department of Neurosurgery, Yale University, New Haven, CT, 06510, USA
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Jun Liu
- Department of Neurosurgery, Yale University, New Haven, CT, 06510, USA
| | - Fuyao Liu
- Department of Neurosurgery, Yale University, New Haven, CT, 06510, USA
| | - Zeming Chen
- Department of Neurosurgery, Yale University, New Haven, CT, 06510, USA
| | - Ann T. Chen
- Department of Biomedical Engineering, Yale University, New Haven, CT, 06510, USA
| | - Xin Yang
- Department of Neurosurgery, Yale University, New Haven, CT, 06510, USA
- School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin 150090, China
| | - Jonathan Avery
- Department of Neurosurgery, Yale University, New Haven, CT, 06510, USA
| | - Pan Zou
- Department of Neurosurgery, Yale University, New Haven, CT, 06510, USA
| | - Fengyi Du
- Department of Neurosurgery, Yale University, New Haven, CT, 06510, USA
| | - Keun-poong Lim
- PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, 06510, USA
| | - Daniel Holden
- PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, 06510, USA
| | - Songye Li
- PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, 06510, USA
| | - Richard E. Carson
- Department of Biomedical Engineering, Yale University, New Haven, CT, 06510, USA
- PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, 06510, USA
| | - Yiyun Huang
- Department of Biomedical Engineering, Yale University, New Haven, CT, 06510, USA
| | - Qianxue Chen
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - W. Taylor Kimberly
- Department of Neurology, Division of Neurocritical Care, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - J. Marc Simard
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Kevin N. Sheth
- Department of Neurology, Yale University, New Haven, CT, 06510, USA
| | - Jiangbing Zhou
- Department of Neurosurgery, Yale University, New Haven, CT, 06510, USA
- Department of Biomedical Engineering, Yale University, New Haven, CT, 06510, USA
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48
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Song S, Luo L, Sun B, Sun D. Roles of glial ion transporters in brain diseases. Glia 2019; 68:472-494. [PMID: 31418931 DOI: 10.1002/glia.23699] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 07/22/2019] [Accepted: 07/26/2019] [Indexed: 12/21/2022]
Abstract
Glial ion transporters are important in regulation of ionic homeostasis, cell volume, and cellular signal transduction under physiological conditions of the central nervous system (CNS). In response to acute or chronic brain injuries, these ion transporters can be activated and differentially regulate glial functions, which has subsequent impact on brain injury or tissue repair and functional recovery. In this review, we summarized the current knowledge about major glial ion transporters, including Na+ /H+ exchangers (NHE), Na+ /Ca2+ exchangers (NCX), Na+ -K+ -Cl- cotransporters (NKCC), and Na+ -HCO3 - cotransporters (NBC). In acute neurological diseases, such as ischemic stroke and traumatic brain injury (TBI), these ion transporters are rapidly activated and play significant roles in regulation of the intra- and extracellular pH, Na+ , K+ , and Ca2+ homeostasis, synaptic plasticity, and myelin formation. However, overstimulation of these ion transporters can contribute to glial apoptosis, demyelination, inflammation, and excitotoxicity. In chronic brain diseases, such as glioma, Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), glial ion transporters are involved in the glioma Warburg effect, glial activation, neuroinflammation, and neuronal damages. These findings suggest that glial ion transporters are involved in tissue structural and functional restoration, or brain injury and neurological disease development and progression. A better understanding of these ion transporters in acute and chronic neurological diseases will provide insights for their potential as therapeutic targets.
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Affiliation(s)
- Shanshan Song
- Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania.,Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Lanxin Luo
- Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania.,Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, Pennsylvania.,School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China.,School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, China
| | - Baoshan Sun
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, China.,Pólo Dois Portos, Instituto National de Investigação Agrária e Veterinária, Dois Portos, Portugal
| | - Dandan Sun
- Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania.,Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, Pennsylvania.,Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, Pennsylvania
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49
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Mamtilahun M, Tang G, Zhang Z, Wang Y, Tang Y, Yang GY. Targeting Water in the Brain: Role of Aquaporin-4 in Ischemic Brain Edema. Curr Drug Targets 2019; 20:748-755. [DOI: 10.2174/1389450120666190214115309] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 01/20/2019] [Accepted: 01/22/2019] [Indexed: 01/21/2023]
Abstract
Brain edema primarily occurs as a consequence of various cerebral injuries including
ischemic stroke. Excessive accumulation of brain water content causes a gradual expansion of brain
parenchyma, decreased blood flow and increased intracranial pressure and, ultimately, cerebral herniation
and death. Current clinical treatment for ischemic edema is very limited, therefore, it is urgent to
develop novel treatment strategies. Mounting evidence has demonstrated that AQP4, a water channel
protein, is closely correlated with brain edema and could be an optimal therapeutic target for the reduction
of ischemic brain edema. AQP4 is prevalently distributed in the central nervous system, and
mainly regulates water flux in brain cells under normal and pathological conditions. This review focuses
on the underlying mechanisms of AQP4 related to its dual role in edema formation and elimination.
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Affiliation(s)
- Muyassar Mamtilahun
- Neuroscience and Neuroengineering Research Center, Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Guanghui Tang
- Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland
| | - Zhijun Zhang
- Neuroscience and Neuroengineering Research Center, Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Yongting Wang
- Neuroscience and Neuroengineering Research Center, Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Yaohui Tang
- Neuroscience and Neuroengineering Research Center, Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Guo-Yuan Yang
- Neuroscience and Neuroengineering Research Center, Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China
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50
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Yang D, Ma L, Wang P, Yang D, Zhang Y, Zhao X, Lv J, Zhang J, Zhang Z, Gao F. Normobaric oxygen inhibits AQP4 and NHE1 expression in experimental focal ischemic stroke. Int J Mol Med 2018; 43:1193-1202. [PMID: 30592266 PMCID: PMC6365048 DOI: 10.3892/ijmm.2018.4037] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2018] [Accepted: 12/07/2018] [Indexed: 12/16/2022] Open
Abstract
The aim of the present study was to determine the effect of 60% normobaric oxygen (NBO) on neurological function, brain edema and the expression of hypoxia-inducible factor-1α (HIF-1α), aquaporin 4 (AQP4) and Na+/H+ exchanger 1 (NHE1) in a rat model of cerebral ischemia-reperfusion injury. Male Sprague-Dawley rats underwent transient focal cerebral ischemia via right middle cerebral artery occlusion (MCAO) for 120 min followed by 48 h of reperfusion. The rats were exposed to NBO at 60 and 100% or no treatment during reperfusion for 48 h. Neurological impairment score (NIS) was evaluated prior to the sacrifice of all rats. Hematoxylin-eosin staining was performed after 48 h of reperfusion with NBO treatment. The infarct volume and brain water content (BWC) were determined to assess brain ischemic injury at 24 and 48 h. The levels of HIF-1α, AQP4 and NHE1 expression in brain tissue samples were determined by western blotting and reverse transcription-quantitative polymerase chain reaction analysis. During reperfusion, the protein and mRNA expression of HIF-1α, AQP4 and NHE1 increased over time (up to 48 h). Exposure to 60 and 100% NBO during reperfusion following MCAO improved NIS, and alleviated BWC and infarct volume after 24 and 48 h, with further improvements in the 100% NBO group, compared with 60%. Additionally, the molecular mechanisms involved in the effects of NBO may be associated with reduced AQP4 and NHE1 expression and increased HIF-1α expression. However, 60% NBO therapy during reperfusion following an acute ischemic stroke did not achieve the same effects as 100% NBO. Further experimental studies should be performed to elucidate the mechanism and beneficial effects of 60% NBO, as it is more cost-effective to use, compared with 100% NBO.
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Affiliation(s)
- Dongbin Yang
- Department of Medical Nursing, School of Nursing, Zhengzhou University, Zhengzhou, Henan 450051, P.R. China
| | - Liyan Ma
- Department of Neurosurgery, The People's Hospital of Hebi, Hebi, Henan 458000, P.R. China
| | - Peng Wang
- Department of Medical Nursing, School of Nursing, Zhengzhou University, Zhengzhou, Henan 450051, P.R. China
| | - Dongjing Yang
- Department of Neurosurgery, The People's Hospital of Hebi, Hebi, Henan 458000, P.R. China
| | - Yingna Zhang
- Department of Neuroimmunology, The Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450054, P.R. China
| | - Xue Zhao
- Department of Neuroimmunology, The Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450054, P.R. China
| | - Jie Lv
- Department of Neuroimmunology, The Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450054, P.R. China
| | - Jing Zhang
- Department of Neuroimmunology, The Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450054, P.R. China
| | - Zhenxiang Zhang
- Department of Medical Nursing, School of Nursing, Zhengzhou University, Zhengzhou, Henan 450051, P.R. China
| | - Feng Gao
- Department of Neuroimmunology, The Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450054, P.R. China
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