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Anaya-Prado R, Canseco-Villegas AI, Anaya-Fernández R, Anaya-Fernandez MM, Guerrero-Palomera MA, Guerrero-Palomera C, Garcia-Ramirez IF, Gonzalez-Martinez D, Azcona-Ramírez CC, Garcia-Perez C, Lizarraga-Valencia AL, Hernandez-Zepeda A, Palomares-Covarrubias JF, Blackaller-Medina JHA, Soto-Hintze J, Velarde-Castillo MC, Cruz-Melendrez DA. Role of nitric oxide in cerebral ischemia/reperfusion injury: A biomolecular overview. World J Clin Cases 2025; 13:101647. [PMID: 40191680 PMCID: PMC11670034 DOI: 10.12998/wjcc.v13.i10.101647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 11/19/2024] [Accepted: 12/02/2024] [Indexed: 12/19/2024] Open
Abstract
Nitric oxide (NO) is a gaseous molecule produced by 3 different NO synthase (NOS) isoforms: Neural/brain NOS (nNOS/bNOS, type 1), endothelial NOS (eNOS, type 3) and inducible NOS (type 2). Type 1 and 3 NOS are constitutively expressed. NO can serve different purposes: As a vasoactive molecule, as a neurotransmitter or as an immunomodulator. It plays a key role in cerebral ischemia/reperfusion injury (CIRI). Hypoxic episodes simulate the production of oxygen free radicals, leading to mitochondrial and phospholipid damage. Upon reperfusion, increased levels of oxygen trigger oxide synthases; whose products are associated with neuronal damage by promoting lipid peroxidation, nitrosylation and excitotoxicity. Molecular pathways in CIRI can be altered by NOS. Neuroprotective effects are observed with eNOS activity. While nNOS interplay is prone to endothelial inflammation, oxidative stress and apoptosis. Therefore, nNOS appears to be detrimental. The interaction between NO and other free radicals develops peroxynitrite; which is a cytotoxic agent. It plays a main role in the likelihood of hemorrhagic events by tissue plasminogen activator (t-PA). Peroxynitrite scavengers are currently being studied as potential targets to prevent hemorrhagic transformation in CIRI.
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Affiliation(s)
- Roberto Anaya-Prado
- Department of Research & Department of Surgery, School of Medicine and Health Sciences, Tecnologico de Monterrey, Corporate Hospitals Puerta de Hierro, Zapopan 45116, Jalisco, Mexico
- Direction of Research and Education, Corporate Hospitals Puerta de Hierro, Zapopan 45116, Jalisco, Mexico
| | - Abraham I Canseco-Villegas
- Department of Research, School of Medicine and Health Sciences, Tecnologico de Monterrey, Zapopan 45116, Jalisco, Mexico
- Division of Research and Education, Corporate Hospitals Puerta de Hierro, Zapopan 45116, Jalisco, Mexico
| | - Roberto Anaya-Fernández
- Division of Research and Education, Corporate Hospitals Puerta de Hierro, Zapopan 45116, Jalisco, Mexico
- Division of Research, School of Medicine, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - Michelle Marie Anaya-Fernandez
- Division of Research and Education, Corporate Hospitals Puerta de Hierro, Zapopan 45116, Jalisco, Mexico
- Division of Research, School of Medicine, Autonomous University of Guadalajara, Zapopan 45116, Jalisco, Mexico
| | - Miguel A Guerrero-Palomera
- Division of Research, School of Medicine, Autonomous University of Guadalajara, Zapopan 45116, Jalisco, Mexico
- Research & Education, Corporate Hospitals Puerta de Hierro, Zapopan 45116, Jalisco, Mexico
| | - Citlalli Guerrero-Palomera
- Division of Research, School of Medicine, Autonomous University of Guadalajara, Zapopan 45116, Jalisco, Mexico
- Research & Education, Corporate Hospitals Puerta de Hierro, Zapopan 45116, Jalisco, Mexico
| | - Ivan F Garcia-Ramirez
- Division of Research, School of Medicine, Autonomous University of Guadalajara, Zapopan 45116, Jalisco, Mexico
- Division of Research, Corporate Hospitals Puerta de Hierro, Zapopan 45116, Jalisco, Mexico
| | - Daniel Gonzalez-Martinez
- Division of Research, School of Medicine, Autonomous University of Guadalajara, Zapopan 45116, Jalisco, Mexico
- Research & Education, Corporate Hospitals Puerta de Hierro, Zapopan 45116, Jalisco, Mexico
| | - Consuelo Cecilia Azcona-Ramírez
- Division of Research, School of Medicine, Autonomous University of Guadalajara, Zapopan 45116, Jalisco, Mexico
- Research & Education, Corporate Hospitals Puerta de Hierro, Zapopan 45116, Jalisco, Mexico
| | - Claudia Garcia-Perez
- Research & Education, Corporate Hospitals Puerta de Hierro, Zapopan 45116, Jalisco, Mexico
| | - Airim L Lizarraga-Valencia
- Division of Research, School of Medicine, Autonomous University of Guadalajara, Zapopan 45116, Jalisco, Mexico
- Research & Education, Corporate Hospitals Puerta de Hierro, Zapopan 45116, Jalisco, Mexico
| | - Aranza Hernandez-Zepeda
- Division of Research, School of Medicine, Autonomous University of Guadalajara, Zapopan 45116, Jalisco, Mexico
- Research & Education, Corporate Hospitals Puerta de Hierro, Zapopan 45116, Jalisco, Mexico
| | - Jacqueline F Palomares-Covarrubias
- Division of Research and Education, Corporate Hospitals Puerta de Hierro, Zapopan 45116, Jalisco, Mexico
- Division of Research, School of Medicine, Autonomous University of Guadalajara, Zapopan 45116, Jalisco, Mexico
| | - Jorge HA Blackaller-Medina
- Research & Education, Corporate Hospitals Puerta de Hierro, Zapopan 45116, Jalisco, Mexico
- Research, School of Medicine, UNIVA University, Zapopan 45116, Jalisco, Mexico
| | - Jacqueline Soto-Hintze
- Department of Research, School of Medicine and Health Sciences, Tecnologico de Monterrey, Zapopan 45116, Jalisco, Mexico
- Division of Research and Education, Corporate Hospitals Puerta de Hierro, Zapopan 45116, Jalisco, Mexico
| | - Mayra C Velarde-Castillo
- Division of Research and Education, Corporate Hospitals Puerta de Hierro, Zapopan 45116, Jalisco, Mexico
- Division of Research, School of Medicine, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - Dayri A Cruz-Melendrez
- Division of Research, School of Medicine, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico
- Research & Education, Corporate Hospitals Puerta de Hierro, Zapopan 45116, Jalisco, Mexico
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Anaya-Fernández R, Anaya-Prado R, Anaya-Fernandez MM, Guerrero-Palomera MA, Garcia-Ramirez IF, Gonzalez-Martinez D, Azcona-Ramirez CC, Guerrero-Palomera CS, Garcia-Perez C, Tenorio-Gonzalez B, Tenorio-Gonzalez JE, Vargas-Ascencio LF, Canseco-Villegas AI, Servin-Romero G, Barragan-Arias AR, Reyna-Rodriguez B. Oxidative Stress in Cerebral Ischemia/Reperfusion Injury. OBM NEUROBIOLOGY 2024; 08:1-15. [DOI: 10.21926/obm.neurobiol.2403239] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
Oxidative stress in cerebral ischemia/reperfusion injury (CIRI) involves reactive oxygen and nitrogen species (ROS and RNS). Despite efficient antioxidant pathways in the brain, hypoxia triggers the production of oxygen free radicals and downregulates ATP, which leads to oxidative stress. Sources of free radicals during CIRI include Ca<sup>2+</sup>-dependent enzymes, phospholipid degradation and mitochondrial enlargement. Upon reperfusion, the abrupt increase of oxygen triggers a massive radical production via enzymes like xantin oxidase (XO), phospholipase A2 (PLA2) and oxide synthases (OS). These enzymes play an essential role in neuronal damage by excitotoxicity, lipoperoxidation, nitrosylation, inflammation and programmed cell death (PCD). Endothelial nitric oxide synthase (eNOS) decreases as compared to neuronal nitric oxide synthase (nNOS). This is associated with neuronal damage, endothelial inflammation, apoptosis and oxidative stress. Strategies promoting activation of eNOS while inhibiting nNOS could offer neuroprotective benefits in CIRI. Understanding and targeting these pathways could mitigate brain damage in ischemia/reperfusion events. Clinically, tissue plasminogen activator (t-PA) has been shown to restore cerebral blood flow. However, serious side effects have been described, including hemorrhagic transformation. Different treatments are currently under investigation to avoid I/R injury. Baicalin has been reported as a potential agent that could improve t-PA adverse effects, which have to do with peroxynitrite synthesis and matrix metalloproteinase (MMP) expression. In this review, CIRI and interventions in oxidative stress are addressed. Special attention is paid to efficient antioxidant mechanisms in the brain and the production of free radicals, especially nNOS-derived nitric oxide (NO). The primary purpose is to describe accessible radical pathways with the activity of Ca<sup>2+</sup>-dependent oxidative enzymes, leading to membrane phospholipids and mitochondrial breakdown. <strong>Key</strong><strong>w</strong><strong>ords</strong>Oxidative stress; cerebral ischemia/reperfusion; nitric oxide; reactive oxygen species; nitric oxide synthase
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Fan G, Liu M, Liu J, Huang Y, Mu W. Traditional Chinese medicines treat ischemic stroke and their main bioactive constituents and mechanisms. Phytother Res 2024; 38:411-453. [PMID: 38051175 DOI: 10.1002/ptr.8033] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 09/12/2023] [Accepted: 09/24/2023] [Indexed: 12/07/2023]
Abstract
Ischemic stroke (IS) remains one of the leading causes of death and disability in humans. Unfortunately, none of the treatments effectively provide functional benefits to patients with IS, although many do so by targeting different aspects of the ischemic cascade response. The advantages of traditional Chinese medicine (TCM) in preventing and treating IS are obvious in terms of early treatment and global coordination. The efficacy of TCM and its bioactive constituents has been scientifically proven over the past decades. Based on clinical trials, this article provides a review of commonly used TCM patent medicines and herbal decoctions indicated for IS. In addition, this paper also reviews the mechanisms of bioactive constituents in TCM for the treatment of IS in recent years, both domestically and internationally. A comprehensive review of preclinical and clinical studies will hopefully provide new ideas to address the threat of IS.
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Affiliation(s)
- Genhao Fan
- Tianjin University of Chinese Medicine, Tianjin, China
- Clinical Pharmacology Department, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Menglin Liu
- Tianjin University of Chinese Medicine, Tianjin, China
| | - Jia Liu
- Clinical Pharmacology Department, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuhong Huang
- Clinical Pharmacology Department, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Wei Mu
- Clinical Pharmacology Department, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
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Lin W, Zhao XY, Cheng JW, Li LT, Jiang Q, Zhang YX, Han F. Signaling pathways in brain ischemia: Mechanisms and therapeutic implications. Pharmacol Ther 2023; 251:108541. [PMID: 37783348 DOI: 10.1016/j.pharmthera.2023.108541] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 09/18/2023] [Accepted: 09/25/2023] [Indexed: 10/04/2023]
Abstract
Ischemic stroke occurs when the arteries supplying blood to the brain are narrowed or blocked, inducing damage to brain tissue due to a lack of blood supply. One effective way to reduce brain damage and alleviate symptoms is to reopen blocked blood vessels in a timely manner and reduce neuronal damage. To achieve this, researchers have focused on identifying key cellular signaling pathways that can be targeted with drugs. These pathways include oxidative/nitrosative stress, excitatory amino acids and their receptors, inflammatory signaling molecules, metabolic pathways, ion channels, and other molecular events involved in stroke pathology. However, evidence suggests that solely focusing on protecting neurons may not yield satisfactory clinical results. Instead, researchers should consider the multifactorial and complex mechanisms underlying stroke pathology, including the interactions between different components of the neurovascular unit. Such an approach is more representative of the actual pathological process observed in clinical settings. This review summarizes recent research on the multiple molecular mechanisms and drug targets in ischemic stroke, as well as recent advances in novel therapeutic strategies. Finally, we discuss the challenges and future prospects of new strategies based on the biological characteristics of stroke.
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Affiliation(s)
- Wen Lin
- Medical Basic Research Innovation Center for Cardiovascular and Cerebrovascular Diseases, Ministry of Education, China; International Joint Laboratory for Drug Target of Critical Illnesses, Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
| | - Xiang-Yu Zhao
- Medical Basic Research Innovation Center for Cardiovascular and Cerebrovascular Diseases, Ministry of Education, China; International Joint Laboratory for Drug Target of Critical Illnesses, Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
| | - Jia-Wen Cheng
- Department of Physiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China
| | - Li-Tao Li
- Department of Neurology, Hebei General Hospital, Shijiazhuang 050051, Hebei, China
| | - Quan Jiang
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Yi-Xuan Zhang
- Medical Basic Research Innovation Center for Cardiovascular and Cerebrovascular Diseases, Ministry of Education, China; International Joint Laboratory for Drug Target of Critical Illnesses, Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China; Gusu School, Nanjing Medical University, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215002, China.
| | - Feng Han
- Medical Basic Research Innovation Center for Cardiovascular and Cerebrovascular Diseases, Ministry of Education, China; International Joint Laboratory for Drug Target of Critical Illnesses, Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China; Gusu School, Nanjing Medical University, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215002, China; Institute of Brain Science, the Affiliated Brain Hospital of Nanjing Medical University, Nanjing 211166, China.
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Daniel JM, Lindsey SH, Mostany R, Schrader LA, Zsombok A. Cardiometabolic health, menopausal estrogen therapy and the brain: How effects of estrogens diverge in healthy and unhealthy preclinical models of aging. Front Neuroendocrinol 2023; 70:101068. [PMID: 37061205 PMCID: PMC10725785 DOI: 10.1016/j.yfrne.2023.101068] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/23/2023] [Accepted: 04/10/2023] [Indexed: 04/17/2023]
Abstract
Research in preclinical models indicates that estrogens are neuroprotective and positively impact cognitive aging. However, clinical data are equivocal as to the benefits of menopausal estrogen therapy to the brain and cognition. Pre-existing cardiometabolic disease may modulate mechanisms by which estrogens act, potentially reducing or reversing protections they provide against cognitive decline. In the current review we propose mechanisms by which cardiometabolic disease may alter estrogen effects, including both alterations in actions directly on brain memory systems and actions on cardiometabolic systems, which in turn impact brain memory systems. Consideration of mechanisms by which estrogen administration can exert differential effects dependent upon health phenotype is consistent with the move towards precision or personalized medicine, which aims to determine which treatment interventions will work for which individuals. Understanding effects of estrogens in both healthy and unhealthy models of aging is critical to optimizing the translational link between preclinical and clinical research.
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Affiliation(s)
- Jill M Daniel
- Department of Psychology and Brain Institute, Tulane University, New Orleans, LA, United States.
| | - Sarah H Lindsey
- Department of Pharmacology and Brain Institute, Tulane University, New Orleans, LA, United States
| | - Ricardo Mostany
- Department of Pharmacology and Brain Institute, Tulane University, New Orleans, LA, United States
| | - Laura A Schrader
- Department of Cell & Molecular Biology and Brain Institute, Tulane University, New Orleans, LA, United States
| | - Andrea Zsombok
- Department of Physiology and Brain Institute, Tulane University, New Orleans, LA, United States
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Che P, Zhang J, Yu M, Tang P, Wang Y, Lin A, Xu J, Zhang N. Dl-3-n-butylphthalide promotes synaptic plasticity by activating the Akt/ERK signaling pathway and reduces the blood-brain barrier leakage by inhibiting the HIF-1α/MMP signaling pathway in vascular dementia model mice. CNS Neurosci Ther 2023; 29:1392-1404. [PMID: 36756709 PMCID: PMC10068471 DOI: 10.1111/cns.14112] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 12/29/2022] [Accepted: 01/20/2023] [Indexed: 02/10/2023] Open
Abstract
AIMS DL-3-n-butylphthalide (NBP) exerts beneficial effects on global cognitive functions, but the underlying molecular mechanisms are still poorly understood. The present study aimed to investigate whether NBP mediates synaptic plasticity and blood-brain barrier (BBB) function, which play a pivotal role in the pathogenesis of vascular dementia (VaD), in a mouse model of bilateral common carotid artery stenosis (BCAS). METHODS NBP was administered to model mice at a dose of 80 mg/kg by gavage for 28 days after surgery. Cognitive function was evaluated by behavioral tests, and hippocampal synaptic plasticity was evaluated by in vivo electrophysiological recording. Cerebral blood flow (CBF), hippocampal volume, and white matter integrity were measured with laser speckle imaging (LSI) and MRI. In addition, BBB leakage and the expression of proteins related to the Akt/ERK and HIF-1α/MMP signaling pathways were assessed by biochemical assays. RESULTS NBP treatment alleviated cognitive impairment, hippocampal atrophy, and synaptic plasticity impairment induced by BCAS. In addition, NBP treatment increased CBF, promoted white matter integrity, and decreased BBB leakage. Regarding the molecular mechanisms, in mice with BCAS, NBP may activate the Akt/ERK signaling pathway, which upregulates the expression of synapse-associated proteins, and it may also inhibit the HIF-1α/MMP signaling pathway, thereby increasing the expression of tight junction (TJ) proteins. CONCLUSION In conclusion, our results demonstrated the therapeutic effects of NBP in improving cognitive function via a wide range of targets in mice subjected to BCAS.
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Affiliation(s)
- Ping Che
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Juan Zhang
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.,Department of Neurology, Gucheng Hospital in Hebei Province, Hengshui, China
| | - Mingqian Yu
- School of Medicine, Nankai University, Tianjin, China
| | - Ping Tang
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Yanhui Wang
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Aolei Lin
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Jing Xu
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Nan Zhang
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.,Department of Neurology, Tianjin Medical University General Hospital Airport Site, Tianjin, China
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Anwar MM, Özkan E, Gürsoy-Özdemir Y. The role of extracellular matrix alterations in mediating astrocyte damage and pericyte dysfunction in Alzheimer's disease: A comprehensive review. Eur J Neurosci 2022; 56:5453-5475. [PMID: 34182602 DOI: 10.1111/ejn.15372] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 06/19/2021] [Accepted: 06/21/2021] [Indexed: 12/14/2022]
Abstract
The brain is a highly vascularized tissue protected by the blood-brain barrier (BBB), a complex structure allowing only necessary substances to pass through into the brain while limiting the entrance of harmful toxins. The BBB comprises several components, and the most prominent features are tight junctions between endothelial cells (ECs), which are further wrapped in a layer of pericytes. Pericytes are multitasked cells embedded in a thick basement membrane (BM) that consists of a fibrous extracellular matrix (ECM) and are surrounded by astrocytic endfeet. The primary function of astrocytes and pericytes is to provide essential blood supply and vital nutrients to the brain. In Alzheimer's disease (AD), long-term neuroinflammatory cascades associated with infiltration of harmful neurotoxic proteins may lead to BBB dysfunction and altered ECM components resulting in brain homeostatic imbalance, synaptic damage, and declined cognitive functions. Moreover, BBB structure and functional integrity may be lost due to induced ECM alterations, astrocyte damage, and pericytes dysfunction, leading to amyloid-beta (Aβ) hallmarks deposition in different brain regions. Herein, we highlight how BBB, ECM, astrocytes, and pericytes dysfunction can play a leading role in AD's pathogenesis and discuss their impact on brain functions.
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Affiliation(s)
- Mai M Anwar
- Neuroscience Research Lab, Research Center for Translational Medicine (KUTTAM), Koç University, Istanbul, Turkey.,Department of Biochemistry, National Organization for Drug Control and Research (NODCAR)/Egyptian Drug Authority, Cairo, Egypt
| | - Esra Özkan
- Neuroscience Research Lab, Research Center for Translational Medicine (KUTTAM), Koç University, Istanbul, Turkey
| | - Yasemin Gürsoy-Özdemir
- Neuroscience Research Lab, Research Center for Translational Medicine (KUTTAM), Koç University, Istanbul, Turkey.,Department of Neurology, School of Medicine, Koç University, Istanbul, Turkey
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Nitrative Stress and Auditory Dysfunction. Pharmaceuticals (Basel) 2022; 15:ph15060649. [PMID: 35745568 PMCID: PMC9227425 DOI: 10.3390/ph15060649] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/12/2022] [Accepted: 05/20/2022] [Indexed: 11/24/2022] Open
Abstract
Nitrative stress is increasingly recognized as a critical mediator of apoptotic cell death in many pathological conditions. The accumulation of nitric oxide along with superoxide radicals leads to the generation of peroxynitrite that can eventually result in the nitration of susceptible proteins. Nitrotyrosine is widely used as a biomarker of nitrative stress and indicates oxidative damage to proteins. Ototoxic insults, such as exposure to noise and ototoxic drugs, enhance the generation of 3-nitrotyrosine in different cell types in the cochlea. Nitrated proteins can disrupt critical signaling pathways and eventually lead to apoptosis and loss of sensory receptor cells in the cochlea. Accumulating evidence shows that selective targeting of nitrative stress attenuates cellular damage. Anti-nitrative compounds, such as peroxynitrite decomposition catalysts and inducible nitric oxide synthase inhibitors, prevent nitrative stress-mediated auditory damage. However, the role of nitrative stress in acquired hearing loss and its potential significance as a promising interventional target is yet to be fully characterized. This review provides an overview of nitrative stress mechanisms, the induction of nitrative stress in the auditory tissue after ototoxic insults, and the therapeutic value of targeting nitrative stress for mitigating auditory dysfunction.
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Dhote V, Mandloi AS, Singour PK, Kawadkar M, Ganeshpurkar A, Jadhav MP. Neuroprotective effects of combined trimetazidine and progesterone on cerebral reperfusion injury. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2022; 3:100108. [PMID: 35602337 PMCID: PMC9118508 DOI: 10.1016/j.crphar.2022.100108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 04/28/2022] [Accepted: 04/29/2022] [Indexed: 11/26/2022] Open
Abstract
Cerebral ischemia-reperfusion injury induces multi-dimensional damage to neuronal cells through exacerbation of critical protective mechanisms. Targeting more than one mechanism simultaneously namely, inflammatory responses and metabolic energy homeostasis could provide additional benefits to restrict or manage cerebral injury. Being proven neuroprotective agents both, progesterone (PG) and trimetazidine (TMZ) has the potential to add on the individual therapeutic outcomes. We hypothesized the simultaneous administration of PG and TMZ could complement each other to synergize, or at least enhance neuroprotection in reperfusion injury. We investigated the combination of PG and TMZ on middle cerebral artery occlusion (MCAO) induced cerebral reperfusion injury in rats. Molecular docking on targets of energy homeostasis and apoptosis assessed the initial viability of PG and TMZ for neuroprotection. Animal experimentation with MCA induced ischemia-reperfusion (I/R) injury in rats was performed on five randomized groups. Sham operated control group received vehicle (saline) while the other four I-R groups were pre-treated with vehicle (saline), PG (8 mg/kg), TMZ treated (25 mg/kg), and PG + TMZ (8 and 25 mg/kg) for 7 days by intraperitoneal route. Neurological deficit, infarct volume, and oxidative stress were evaluated to assess the extent of injury in rats. Inflammatory reactivity and apoptotic activity were determined with alterations in myeloperoxidase (MPO) activity, blood-brain barrier (BBB) permeability, and DNA fragments. Reperfusion injury inflicted cerebral infarct, neurological deficit, and shattered BBB integrity. The combination treatment of PG and TMZ restricted cellular damage indicated by significant (p < 0.05) decrease in infarct volume and improvement in free radical scavenging ability (SOD activity and GSH level). MPO activity and LPO decreased which contributed in improved BBB integrity in treated rats. We speculate that inhibition of inflammatory and optimum energy utilization would critically contribute to observed neuroprotection with combined PG and TMZ treatment. Further exploration of this neuroprotective approach for post-recovery cognitive improvement is worth investigating.
Molecular docking study. Drug repurposing. Combinatorial approach. Network Pharmacology.
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Li T, Xu T, Zhao J, Gao H, Xie W. Depletion of iNOS-positive inflammatory cells decelerates neuronal degeneration and alleviates cerebral ischemic damage by suppressing the inflammatory response. Free Radic Biol Med 2022; 181:209-220. [PMID: 35150825 DOI: 10.1016/j.freeradbiomed.2022.02.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 01/25/2022] [Accepted: 02/08/2022] [Indexed: 01/05/2023]
Abstract
Ischemic stroke leads to neuronal damage and severe inflammation that activate iNOS expression in different cell types, especially inflammatory cells in the brain. It is shown that NO released from iNOS contributes to the pathological development of cerebral ischemia. However, the role of these iNOS-expressing inflammatory cells in ischemic stroke has not been fully elucidated. Our purpose is to test if ischemia-induced iNOS+ inflammatory cells may exaggerate cerebral inflammation to exacerbate neuronal deficit. We studied the dynamics of iNOS+ cells after stroke and found an early and sustained iNOS expression at lesion site. Since iNOS is highly expressed in inflammatory cells after injury, we depleted the iNOS + inflammatory cells via the selective scavenger GdCl3, and investigated its effect on stroke outcome, neuronal and vascular deficit, and inflammatory response. After GdCl3 treatment, half of iNOS+ inflammatory cells were depleted, including mainly activated microglia/macrophages and some astrocytes. Selective depletion of iNOS+ inflammatory cells resulted in a pronounced reduction in brain damage, resulting in improvement of motor ability. Histologic studies and in vivo two-photon imaging data revealed a slowdown of neuronal degeneration after the depletion of iNOS+ inflammatory cells. In contrast to iNOS inhibition alone, depletion of iNOS+ inflammatory cells profoundly altered the immune microenvironment profile, in addition to reducing NO production. qRT-PCR analysis showed that depletion of iNOS+ inflammatory cells significantly restrained the production of pro-inflammatory cytokines, which moderated the immune microenvironment at the lesion site. Taken together, our data demonstrate that depleting iNOS+ inflammatory cells prevents neuronal damage not only by inhibiting NO, but also importantly by suppressing the inflammatory response, which is beneficial to ischemic injury. These results provide evidence that iNOS+ inflammatory cells, as a vital source of pro-inflammatory cytokines, contribute to the development of ischemic damage and could be a potential therapeutic target for the treatment of ischemia.
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Affiliation(s)
- Ting Li
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou, 73000, China.
| | - Ting Xu
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou, 73000, China
| | - Jin Zhao
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou, 73000, China
| | - Hao Gao
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou, 73000, China
| | - Wenguang Xie
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou, 73000, China
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Kawadkar M, Mandloi AS, Singh N, Mukharjee R, Dhote VV. Combination therapy for cerebral ischemia: do progesterone and noscapine provide better neuroprotection than either alone in the treatment? NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2022; 395:167-185. [PMID: 34988596 DOI: 10.1007/s00210-021-02187-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 11/20/2021] [Indexed: 10/19/2022]
Abstract
Ischemic stroke presents multifaceted pathological outcomes with overlapping mechanisms of cerebral injury. High mortality and disability with stroke warrant a novel multi-targeted therapeutic approach. The neuroprotection with progesterone (PG) and noscapine (NOS) on cerebral ischemia-reperfusion (I-R) injury was demonstrated individually, but the outcome of combination treatment to alleviate cerebral damage is still unexplored. Randomly divided groups of rats (n = 6) were Sham-operated, I-R, PG (8 mg/kg), NOS (10 mg/kg), and PG + NOS (8 mg/kg + 10 mg/kg). The rats were exposed to bilateral common carotid artery occlusion, except Sham-operated, to investigate the therapeutic outcome of PG and NOS alone and in combination on I-R injury. Besides the alterations in cognitive and motor abilities, we estimated infarct area, oxidative stress, blood-brain barrier (BBB) permeability, and histology after treatment. Pharmacokinetic parameters like Cmax, Tmax, half-life, and AUC0-t were estimated in biological samples to substantiate the therapeutic outcomes of the combination treatment. We report PG and NOS prevent loss of motor ability and improve spatial memory after cerebral I-R injury. Combination treatment significantly reduced inflammation and restricted infarction; it attenuated oxidative stress and BBB damage and improved grip strength. Histopathological analysis demonstrated a significant reduction in leukocyte infiltration with the most profound effect in the combination group. Simultaneous analysis of PG and NOS in plasma revealed enhanced peak drug concentration, improved AUC, and prolonged half-life; the drug levels in the brain have increased significantly for both. We conclude that PG and NOS have beneficial effects against brain damage and the co-administration further reinforced neuroprotection in the cerebral ischemia-reperfusion injury.
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Affiliation(s)
- Manisha Kawadkar
- Department of Pharmacology, Faculty of Pharmacy, VNS Group of Institutions, Vidya Vihar, Neelbud, Bhopal, Madhya Pradesh, 462044, India
| | - Avinash S Mandloi
- Department of Pharmacology, Faculty of Pharmacy, VNS Group of Institutions, Vidya Vihar, Neelbud, Bhopal, Madhya Pradesh, 462044, India
| | - Nidhi Singh
- Department of Pharmacology, Faculty of Pharmacy, VNS Group of Institutions, Vidya Vihar, Neelbud, Bhopal, Madhya Pradesh, 462044, India
| | - Rajesh Mukharjee
- Department of Pharmacology, Faculty of Pharmacy, VNS Group of Institutions, Vidya Vihar, Neelbud, Bhopal, Madhya Pradesh, 462044, India
| | - Vipin V Dhote
- Department of Pharmacology, Faculty of Pharmacy, VNS Group of Institutions, Vidya Vihar, Neelbud, Bhopal, Madhya Pradesh, 462044, India.
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WANG X, LI T, DONG K. Effect of formononetin from Trifolium pratense L. on oxidative stress, energy metabolism and inflammatory response after cerebral ischemia-reperfusion injury in mice. FOOD SCIENCE AND TECHNOLOGY 2022. [DOI: 10.1590/fst.57821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Xueyan WANG
- The Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, China
| | - Tie LI
- The Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, China
| | - Kun DONG
- The Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, China
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Przykaza Ł. Understanding the Connection Between Common Stroke Comorbidities, Their Associated Inflammation, and the Course of the Cerebral Ischemia/Reperfusion Cascade. Front Immunol 2021; 12:782569. [PMID: 34868060 PMCID: PMC8634336 DOI: 10.3389/fimmu.2021.782569] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 10/29/2021] [Indexed: 01/13/2023] Open
Abstract
Despite the enormous progress in the understanding of the course of the ischemic stroke over the last few decades, a therapy that effectively protects neurovascular units (NVUs) and significantly improves neurological functions in stroke patients has still not been achieved. The reasons for this state are unclear, but it is obvious that the cerebral ischemia and reperfusion cascade is a highly complex phenomenon, which includes the intense neuroinflammatory processes, and comorbid stroke risk factors strongly worsen stroke outcomes and likely make a substantial contribution to the pathophysiology of the ischemia/reperfusion, enhancing difficulties in searching of successful treatment. Common concomitant stroke risk factors (arterial hypertension, diabetes mellitus and hyperlipidemia) strongly drive inflammatory processes during cerebral ischemia/reperfusion; because these factors are often present for a long time before a stroke, causing low-grade background inflammation in the brain, and already initially disrupting the proper functions of NVUs. Broad consideration of this situation in basic research may prove to be crucial for the success of future clinical trials of neuroprotection, vasculoprotection and immunomodulation in stroke. This review focuses on the mechanism by which coexisting common risk factors for stroke intertwine in cerebral ischemic/reperfusion cascade and the dysfunction and disintegration of NVUs through inflammatory processes, principally activation of pattern recognition receptors, alterations in the expression of adhesion molecules and the subsequent pathophysiological consequences.
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Affiliation(s)
- Łukasz Przykaza
- Laboratory of Experimental and Clinical Neurosurgery, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
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Li C, Sun T, Jiang C. Recent advances in nanomedicines for the treatment of ischemic stroke. Acta Pharm Sin B 2021; 11:1767-1788. [PMID: 34386320 PMCID: PMC8343119 DOI: 10.1016/j.apsb.2020.11.019] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 08/27/2020] [Accepted: 09/13/2020] [Indexed: 12/20/2022] Open
Abstract
Ischemic stroke is a cerebrovascular disease normally caused by interrupted blood supply to the brain. Ischemia would initiate the cascade reaction consisted of multiple biochemical events in the damaged areas of the brain, where the ischemic cascade eventually leads to cell death and brain infarction. Extensive researches focusing on different stages of the cascade reaction have been conducted with the aim of curing ischemic stroke. However, traditional treatment methods based on antithrombotic therapy and neuroprotective therapy are greatly limited for their poor safety and treatment efficacy. Nanomedicine provides new possibilities for treating stroke as they could improve the pharmacokinetic behavior of drugs in vivo, achieve effective drug accumulation at the target site, enhance the therapeutic effect and meanwhile reduce the side effect. In this review, we comprehensively describe the pathophysiology of stroke, traditional treatment strategies and emerging nanomedicines, summarize the barriers and methods for transporting nanomedicine to the lesions, and illustrate the latest progress of nanomedicine in treating ischemic stroke, with a view to providing a new feasible path for the treatment of cerebral ischemia.
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Key Words
- AEPO, asialo-erythropoietin
- APOE, apolipoprotein E
- BBB, blood‒brain barrier
- BCECs, brain capillary endothelial cells
- Blood‒brain barrier
- CAT, catalase
- COX-1, cyclooxygenase-1
- CXCR-4, C-X-C chemokine receptor type 4
- Ce-NPs, ceria nanoparticles
- CsA, cyclosporine A
- DAMPs, damage-associated molecular patterns
- GFs, growth factors
- GPIIb/IIIa, glycoprotein IIb/IIIa
- HMGB1, high mobility group protein B1
- Hb, hemoglobin
- ICAM-1, intercellular adhesion molecule-1
- IL-1β, interleukin-1β
- IL-6, interleukin-6
- Ischemic cascade
- LFA-1, lymphocyte function-associated antigen-1
- LHb, liposomal Hb
- MCAO, middle cerebral artery occlusion
- MMPs, matrix metalloproteinases
- MSC, mesenchymal stem cell
- NF-κB, nuclear factor-κB
- NGF, nerve growth factor
- NMDAR, N-methyl-d-aspartate receptor
- NOS, nitric oxide synthase
- NPs, nanoparticles
- NSCs, neural stem cells
- Nanomedicine
- Neuroprotectant
- PBCA, poly-butylcyanoacrylate
- PCMS, poly (chloromethylstyrene)
- PEG, poly-ethylene-glycol
- PEG-PLA, poly (ethylene-glycol)-b-poly (lactide)
- PLGA NPs, poly (l-lactide-co-glycolide) nanoparticles
- PSD-95, postsynaptic density protein-95
- PSGL-1, P-selectin glycoprotein ligand-1
- RBCs, red blood cells
- RES, reticuloendothelial system
- RGD, Arg-Gly-Asp
- ROS, reactive oxygen species
- Reperfusion
- SDF-1, stromal cell-derived factor-1
- SHp, stroke homing peptide
- SOD, superoxide dismutase
- SUR1-TRPM4, sulfonylurea receptor 1-transient receptor potential melastatin-4
- Stroke
- TEMPO, 2,2,6,6-tetramethylpiperidine-1-oxyl
- TIA, transient ischemic attack
- TNF-α, tumor necrosis factor-α
- Thrombolytics
- cRGD, cyclic Arg-Gly-Asp
- e-PAM-R, arginine-poly-amidoamine ester
- iNOS, inducible nitric oxide synthase
- miRNAs, microRNAs
- nNOS, neuron nitric oxide synthase
- siRNA, small interfering RNA
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Chavda V, Madhwani K, Chaurasia B. Stroke and immunotherapy: Potential mechanisms and its implications as immune-therapeutics. Eur J Neurosci 2021; 54:4338-4357. [PMID: 33829590 DOI: 10.1111/ejn.15224] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/01/2021] [Accepted: 04/02/2021] [Indexed: 12/19/2022]
Abstract
Ischemia or brain injuries are mostly associated with emergency admissions and huge mortality rates. Stroke is a fatal cerebrovascular malady and second top root of disability and death in both developing and developed countries with a projected rise of 24.9% (from 2010) by 2030. It's the most frequent cause of morbidities and systemic permanent morbidities due to its multi-organ systemic pathology. Brain edema or active immune response cause disturbed or abnormal systemic affects causing inflammatory damage leading to secondary infection and secondary immune response which leads to activation like pneumonia or urine tract infections. There are a variety of post stroke treatments available which claims their usefulness in reducing or inhibiting post stroke and recurrent stroke damage followed by heavy inflammatory actions. Stroke does change the quality of life and also ensures daily chronic rapid neurodegeneration and cognitive decline. The only approved therapies for stroke are alteplase and thrombectomy which is associated with adverse outcomes and are not a total cure for ischemic stroke. Stroke and immune response are reciprocal to the pathology and time of event and it progresses till untreated. The immune reaction during ischemia opens new doors for advanced targeted therapeutics. Nowadays stem cell therapy has shown better results in stroke-prone individuals. Few monoclonal antibodies like natalizumab have shown great impact on pre-clinical and clinical stroke trial studies. In this current review, we have explored an immunology of stroke, current therapeutic scenario and future potential targets as immunotherapeutic agents in stroke therapeutics.
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Affiliation(s)
- Vishal Chavda
- Division of Anesthesia, Sardar Women's Hospital, Ahmadabad, Gujarat, India
| | - Kajal Madhwani
- Department of Microbiology, Nirma University, Ahmadabad, Gujarat, India
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Chronic Exposure to Tramadol Induces Neurodegeneration in the Cerebellum of Adult Male Rats. Neurotox Res 2021; 39:1134-1147. [PMID: 33818692 DOI: 10.1007/s12640-021-00354-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 03/09/2021] [Accepted: 03/11/2021] [Indexed: 12/24/2022]
Abstract
Tramadol is a centrally acting synthetic opioid analgesic and SNRI (serotonin/norepinephrine reuptake-inhibitor) that structurally resembles codeine and morphine. Given the tramadol neurotoxic effect and the body of studies on the effect of tramadol on the cerebellum, this study aims to provide deeper insights into molecular and histological alterations in the cerebellar cortex related to tramadol administration. In this study, twenty-four adult male albino rats were randomly and equally divided into two groups: control and tramadol groups. The tramadol group received 50 mg/kg of tramadol daily for 3 weeks via oral gavage. The functional and structural change of the cerebellum under chronic exposure of tramadol were measured. Our data revealed that treating rats with tramadol not only lead to cerebellum atrophy but also resulted in the actuation of microgliosis, neuroinflammatoin, and apoptotic biomarkers. Our results illustrated a significant drop in VEGF (vascular endothelial growth factor) level in the tramadol group. Additionally, tramadol impaired motor coordination and neuromuscular activity. We also identified several signaling cascades chiefly related to neurodegenerative disease and energy metabolism that considerably deregulated in the cerebellum of tramadol-treated rats. Overall, the outcomes of this study suggest that tramadol administration has a neurodegeneration effect on the cerebellar cortex via several pathways consisting of microgliosis, apoptosis, necroptosis, and neuroinflammatoin.
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Kawadkar M, Mandloi AS, Saxena V, Tamadaddi C, Sahi C, Dhote VV. Noscapine alleviates cerebral damage in ischemia-reperfusion injury in rats. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2021; 394:669-683. [PMID: 33106921 DOI: 10.1007/s00210-020-02005-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 10/15/2020] [Indexed: 02/06/2023]
Abstract
With high unmet medical needs, stroke remains an intensely focused research area. Although noscapine is a neuroprotective agent, its mechanism of action in ischemic-reperfusion (I-R) injury is yet to be ascertained. We investigated the effect of noscapine on the molecular mechanisms of cell damage using yeast, and its neuroprotection on cerebral I-R injury in rats. Yeast, both wild-type and Δtrx2 strains, was evaluated for cell growth and viability, and oxidative stress to assess the noscapine effect at 8, 10, 12, and 20 μg/ml concentrations. The neuroprotective activity of noscapine (5 and 10 mg/kg; po for 8 days) was investigated in rats using middle cerebral artery occlusion-induced I-R injury. Infarct volume, neurological deficit, oxidative stress, myeloperoxidase activity, and histological alterations were determined in I-R rats. In vitro yeast assays exhibited significant antioxidant activity and enhanced cell tolerance against oxidative stress after noscapine treatment. Similarly, noscapine pretreatment significantly reduced infarct volume and edema in the brain. The neurological deficit was decreased and oxidative stress biomarkers, superoxide dismutase activity and glutathione levels, were significantly increased while lipid peroxidation showed significant decrease in comparison to vehicle-treated I-R rats. Myeloperoxidase activity, an indicator of inflammation, was also reduced significantly in treated rats; histological changes were attenuated with noscapine. The study demonstrates the protective effect of noscapine in yeast and I-R rats by improving cell viability and attenuating neuronal damage, respectively. This protective activity of noscapine could be attributed to potent free radical scavenging and inhibition of inflammation in cerebral ischemia-reperfusion injury.
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Affiliation(s)
- Manisha Kawadkar
- Department of Pharmacology, Faculty of Pharmacy, VNS Group of Institutions, VidyaVihar, Neelbud, Bhopal, Madhya Pradesh, 462044, India
| | - Avinash S Mandloi
- Department of Pharmacology, Faculty of Pharmacy, VNS Group of Institutions, VidyaVihar, Neelbud, Bhopal, Madhya Pradesh, 462044, India
| | - Vidhu Saxena
- Department of Pharmacology, Faculty of Pharmacy, VNS Group of Institutions, VidyaVihar, Neelbud, Bhopal, Madhya Pradesh, 462044, India
| | - Chetana Tamadaddi
- Chaperone and Stress Biology Lab, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER), Bhopal, Madhya Pradesh, 462066, India
| | - Chandan Sahi
- Chaperone and Stress Biology Lab, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER), Bhopal, Madhya Pradesh, 462066, India
| | - Vipin V Dhote
- Department of Pharmacology, Faculty of Pharmacy, VNS Group of Institutions, VidyaVihar, Neelbud, Bhopal, Madhya Pradesh, 462044, India.
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18
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Albuck AL, Sakamuri SSVP, Sperling JA, Evans WR, Kolli L, Sure VN, Mostany R, Katakam PVG. Peroxynitrite decomposition catalyst enhances respiratory function in isolated brain mitochondria. Am J Physiol Heart Circ Physiol 2021; 320:H630-H641. [PMID: 33164581 PMCID: PMC8082788 DOI: 10.1152/ajpheart.00389.2020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 10/07/2020] [Accepted: 11/02/2020] [Indexed: 02/06/2023]
Abstract
Peroxynitrite (PN), generated from the reaction of nitric oxide (NO) and superoxide, is implicated in the pathogenesis of ischemic and neurodegenerative brain injuries. Mitochondria produce NO from mitochondrial NO synthases and superoxide by the electron transport chain. Our objective was to detect the generation of PN of mitochondrial origin and characterize its effects on mitochondrial respiratory function. Freshly isolated brain nonsynaptosomal mitochondria from C57Bl/6 (wild type, WT) and endothelial NO synthase knockout (eNOS-KO) mice were treated with exogenous PN (0.1, 1, 5 µmol/L) or a PN donor (SIN-1; 50 µmol/L) or a PN scavenger (FeTMPyP; 2.5 µmol/L). Oxygen consumption rate (OCR) was measured using Agilent Seahorse XFe24 analyzer and mitochondrial respiratory parameters were calculated. Mitochondrial membrane potential, superoxide, and PN were determined from rhodamine 123, dihydroethidium, and DAX-J2 PON green fluorescence measurements, respectively. Mitochondrial protein nitrotyrosination was determined by Western blots. Both exogenous PN and SIN-1 decreased respiratory function in WT isolated brain mitochondria. FeTMPyP enhanced state III and state IVo mitochondrial respiration in both WT and eNOS-KO mitochondria. FeTMPyP also elevated state IIIu respiration in eNOS-KO mitochondria. Unlike PN, neither SIN-1 nor FeTMPyP depolarized the mitochondria. Although mitochondrial protein nitrotyrosination was unaffected by SIN-1 or FeTMPyP, FeTMPyP reduced mitochondrial PN levels. Mitochondrial superoxide levels were increased by FeTMPyP but were unaffected by PN or SIN-1. Thus, we present the evidence of functionally significant PN generation in isolated brain mitochondria. Mitochondrial PN activity was physiologically relevant in WT mice and pathologically significant under conditions with eNOS deficiency.NEW & NOTEWORTHY Mitochondria generate superoxide and nitric oxide that could potentially react with each other to produce PN. We observed eNOS and nNOS immunoreactivity in isolated brain and heart mitochondria with pharmacological inhibition of nNOS found to modulate the mitochondrial respiratory function. This study provides evidence of generation of functionally significant PN in isolated brain mitochondria that affects respiratory function under physiological conditions. Importantly, the mitochondrial PN levels and activity were exaggerated in the eNOS-deficient mice, suggesting its pathological significance.
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Affiliation(s)
- Aaron L Albuck
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana
- Tulane Brain Institute, Tulane University, New Orleans, Louisiana
| | - Siva S V P Sakamuri
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Jared A Sperling
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Wesley R Evans
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana
- Tulane Brain Institute, Tulane University, New Orleans, Louisiana
| | - Lahari Kolli
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Venkata N Sure
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Ricardo Mostany
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana
- Tulane Brain Institute, Tulane University, New Orleans, Louisiana
| | - Prasad V G Katakam
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana
- Tulane Brain Institute, Tulane University, New Orleans, Louisiana
- Clinical Neuroscience Research Center, New Orleans, Louisiana
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19
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Role of the Platelets and Nitric Oxide Biotransformation in Ischemic Stroke: A Translative Review from Bench to Bedside. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:2979260. [PMID: 32908630 PMCID: PMC7474795 DOI: 10.1155/2020/2979260] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 07/27/2020] [Indexed: 12/13/2022]
Abstract
Ischemic stroke remains the fifth cause of death, as reported worldwide annually. Endothelial dysfunction (ED) manifesting with lower nitric oxide (NO) bioavailability leads to increased vascular tone, inflammation, and platelet activation and remains among the major contributors to cardiovascular diseases (CVD). Moreover, temporal fluctuations in the NO bioavailability during ischemic stroke point to its key role in the cerebral blood flow (CBF) regulation, and some data suggest that they may be responsible for the maintenance of CBF within the ischemic penumbra in order to reduce infarct size. Several years ago, the inhibitory role of the platelet NO production on a thrombus formation has been discovered, which initiated the era of extensive studies on the platelet-derived nitric oxide (PDNO) as a platelet negative feedback regulator. Very recently, Radziwon-Balicka et al. discovered two subpopulations of human platelets, based on the expression of the endothelial nitric oxide synthase (eNOS-positive or eNOS-negative platelets, respectively). The e-NOS-negative ones fail to produce NO, which attenuates their cyclic guanosine monophosphate (cGMP) signaling pathway and-as result-promotes adhesion and aggregation while the e-NOS-positive ones limit thrombus formation. Asymmetric dimethylarginine (ADMA), a competitive NOS inhibitor, is an independent cardiovascular risk factor, and its expression alongside with the enzymes responsible for its synthesis and degradation was recently shown also in platelets. Overproduction of ADMA in this compartment may increase platelet activation and cause endothelial damage, additionally to that induced by its plasma pool. All the recent discoveries of diverse eNOS expression in platelets and its role in regulation of thrombus formation together with studies on the NOS inhibitors have opened a new chapter in translational medicine investigating the onset of acute cardiovascular events of ischemic origin. This translative review briefly summarizes the role of platelets and NO biotransformation in the pathogenesis and clinical course of ischemic stroke.
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20
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Abdel-Rahman RF, El Awdan SA, Hegazy RR, Mansour DF, Ogaly HA, Abdelbaset M. Neuroprotective effect of Crocus sativus against cerebral ischemia in rats. Metab Brain Dis 2020; 35:427-439. [PMID: 31728890 DOI: 10.1007/s11011-019-00505-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 10/10/2019] [Indexed: 12/16/2022]
Abstract
The present study aimed to investigate the role of vascular endothelial growth factor (VEGF) in the neuroprotective effect of Crocus sativus (saffron) against cerebral ischemia/reperfusion injury (I/R) in rats. Four groups of a total forty I/R rats with 60-min occlusion followed by 48 h reperfusion or sham surgery were used. The sham and left-brain I/R control groups where treated with normal saline. The rats of the other two groups received saffron extract (100 or 200 mg/kg, ip, respectively) for 3 successive weeks prior to left-brain I/R. Other four doses of saffron extract were received by the rats of the last 2 groups 60 min prior to operation, during the surgery, and on days 1 and 2 following reperfusion. I/R group showed marked neurobehavioral, neurochemical and histopathological alterations. The results revealed a significant reduction in neurological deficit scores in the saffron-treated rats at both doses. Saffron significantly attenuated lipid peroxidation, decreased NO and brain natriuretic peptide (BNP) contents in I/R-brain tissue. On the other hand, saffron reversed the depletion of GSH in the injured brain. Moreover, saffron treatment evidently reduced apoptosis as revealed by a decrease in caspase-3 and Bax protein expression with a marked decrease in the apoptotic neuronal cells compared to I/R group. In addition, saffron administration effectively upregulated the expression of VEGF in I/R-brain tissue. In conclusion, saffron treatment offers significant neuroprotection against I/R damage possibly through diminishing oxidative stress and apoptosis and enhancement of VEGF.
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Affiliation(s)
| | | | - Rehab R Hegazy
- Pharmacology Department, National Research Centre, Giza, Egypt
| | - Dina F Mansour
- Pharmacology Department, National Research Centre, Giza, Egypt
| | - H A Ogaly
- Chemistry Department, College of Science, King Khalid University, Abha, Saudi Arabia
- Biochemistry Department, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
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Chen HS, Chen X, Li WT, Shen JG. Targeting RNS/caveolin-1/MMP signaling cascades to protect against cerebral ischemia-reperfusion injuries: potential application for drug discovery. Acta Pharmacol Sin 2018; 39:669-682. [PMID: 29595191 PMCID: PMC5943912 DOI: 10.1038/aps.2018.27] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 01/26/2018] [Indexed: 02/07/2023]
Abstract
Reactive nitrogen species (RNS) play important roles in mediating cerebral ischemia-reperfusion injury. RNS activate multiple signaling pathways and participate in different cellular events in cerebral ischemia-reperfusion injury. Recent studies have indicated that caveolin-1 and matrix metalloproteinase (MMP) are important signaling molecules in the pathological process of ischemic brain injury. During cerebral ischemia-reperfusion, the production of nitric oxide (NO) and peroxynitrite (ONOO−), two representative RNS, down-regulates the expression of caveolin-1 (Cav-1) and, in turn, further activates nitric oxide synthase (NOS) to promote RNS generation. The increased RNS further induce MMP activation and mediate disruption of the blood-brain barrier (BBB), aggravating the brain damage in cerebral ischemia-reperfusion injury. Therefore, the feedback interaction among RNS/Cav-1/MMPs provides an amplified mechanism for aggravating ischemic brain damage during cerebral ischemia-reperfusion injury. Targeting the RNS/Cav-1/MMP pathway could be a promising therapeutic strategy for protecting against cerebral ischemia-reperfusion injury. In this mini-review article, we highlight the important role of the RNS/Cav-1/MMP signaling cascades in ischemic stroke injury and review the current progress of studies seeking therapeutic compounds targeting the RNS/Cav-1/MMP signaling cascades to attenuate cerebral ischemia-reperfusion injury. Several representative natural compounds, including calycosin-7-O-β-D-glucoside, baicalin, Momordica charantia polysaccharide (MCP), chlorogenic acid, lutein and lycopene, have shown potential for targeting the RNS/Cav-1/MMP signaling pathway to protect the brain in ischemic stroke. Therefore, the RNS/Cav-1/MMP pathway is an important therapeutic target in ischemic stroke treatment.
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Free Radical Damage in Ischemia-Reperfusion Injury: An Obstacle in Acute Ischemic Stroke after Revascularization Therapy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:3804979. [PMID: 29770166 PMCID: PMC5892600 DOI: 10.1155/2018/3804979] [Citation(s) in RCA: 316] [Impact Index Per Article: 45.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Accepted: 12/07/2017] [Indexed: 12/16/2022]
Abstract
Acute ischemic stroke is a common cause of morbidity and mortality worldwide. Thrombolysis with recombinant tissue plasminogen activator and endovascular thrombectomy are the main revascularization therapies for acute ischemic stroke. However, ischemia-reperfusion injury after revascularization therapy can result in worsening outcomes. Among all possible pathological mechanisms of ischemia-reperfusion injury, free radical damage (mainly oxidative/nitrosative stress injury) has been found to play a key role in the process. Free radicals lead to protein dysfunction, DNA damage, and lipid peroxidation, resulting in cell death. Additionally, free radical damage has a strong connection with inducing hemorrhagic transformation and cerebral edema, which are the major complications of revascularization therapy, and mainly influencing neurological outcomes due to the disruption of the blood-brain barrier. In order to get a better clinical prognosis, more and more studies focus on the pharmaceutical and nonpharmaceutical neuroprotective therapies against free radical damage. This review discusses the pathological mechanisms of free radicals in ischemia-reperfusion injury and adjunctive neuroprotective therapies combined with revascularization therapy against free radical damage.
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Wang Y, Wang MD, Xia YP, Gao Y, Zhu YY, Chen SC, Mao L, He QW, Yue ZY, Hu B. MicroRNA-130a regulates cerebral ischemia-induced blood-brain barrier permeability by targeting Homeobox A5. FASEB J 2018; 32:935-944. [PMID: 29070584 DOI: 10.1096/fj.201700139rrr] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Blood-brain barrier (BBB) disruption plays a critical role in brain injury induced by cerebral ischemia, and preserving BBB integrity during ischemia could alleviate cerebral injury. We examined the role of miR-130a in ischemic BBB disruption by using models of rat middle cerebral artery occlusion and cell oxygen-glucose deprivation. We found that ischemia significantly increased microRNA-130a (miR-130a) level and that miR-130a was predominantly from brain microvascular endothelial cells. Antagomir-130a, an antagonist of miR-130a, could attenuate brain edema, lower BBB permeability, reduce infarct volume, and improve neurologic function. MiR-130a overexpression induced by miR-130a mimic increased monolayer permeability, and intercellular inhibition of miR-130a by a miR-130a inhibitor suppressed oxygen-glucose deprivation-induced increase in monolayer permeability. Moreover, dual luciferase reporter system showed that Homeobox A5 was the direct target of miR-130a. MiR-130a, by inhibiting Homeobox A5 expression, could down-regulate occludin, thereby increasing BBB permeability. Our results suggested that miR-130a might be implicated in ischemia-induced BBB dysfunction and serve as a target for the treatment of ischemic stroke.-Wang, Y., Wang, M.-D., Xia, Y.-P., Gao, Y., Zhu, Y.-Y., Chen, S.-C., Mao, L., He, Q.-W., Yue, Z.-Y., Hu, B. MicroRNA-130a regulates cerebral ischemia-induced blood-brain barrier permeability by targeting Homeobox A5.
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Affiliation(s)
- Yong Wang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Meng-Die Wang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan-Peng Xia
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan Gao
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi-Yi Zhu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sheng-Cai Chen
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ling Mao
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Quan-Wei He
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhen-Yu Yue
- Department of Neurology, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Bo Hu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Abstract
Stroke is considered to be an acute cerebrovascular disease, including ischemic stroke and hemorrhagic stroke. The high incidence and poor prognosis of stroke suggest that it is a highly disabling and highly lethal disease which can pose a serious threat to human health. Nitric oxide (NO), a common gas in nature, which is often thought as a toxic gas, because of its intimate relationship with the pathological processes of many diseases, especially in the regulation of blood flow and cell inflammation. However, recent years have witnessed an increased interest that NO plays a significant and positive role in stroke as an essential gas signal molecule. In view of the fact that the neuroprotective effect of NO is closely related to its concentration, cell type and time, only in the appropriate circumstances can NO play a protective effect. The purpose of this review is to summarize the roles of NO in ischemic stroke and hemorrhagic stroke.
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Affiliation(s)
- Zhou-Qing Chen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Ru-Tao Mou
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Dong-Xia Feng
- Department of Scott & White Clinic-Temple, Temple, TX, USA
| | - Zhong Wang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Gang Chen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
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25
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Arbeláez-Quintero I, Palacios M. To Use or Not to Use Metformin in Cerebral Ischemia: A Review of the Application of Metformin in Stroke Rodents. Stroke Res Treat 2017; 2017:9756429. [PMID: 28634570 PMCID: PMC5467394 DOI: 10.1155/2017/9756429] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2016] [Revised: 10/22/2016] [Accepted: 10/26/2016] [Indexed: 12/11/2022] Open
Abstract
Ischemic strokes are major causes of death and disability. Searching for potential therapeutic strategies to prevent and treat stroke is necessary, given the increase in overall life expectancy. Epidemiological reports indicate that metformin is an oral antidiabetic medication that can reduce the incidence of ischemic events in patients with diabetes mellitus. Its mechanism of action has not been elucidated, but metformin pleiotropic effects involve actions in addition to glycemic control. AMPK activation has been described as one of the pharmacological mechanisms that explain the action of metformin and that lead to neuroprotective effects. Most experiments done in the cerebral ischemia model, via middle cerebral artery occlusion in rodents (MCAO), had positive results favoring metformin's neuroprotective role and involve several cellular pathways like oxidative stress, endothelial nitric oxide synthase activation, activation of angiogenesis and neurogenesis, autophagia, and apoptosis. We will review the pharmacological properties of metformin and its possible mechanisms that lead to neuroprotection in cerebral ischemia.
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Affiliation(s)
| | - Mauricio Palacios
- Centro de Estudios Cerebrales, Facultad de Salud, Universidad del Valle, Cali, Colombia
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26
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Chen C, Xi C, Liang X, Ma J, Su D, Abel T, Liu R. The Role of κ Opioid Receptor in Brain Ischemia. Crit Care Med 2017; 44:e1219-e1225. [PMID: 27495821 DOI: 10.1097/ccm.0000000000001959] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
OBJECTIVES Our previous studies indicated that highly selective κ opioid receptor agonists could protect the brain, indicating an important role of κ opioid receptor agonist in brain ischemia. In this study, we investigated the role and related mechanisms of κ opioid receptor agonists in brain ischemia in a middle cerebral artery occlusion mouse model. DESIGN Animal model. SETTING Laboratory. SUBJECTS The middle cerebral artery occlusion model was established by 120 minutes of ischemia followed by 24-hour reperfusion in male adult mice. INTERVENTIONS Various doses of salvinorin A, a highly selective and potent κ opioid receptor agonist, were administered intranasally 10 minutes after initiation of reperfusion. Norbinaltorphimine (2.5 mg/kg, IP) as a κ opioid receptor antagonist was administered in one group before administration of salvinorin A (50μg/kg) to investigate the specific role of κ opioid receptor. MEASUREMENTS AND MAIN RESULTS Infarct volume, κ opioid receptor expression, and Evans blue extravasation in the brain, and neurobehavioral outcome were determined. Immunohistochemistry and western blot were performed to detect the activated caspase-3, interleukin-10, and tumor necrosis factor-α levels to investigate the role of apoptosis and inflammation. κ opioid receptor expression was elevated significantly in the ischemic penumbral area compared with that in the nonischemic area. Salvinorin A reduced infarct volume and improved neurologic deficits dose-dependently. Salvinorin A at the dose of 50 μg/kg reduced Evans blue extravasation, suggesting reduced impairment of the blood-brain barrier and decreased the expression of cleaved caspase-3, interleukin-10, and tumor necrosis factor-α in the penumbral areas. All these changes were blocked or alleviated by norbinaltorphimine. CONCLUSIONS κ opioid receptors were up-regulated and played a critical role in brain ischemia and reperfusion. κ opioid receptor activation could potentially protect the brain and improve neurologic outcome via blood-brain barrier protection, apoptosis reduction, and inflammation inhibition.
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Affiliation(s)
- Chunhua Chen
- 1Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.2Department of Anesthesiology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.3Department of Anesthesiology, Renji Hospital, Jiaotong University School of Medicine, Shanghai, China.4Department of Biology, University of Pennsylvania, Philadelphia, PA
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27
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Sheu JR, Chen ZC, Jayakumar T, Chou DS, Yen TL, Lee HN, Pan SH, Hsia CH, Yang CH, Hsieh CY. A novel indication of platonin, a therapeutic immunomodulating medicine, on neuroprotection against ischemic stroke in mice. Sci Rep 2017; 7:42277. [PMID: 28165057 PMCID: PMC5292718 DOI: 10.1038/srep42277] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Accepted: 01/09/2017] [Indexed: 12/19/2022] Open
Abstract
Thrombosis and stroke are major causes of disability and death worldwide. However, the regular antithrombotic drugs may have unsatisfactory results and side effects. Platonin, a cyanine photosensitizing dye, has been used to treat trauma, ulcers and some acute inflammation. Here, we explored the neuroprotective effects of platonin against middle cerebral artery occlusion (MCAO)-induced ischemic stroke in mice. Platonin(200 μg/kg) substantially reduced cerebral infarct volume, brain edema, neuronal cell death and neurological deficit scores, and improved the MCAO-reduced locomotor activity and rotarod performance. Platonin(5–10 μM) potently inhibited platelet aggregation and c-Jun NH2-terminal kinase (JNK) phosphorylation in collagen-activated platelets. The antiaggregation effect did not affect bleeding time but increased occlusion time in platonin(100 and 200 μg/kg)-treated mice. Platonin(2–10 μM) was potent in diminishing collagen- and Fenton reaction-induced ∙OH formation. Platonin(5–10 μM) also suppressed the expression of nitric oxide, inducible nitric oxide synthase, cyclooxygenase-2, interleukin-1β, and JNK phosphorylation in lipopolysaccharide-stimulated macrophages. MCAO-induced expression of 3-nitrotyrosine and Iba1 was apparently attenuated in platonin(200 μg/kg)-treated mice. In conclusion, platonin exhibited remarkable neuroprotective properties against MCAO-induced ischemia in a mouse model through its antiaggregation, antiinflammatory and antiradical properties. The observed therapeutic efficacy of platonin may consider being a novel medcine against ischemic stroke.
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Affiliation(s)
- Joen-Rong Sheu
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Zhih-Cherng Chen
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Cardiology, Chi-Mei Medical Center, Tainan City, Taiwan.,Department of Pharmacy, Chia Nan University of Pharmacy &Science, Tainan City, Taiwan
| | - Thanasekaran Jayakumar
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Duen-Suey Chou
- Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Ting-Lin Yen
- Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Hsing-Ni Lee
- Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Szu-Han Pan
- Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chih-Hsuan Hsia
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chih-Hao Yang
- Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Cheng-Ying Hsieh
- Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei, Taiwan
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28
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Wang H, Song Y, Hao D, Du L. Molecular mechanisms for N G-nitro-L-arginine methyl ester action against cerebral ischemia–reperfusion injury-induced blood–brain barrier dysfunction. ASIAN BIOMED 2017. [DOI: 10.5372/1905-7415.0802.277] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Abstract
Background: Ischemic stroke, an acute neurological injury lacking an effective therapy, is a leading cause of death worldwide. The unmet need in stroke research is to identify viable therapeutic targets and to understand their interplay during cerebral ischemia-reperfusion (I/R) injury.
Objective: To explore the protective effects and molecular mechanism of NG-nitro-L-arginine methyl ester (L-NAME) in cerebral ischemia-reperfusion injury-induced blood-brain barrier (BBB) dysfunction.
Methods: Two hundred fifty-six rats were randomly assigned to a sham operation group, I/R group, and I/R with L-NAME treatment group. Brain water content was determined by calculating dry/wet weight. The permeability of the BBB was observed using an electron microscope and by determining the Evans Blue leakage from brain tissue on the ischemic side. The expression of brain MMP-9 and GFAP was determined using an immunohistochemical method. The expression of ZO-1 protein was determined by western blotting.
Results: We found that L-NAME remarkably attenuated the permeability of the BBB after I/R as assessed by Evans Blue leakage and brain water content (p < 0.05). This was further confirmed by examination of the ultrastructural morphology of the BBB using a transmission electron microscope. Furthermore, we found that expression of the zonae occludens-1 (ZO-1) was decreased in endothelial cells, and expression of MMP-9 and GFAP was increased in the basement membrane and astrocyte end-feet in vehicle control groups, respectively, but these changes could be prevented by L-NAME pretreatment.
Conclusion: These results suggested that the neuroprotective effects of L-NAME against BBB damage induced by I/R might be related to the upregulation of tight junction proteins and inhibition of MMP-9 and GFAP expression. L-NAME can be used as a potential MMP-9-based multiple targeting therapeutic strategy in cerebral I/R injury.
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Affiliation(s)
- Hanghui Wang
- Department of Ultrasound, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China China
- Hong Hui Hospital, Xi’an Jiaotong University College of Medicine, Shaanxi 710054, China
| | - Yixin Song
- Department of Ultrasound, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China China
- Hong Hui Hospital, Xi’an Jiaotong University College of Medicine, Shaanxi 710054, China
| | - Dingjun Hao
- Department of Ultrasound, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China China
- Correspondence to: Hong Hui Hospital, Xi’an Jiaotong University College of Medicine, Shaanxi, 710054, China
| | - Lianfang Du
- Department of Ultrasound, Shanghai First People’s Hospital Afiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200080, China China
- Hong Hui Hospital, Xi’an Jiaotong University College of Medicine, Shaanxi 710054, China
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29
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Li PY, Wang X, Stetler RA, Chen J, Yu WF. Anti-inflammatory signaling: the point of convergence for medical gases in neuroprotection against ischemic stroke. Med Gas Res 2016; 6:227-231. [PMID: 28217296 PMCID: PMC5223315 DOI: 10.4103/2045-9912.196906] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Recent studies suggest that a variety of medical gases confer neuroprotective effects against cerebral ischemia, extending function beyond their regular clinical applications. The mechanisms underlying ischemic neuroprotection afforded by medical gases have been intensively studied over the past two decades. A number of signaling pathways have been proposed, among which anti-inflammatory signaling has been proven to be critical. Pursuit of the role for anti-inflammatory signaling may shed new light on the translational application of medical gas-afforded neuroprotection.
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Affiliation(s)
- Pei-Ying Li
- Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Xin Wang
- Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - R Anne Stetler
- Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Jun Chen
- Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Wei-Feng Yu
- Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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30
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Chamorro Á, Amaro S, Castellanos M, Gomis M, Urra X, Blasco J, Arenillas JF, Román LS, Muñoz R, Macho J, Cánovas D, Marti-Fabregas J, Leira EC, Planas AM. Uric acid therapy improves the outcomes of stroke patients treated with intravenous tissue plasminogen activator and mechanical thrombectomy. Int J Stroke 2016; 12:377-382. [PMID: 28345429 DOI: 10.1177/1747493016684354] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background Numerous neuroprotective drugs have failed to show benefit in the treatment of acute ischemic stroke, making the search for new treatments imperative. Uric acid is an endogenous antioxidant making it a drug candidate to improve stroke outcomes. Aim To report the effects of uric acid therapy in stroke patients receiving intravenous thrombolysis and mechanical thrombectomy. Methods Forty-five patients with proximal vessel occlusions enrolled in the URICO-ICTUS trial received intravenous recombinant tissue plasminogen activator within 4.5 h after stroke onset and randomized to intravenous 1000 mg uric acid or placebo (NCT00860366). These patients also received mechanical thrombectomy because a brain computed tomogaphy angiography confirmed the lack of proximal recanalization at the end of systemic thrombolysis. The primary outcome was good functional outcome at 90 days (modified Rankin Score 0-2). Safety outcomes included mortality, symptomatic intracerebral bleeding, and gout attacks. Results The rate of successful revascularization was >80% in the uric acid and the placebo groups but good functional outcome was observed in 16 out of 24 (67%) patients treated with uric acid and 10 out of 21 (48%) treated with placebo (adjusted Odds Ratio, 6.12 (95% CI 1.08-34.56)). Mortality was observed in two out of 24 (8.3%) patients treated with uric acid and one out of 21 (4.8%) treated with placebo (adjusted Odds Ratio, 3.74 (95% CI 0.06-226.29)). Symptomatic cerebral bleeding and gout attacks were similar in both groups. Conclusions Uric acid therapy was safe and improved stroke outcomes in stroke patients receiving intravenous thrombolysis followed by thrombectomy. Validation of this simple strategy in a larger trial is urgent.
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Affiliation(s)
| | | | - Mar Castellanos
- 2 Complejo Hospitalario Universitario A Coruña, A Coruña, Spain
| | | | | | | | | | | | | | | | | | | | - Enrique C Leira
- 8 University of Iowa Carver College of Medicine, Iowa City, USA
| | - Anna M Planas
- 9 Institute for Biomedical Research of Barcelona (IIBB), Barcelona, Spain
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31
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Chamorro Á, Dirnagl U, Urra X, Planas AM. Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. Lancet Neurol 2016; 15:869-881. [DOI: 10.1016/s1474-4422(16)00114-9] [Citation(s) in RCA: 556] [Impact Index Per Article: 61.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Revised: 01/15/2016] [Accepted: 03/03/2016] [Indexed: 01/04/2023]
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32
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Li W, Watts L, Long J, Zhou W, Shen Q, Jiang Z, Li Y, Duong TQ. Spatiotemporal changes in blood-brain barrier permeability, cerebral blood flow, T2 and diffusion following mild traumatic brain injury. Brain Res 2016; 1646:53-61. [PMID: 27208495 DOI: 10.1016/j.brainres.2016.05.036] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Revised: 05/12/2016] [Accepted: 05/18/2016] [Indexed: 12/21/2022]
Abstract
The blood-brain barrier (BBB) can be impaired following traumatic brain injury (TBI), however the spatiotemporal dynamics of BBB leakage remain incompletely understood. In this study, we evaluated the spatiotemporal evolution of BBB permeability using dynamic contrast-enhanced MRI and measured the volume transfer coefficient (K(trans)), a quantitative measure of contrast agent leakage across the blood and extravascular compartment. Measurements were made in a controlled cortical impact (CCI) model of mild TBI in rats from 1h to 7 days following TBI. The results were compared with cerebral blood flow, T2 and diffusion MRI from the same animal. Spatially, K(trans) changes were localized to superficial cortical layers within a 1mm thickness, which was dramatically different from the changes in cerebral blood flow, T2 and diffusion, which were localized to not only the superficial layers but also to brain regions up to 2.2mm from the cortical surface. Temporally, K(trans) changes peaked at day 3, similar to CBF and ADC changes, but differed from T2 and FA, whose changes peaked on day 2. The pattern of superficial cortical layer localization of K(trans) was consistent with patterns revealed by Evans Blue extravasation. Collectively, these results suggest that BBB disruption, edema formation, blood flow disturbance and diffusion changes are related to different components of the mechanical impact, and may play different roles in determining injury progression and tissue fate processes following TBI.
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Affiliation(s)
- Wei Li
- Research Imaging Institute, University of Texas Health Science Center at San Antonio, TX 78229, USA; Department of Ophthalmology, University of Texas Health Science Center at San Antonio, TX 78229, USA
| | - Lora Watts
- Research Imaging Institute, University of Texas Health Science Center at San Antonio, TX 78229, USA; Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, TX 78229, USA; Department of Neurology, University of Texas Health Science Center at San Antonio, TX 78229, USA
| | - Justin Long
- Research Imaging Institute, University of Texas Health Science Center at San Antonio, TX 78229, USA
| | - Wei Zhou
- Research Imaging Institute, University of Texas Health Science Center at San Antonio, TX 78229, USA
| | - Qiang Shen
- Research Imaging Institute, University of Texas Health Science Center at San Antonio, TX 78229, USA
| | - Zhao Jiang
- Research Imaging Institute, University of Texas Health Science Center at San Antonio, TX 78229, USA
| | - Yunxia Li
- Research Imaging Institute, University of Texas Health Science Center at San Antonio, TX 78229, USA
| | - Timothy Q Duong
- Research Imaging Institute, University of Texas Health Science Center at San Antonio, TX 78229, USA; Department of Ophthalmology, University of Texas Health Science Center at San Antonio, TX 78229, USA.
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33
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Chen Y, Liu P, Qi R, Wang YH, Liu G, Wang C. Severe hypertriglyceridemia does not protect from ischemic brain injury in gene-modified hypertriglyceridemic mice. Brain Res 2016; 1639:161-73. [DOI: 10.1016/j.brainres.2016.03.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Revised: 03/02/2016] [Accepted: 03/03/2016] [Indexed: 12/12/2022]
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34
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Chen Y, Wei L, Tian J, Wang YH, Liu G, Wang C. Seinpin knockout exacerbates cerebral ischemia/reperfusion damage in mice. Biochem Biophys Res Commun 2016; 474:377-383. [PMID: 27109482 DOI: 10.1016/j.bbrc.2016.04.116] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 04/20/2016] [Indexed: 01/17/2023]
Abstract
BACKGROUND AND PURPOSE Seipin, which regulates adipocyte differentiation and lipolysis, inducing severe lipodystrophy and metabolic syndromes, is also highly expressed in the nervous system and affects some neurological diseases. However, the impacts of seipin in stroke remain unclear. METHODS AND RESULTS In this study, we subjected seipin knockout mice to cerebral ischemia/reperfusion injury and found that seipin knockout mice exhibited exacerbated neurological disorder and enlarged infarct size, companied by blood-brain barrier (BBB) damages. Furthermore, we showed that seipin knockout aggravated endoplasmic reticulum (ER) stress and significantly increased glucose levels, decreased leptin and adiponectin levels in mouse plasma. CONCLUSIONS Our findings reveal that seipin knockout exacerbates cerebral I/R-induced damages by increasing BBB permeability, amplifying ER stress and increasing glucose levels, as well as decreasing leptin and adiponectin levels, indicating that seipin may be a potential therapeutic target for stroke.
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Affiliation(s)
- Yong Chen
- Department of Neurology, People's Hospital of Deyang City, Taishian North Road 173, Deyang City, 618000, China
| | - Lili Wei
- Institute of Cardiovascular Sciences, Peking University Health Science Center, 38 Xueyuan Rd, Hai Dian District, 100083, Beijing, China
| | - Jing Tian
- Department of Neurology, People's Hospital of Deyang City, Taishian North Road 173, Deyang City, 618000, China
| | - Yu-Hui Wang
- Institute of Cardiovascular Sciences, Peking University Health Science Center, 38 Xueyuan Rd, Hai Dian District, 100083, Beijing, China
| | - George Liu
- Institute of Cardiovascular Sciences, Peking University Health Science Center, 38 Xueyuan Rd, Hai Dian District, 100083, Beijing, China.
| | - Chun Wang
- Department of Neurology, People's Hospital of Deyang City, Taishian North Road 173, Deyang City, 618000, China.
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35
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Turner RJ, Sharp FR. Implications of MMP9 for Blood Brain Barrier Disruption and Hemorrhagic Transformation Following Ischemic Stroke. Front Cell Neurosci 2016; 10:56. [PMID: 26973468 PMCID: PMC4777722 DOI: 10.3389/fncel.2016.00056] [Citation(s) in RCA: 341] [Impact Index Per Article: 37.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Accepted: 02/22/2016] [Indexed: 02/03/2023] Open
Abstract
Numerous studies have documented increases in matrix metalloproteinases (MMPs), specifically MMP-9 levels following stroke, with such perturbations associated with disruption of the blood brain barrier (BBB), increased risk of hemorrhagic complications, and worsened outcome. Despite this, controversy remains as to which cells release MMP-9 at the normal and pathological BBB, with even less clarity in the context of stroke. This may be further complicated by the influence of tissue plasminogen activator (tPA) treatment. The aim of the present review is to examine the relationship between neutrophils, MMP-9 and tPA following ischemic stroke to elucidate which cells are responsible for the increases in MMP-9 and resultant barrier changes and hemorrhage observed following stroke.
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Affiliation(s)
- Renée J Turner
- Discipline of Anatomy and Pathology, Adelaide Centre for Neuroscience Research, School of Medicine, The University of Adelaide Adelaide, SA, Australia
| | - Frank R Sharp
- Department of Neurology, MIND Institute, University of California at Davis Medical Center Sacramento, CA, USA
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36
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Abstract
Stroke is a leading cause of death and long-term disability. Methylene blue, a drug grandfathered by the Food and Drug Administration with a long history of safe usage in humans for treating methemoglobinemia and cyanide poisoning, has recently been shown to be neuroprotective in neurodegenerative diseases and brain injuries. The goal of this paper is to review studies on methylene blue in experimental stroke models.
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Affiliation(s)
- Zhao Jiang
- Research Imaging Institute, Radiology, University of Texas Health Science Center, San Antonio, Texas, USA
| | - Timothy Q Duong
- Department of Ophthalmology, Radiology and Physiology, University of Texas Health Science Center, San Antonio, Texas, USA
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37
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Dalkara T, Alarcon-Martinez L. Cerebral microvascular pericytes and neurogliovascular signaling in health and disease. Brain Res 2015; 1623:3-17. [DOI: 10.1016/j.brainres.2015.03.047] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2015] [Revised: 03/10/2015] [Accepted: 03/27/2015] [Indexed: 02/07/2023]
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Ventura NM, Jin AY, Tse MY, Peterson NT, Andrew RD, Mewburn JD, Pang SC. Maternal hypertension programs increased cerebral tissue damage following stroke in adult offspring. Mol Cell Biochem 2015; 408:223-33. [PMID: 26169981 DOI: 10.1007/s11010-015-2498-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2015] [Accepted: 06/19/2015] [Indexed: 12/01/2022]
Abstract
The maternal system is challenged with many physiological changes throughout pregnancy to prepare the body to meet the metabolic needs of the fetus and for delivery. Many pregnancies, however, are faced with pathological stressors or complications that significantly impact maternal health. A shift in this paradigm is now beginning to investigate the implication of pregnancy complications on the fetus and their continued influence on offspring disease risk into adulthood. In this investigation, we sought to determine whether maternal hypertension during pregnancy alters the cerebral response of adult offspring to acute ischemic stroke. Atrial natriuretic peptide gene-disrupted (ANP(-/-)) mothers exhibit chronic hypertension that escalates during pregnancy. Through comparison of heterozygote offspring born from either normotensive (ANP(+/-WT)) or hypertensive (ANP(+/-KO)) mothers, we have demonstrated that offspring exposed to maternal hypertension exhibit larger cerebral infarct volumes following middle cerebral artery occlusion. Observation of equal baseline cardiovascular measures, cerebrovascular structure, and cerebral blood volumes between heterozygote offspring suggests no added influences on offspring that would contribute to adverse cerebral response post-stroke. Cerebral mRNA expression of endothelin and nitric oxide synthase vasoactive systems demonstrated up-regulation of Et-1 and Nos3 in ANP(+/-KO) mice and thus an enhanced acute vascular response compared to ANP(+/-WT) counterparts. Gene expression of Na(+)/K(+) ATPase channel isoforms, Atp1a1, Atp1a3, and Atp1b1, displayed no significant differences. These investigations are the first to demonstrate a fetal programming effect between maternal hypertension and adult offspring stroke outcome. Further mechanistic studies are required to complement epidemiological evidence of this phenomenon in the literature.
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Affiliation(s)
- Nicole M Ventura
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
| | - Albert Y Jin
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada. .,Department of Medicine (Neurology), Kingston General Hospital, Kingston, ON, Canada.
| | - M Yat Tse
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
| | - Nichole T Peterson
- Department of Medicine (Neurology), Kingston General Hospital, Kingston, ON, Canada.
| | - R David Andrew
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada. .,Centre for Neuroscience, Queen's University, Kingston, ON, Canada.
| | | | - Stephen C Pang
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
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Wang B, Tian S, Wang J, Han F, Zhao L, Wang R, Ning W, Chen W, Qu Y. Intraperitoneal administration of thioredoxin decreases brain damage from ischemic stroke. Brain Res 2015; 1615:89-97. [DOI: 10.1016/j.brainres.2015.04.033] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Revised: 04/15/2015] [Accepted: 04/17/2015] [Indexed: 11/26/2022]
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Abdelsaid M, Prakash R, Li W, Coucha M, Hafez S, Johnson MH, Fagan SC, Ergul A. Metformin treatment in the period after stroke prevents nitrative stress and restores angiogenic signaling in the brain in diabetes. Diabetes 2015; 64:1804-17. [PMID: 25524911 PMCID: PMC4407857 DOI: 10.2337/db14-1423] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Accepted: 12/11/2014] [Indexed: 12/04/2022]
Abstract
Diabetes impedes vascular repair and causes vasoregression in the brain after stroke, but mechanisms underlying this response are still unclear. We hypothesized that excess peroxynitrite formation in diabetic ischemia/reperfusion (I/R) injury inactivates the p85 subunit of phosphoinositide 3-kinase (PI3K) by nitration and diverts the PI3K-Akt survival signal to the p38-mitogen-activated protein kinase apoptosis pathway. Nitrotyrosine (NY), Akt and p38 activity, p85 nitration, and caspase-3 cleavage were measured in brains from control, diabetic (GK), or metformin-treated GK rats subjected to sham or stroke surgery and in brain microvascular endothelial cells (BMVECs) from Wistar and GK rats subjected to hypoxia/reoxygenation injury. GK rat brains showed increased NY, caspase-3 cleavage, and p38 activation and decreased Akt activation. Metformin attenuated stroke-induced nitrative signaling in GK rats. GK rat BMVECs showed increased basal nitrative stress compared with controls. A second hit by hypoxia/reoxygenation injury dramatically increased the nitration of p85 and activation of p38 but decreased Akt. These effects were associated with impairment of angiogenic response and were restored by treatment with the peroxynitrite scavenger 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron III chloride or the nitration inhibitor epicatechin. Our results provide evidence that I/R-induced peroxynitrite inhibits survival, induces apoptosis, and promotes peroxynitrite as a novel therapeutic target for the improvement of reparative angiogenesis after stroke in diabetes.
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Affiliation(s)
- Mohammed Abdelsaid
- Charlie Norwood Veterans Administration Medical Center, Augusta, GA Department of Physiology, Georgia Regents University, Augusta, GA
| | - Roshini Prakash
- Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA
| | - Weiguo Li
- Charlie Norwood Veterans Administration Medical Center, Augusta, GA Department of Physiology, Georgia Regents University, Augusta, GA
| | - Maha Coucha
- Department of Physiology, Georgia Regents University, Augusta, GA
| | - Sherif Hafez
- Charlie Norwood Veterans Administration Medical Center, Augusta, GA Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA
| | | | - Susan C Fagan
- Charlie Norwood Veterans Administration Medical Center, Augusta, GA Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA
| | - Adviye Ergul
- Charlie Norwood Veterans Administration Medical Center, Augusta, GA Department of Physiology, Georgia Regents University, Augusta, GA Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA
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Spescha RD, Klohs J, Semerano A, Giacalone G, Derungs RS, Reiner MF, Rodriguez Gutierrez D, Mendez-Carmona N, Glanzmann M, Savarese G, Kränkel N, Akhmedov A, Keller S, Mocharla P, Kaufmann MR, Wenger RH, Vogel J, Kulic L, Nitsch RM, Beer JH, Peruzzotti-Jametti L, Sessa M, Lüscher TF, Camici GG. Post-ischaemic silencing of p66Shc reduces ischaemia/reperfusion brain injury and its expression correlates to clinical outcome in stroke. Eur Heart J 2015; 36:1590-600. [PMID: 25904764 DOI: 10.1093/eurheartj/ehv140] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 04/06/2015] [Indexed: 12/25/2022] Open
Abstract
AIM Constitutive genetic deletion of the adaptor protein p66(Shc) was shown to protect from ischaemia/reperfusion injury. Here, we aimed at understanding the molecular mechanisms underlying this effect in stroke and studied p66(Shc) gene regulation in human ischaemic stroke. METHODS AND RESULTS Ischaemia/reperfusion brain injury was induced by performing a transient middle cerebral artery occlusion surgery on wild-type mice. After the ischaemic episode and upon reperfusion, small interfering RNA targeting p66(Shc) was injected intravenously. We observed that post-ischaemic p66(Shc) knockdown preserved blood-brain barrier integrity that resulted in improved stroke outcome, as identified by smaller lesion volumes, decreased neurological deficits, and increased survival. Experiments on primary human brain microvascular endothelial cells demonstrated that silencing of the adaptor protein p66(Shc) preserves claudin-5 protein levels during hypoxia/reoxygenation by reducing nicotinamide adenine dinucleotide phosphate oxidase activity and reactive oxygen species production. Further, we found that in peripheral blood monocytes of acute ischaemic stroke patients p66(Shc) gene expression is transiently increased and that this increase correlates with short-term neurological outcome. CONCLUSION Post-ischaemic silencing of p66(Shc) upon reperfusion improves stroke outcome in mice while the expression of p66(Shc) gene correlates with short-term outcome in patients with ischaemic stroke.
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Affiliation(s)
- R D Spescha
- Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Schlieren CH-8952, Switzerland Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
| | - J Klohs
- Institute for Biomedical Engineering, Swiss Federal Institute of Technology Zurich (ETHZ), Zurich, Switzerland
| | - A Semerano
- Department of Neurology, San Raffaele Scientific Institute, Milan, Italy
| | - G Giacalone
- Department of Neurology, San Raffaele Scientific Institute, Milan, Italy
| | - R S Derungs
- Division of Psychiatry Research, University of Zurich, Schlieren, Switzerland
| | - M F Reiner
- Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Schlieren CH-8952, Switzerland Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
| | - D Rodriguez Gutierrez
- Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Schlieren CH-8952, Switzerland
| | - N Mendez-Carmona
- Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Schlieren CH-8952, Switzerland
| | - M Glanzmann
- Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Schlieren CH-8952, Switzerland Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
| | - G Savarese
- Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Schlieren CH-8952, Switzerland Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
| | - N Kränkel
- Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Schlieren CH-8952, Switzerland Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland Department of Cardiology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - A Akhmedov
- Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Schlieren CH-8952, Switzerland Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
| | - S Keller
- Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Schlieren CH-8952, Switzerland Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
| | - P Mocharla
- Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Schlieren CH-8952, Switzerland Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
| | - M R Kaufmann
- Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland Institute of Physiology, University of Zurich, Zurich, Switzerland
| | - R H Wenger
- Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland Institute of Physiology, University of Zurich, Zurich, Switzerland
| | - J Vogel
- Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland
| | - L Kulic
- Division of Psychiatry Research, University of Zurich, Schlieren, Switzerland
| | - R M Nitsch
- Division of Psychiatry Research, University of Zurich, Schlieren, Switzerland
| | - J H Beer
- Department of Internal Medicine, Cantonal Hospital of Baden, Baden, Switzerland
| | | | - M Sessa
- Department of Neurology, San Raffaele Scientific Institute, Milan, Italy
| | - T F Lüscher
- Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Schlieren CH-8952, Switzerland Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland Cardiology, University Heart Center, University Hospital, Zurich, Switzerland
| | - G G Camici
- Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Schlieren CH-8952, Switzerland Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
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Feng Q, Wang YI, Yang Y. Neuroprotective effect of interleukin-6 in a rat model of cerebral ischemia. Exp Ther Med 2015; 9:1695-1701. [PMID: 26136879 DOI: 10.3892/etm.2015.2363] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2014] [Accepted: 03/04/2015] [Indexed: 11/06/2022] Open
Abstract
Interleukin (IL)-6 is known to be a key cytokine in immune regulation in addition to serving crucial functions in various autoimmune diseases; however, the neuroprotective potential of IL-6 has not been fully investigated. The aim of the present study was to investigate the neuroprotective effects of the inflammatory cytokine IL-6 in a rat model of cerebral ischemia. Rat cerebral ischemia was induced by intraluminal middle cerebral artery occlusion. Following treatment with 500 or 50 ng IL-6, the infarct volumes and symptoms of neurological deficit were ameliorated. Furthermore, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining suggested that the IL-6 treatment reduced neuronal apoptosis in vivo, which was consistent with a lower percentage of annexin V- and caspase-3-positive cortical neurons. In addition, IL-6 in vitro induced the phosphorylation of signal transducer and activator of transcription (STAT) 3 and the expression of induced myeloid leukemia cell differentiation protein Mcl-1, but not the expression of B-cell lymphoma 2, suggesting the activation of the Janus kinase/STAT pathway by IL-6. IL-6 also appeared to be involved in the regulation of cytokine secretion and blood-brain barrier (BBB) integrity in cerebral ischemia. IL-6 downregulated a number of inflammatory cytokines, including tumor necrosis factor-α and IL-1β, as well as myeloperoxidase activity, indicating the accumulation of granulocytes in the ischemic brain tissue. IL-6 was also observed to support the integrity of the BBB by reducing Evans blue leakage in vivo and suppressing the expression of matrix metalloproteinase-9 in ischemic brain tissue. In conclusion, the results of the present study indicate that the neuroprotective effects of IL-6 in cerebral ischemia are the result of a range of processes, including the modulation of cell apoptosis, cytokine secretion and the integrity of the BBB. IL-6 could therefore be used as a therapeutic agent in clinical practice.
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Affiliation(s)
- Qilin Feng
- Department of Pharmacy, Central Hospital of Wuhan, Wuhan, Hubei 430030, P.R. China
| | - Y I Wang
- Department of Pharmacy, Central Hospital of Wuhan, Wuhan, Hubei 430030, P.R. China
| | - Yingda Yang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
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Yemisci M, Caban S, Gursoy-Ozdemir Y, Lule S, Novoa-Carballal R, Riguera R, Fernandez-Megia E, Andrieux K, Couvreur P, Capan Y, Dalkara T. Systemically administered brain-targeted nanoparticles transport peptides across the blood-brain barrier and provide neuroprotection. J Cereb Blood Flow Metab 2015; 35:469-75. [PMID: 25492116 PMCID: PMC4348388 DOI: 10.1038/jcbfm.2014.220] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 11/07/2014] [Accepted: 11/11/2014] [Indexed: 11/09/2022]
Abstract
Although growth factors and anti-apoptotic peptides have been shown to be neuroprotective in stroke models, translation of these experimental findings to clinic is hampered by limited penetration of peptides to the brain. Here, we show that a large peptide like the basic fibroblast growth factor (bFGF) and a small peptide inhibitor of caspase-3 (z-DEVD-FMK) can effectively be transported to the brain after systemic administration by incorporating these peptides to brain-targeted nanoparticles (NPs). Chitosan NPs were loaded with peptides and then functionalized by conjugating with antibodies directed against the transferrin receptor-1 on brain endothelia to induce receptor-mediated transcytosis across the blood-brain barrier (BBB). Pre-ischemic systemic administration of bFGF- or z-DEVD-FMK-loaded NPs significantly decreased the infarct volume after 2-hour middle cerebral artery occlusion and 22-hour reperfusion in mice. Co-administration of bFGF- or z-DEVD-FMK-loaded NPs reduced the infarct volume further and provided a 3-hour therapeutic window. bFGF-loaded NPs were histologically detected in the brain parenchyma and also restored ischemia-induced Akt dephosphorylation. The neuroprotection was not observed when receptor-mediated transcytosis was inhibited with imatinib or when bFGF-loaded NPs were not conjugated with the targeting antibody, which enables them to cross the BBB. Nanoparticles targeted to brain are promising drug carriers to transport large as well as small BBB-impermeable therapeutics for neuroprotection against stroke.
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Affiliation(s)
- Muge Yemisci
- Department of Neurology, Faculty of Medicine, Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey
| | - Secil Caban
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey
| | - Yasemin Gursoy-Ozdemir
- Department of Neurology, Faculty of Medicine, Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey
| | - Sevda Lule
- Department of Neurology, Faculty of Medicine, Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey
| | - Ramon Novoa-Carballal
- Department of Organic Chemistry and Center for Research in Biological Chemistry and Molecular Materials (CIQUS), University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Ricardo Riguera
- Department of Organic Chemistry and Center for Research in Biological Chemistry and Molecular Materials (CIQUS), University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Eduardo Fernandez-Megia
- Department of Organic Chemistry and Center for Research in Biological Chemistry and Molecular Materials (CIQUS), University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Karine Andrieux
- Institut Galien Paris-Sud UMR CNRS 8612, Faculty of Pharmacy, University of Paris-Sud XI, Chátenay-Malabry, France
| | - Partick Couvreur
- Institut Galien Paris-Sud UMR CNRS 8612, Faculty of Pharmacy, University of Paris-Sud XI, Chátenay-Malabry, France
| | - Yilmaz Capan
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey
| | - Turgay Dalkara
- Department of Neurology, Faculty of Medicine, Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey
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Wang MD, Wang Y, Xia YP, Dai JW, Gao L, Wang SQ, Wang HJ, Mao L, Li M, Yu SM, Tu Y, He QW, Zhang GP, Wang L, Xu GZ, Xu HB, Zhu LQ, Hu B. High Serum MiR-130a Levels Are Associated with Severe Perihematomal Edema and Predict Adverse Outcome in Acute ICH. Mol Neurobiol 2015; 53:1310-1321. [PMID: 25631713 DOI: 10.1007/s12035-015-9099-0] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Accepted: 01/12/2015] [Indexed: 12/12/2022]
Abstract
The development and/or progression of perihematomal edema (PHE) in patients with acute spontaneous intracerebral hemorrhage (ICH) vary substantially with different individuals. Although hematoma volume is a useful indicator for predicting PHE, its predictive power was not good at the early stage of ICH. Better predictors are urgently needed. In this study, we found that miR-130a was elevated in the serum of ICH patients and was an independent indicator positively associated with PHE volume within the first 3 days after onset. The R (2) was further evaluated when it is used in combination with hematoma mass. Serum miR-130a levels were associated with clinical outcome (National Institute of Health Stroke Scale (NIHSS) scores at day 14 and modified Rankin Scale (mRS) scores at day 90) only in patients with deep hematoma. Moreover, miR-130a was significantly increased in rat serum and perihematomal tissues and was in line with the change in brain edema. MiR-130a inhibitors reduced brain edema, blood-brain barrier (BBB) permeability, and increased neurological deficit scores, and miR-130a mimics increased monolayer permeability. Thrombin-stimulated brain microvascular endothelial cells (BMECs) were a main source of miR-130a under ICH. In the experimental model, the elevated miR-130a level was accompanied by the decreased caveolin-1 and increased matrix metalloproleinase (MMP)-2/9. Meanwhile, caveolin-1 (cav-1) was reduced by miR-130a mimics, accompanied by an increase in MMP-2/9 expression. The upregulated MMP-2/9 was then downregulated by cavtratin, a cav-1 scaffolding domain peptide. This regulation mechanism was authenticated in a thrombin-induced cellular ICH model. Our results suggest that serum miR-130a may serve as a useful early biomarker for monitoring post-ICH PHE and predicting prognosis and may be helpful in the decision-making of individualized therapy.
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Affiliation(s)
- Meng-Die Wang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue, Wuhan, 430022, People's Republic of China
| | - Yong Wang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue, Wuhan, 430022, People's Republic of China
| | - Yuan-Peng Xia
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue, Wuhan, 430022, People's Republic of China
| | - Jing-Wen Dai
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue, Wuhan, 430022, People's Republic of China
| | - Lin Gao
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue, Wuhan, 430022, People's Republic of China
| | - Si-Qi Wang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue, Wuhan, 430022, People's Republic of China
| | - Hai-Jun Wang
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue, Wuhan, 430022, People's Republic of China
| | - Ling Mao
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue, Wuhan, 430022, People's Republic of China
| | - Man Li
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue, Wuhan, 430022, People's Republic of China
| | - Shi-Meng Yu
- Department of Neurology, The Attached Hospital of Xinyang Vocational Technical College, Daqing Road, Xinyang, 464000, People's Republic of China
| | - Yan Tu
- Department of Geratology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Donghu Road, Wuhan, 430077, People's Republic of China
| | - Quan-Wei He
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue, Wuhan, 430022, People's Republic of China
| | - Guo-Peng Zhang
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue, Wuhan, 430030, People's Republic of China
| | - Lei Wang
- Department of Neurosurgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Shengli Street, Wuhan, 430014, People's Republic of China
| | - Guo-Zheng Xu
- Department of Neurosurgery, Wuhan General Hospital of Guangzhou Command, Wuluo Road, Wuhan, 430070, People's Republic of China
| | - Hai-Bo Xu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue, Wuhan, 430022, People's Republic of China
| | - Ling-Qiang Zhu
- Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue, Wuhan, 430030, People's Republic of China.
| | - Bo Hu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue, Wuhan, 430022, People's Republic of China. .,Key Laboratory of Neurological Disease, Ministry of Education, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue, Wuhan, 430030, People's Republic of China.
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Momordica charantia polysaccharides could protect against cerebral ischemia/reperfusion injury through inhibiting oxidative stress mediated c-Jun N-terminal kinase 3 signaling pathway. Neuropharmacology 2014; 91:123-34. [PMID: 25510970 DOI: 10.1016/j.neuropharm.2014.11.020] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 11/01/2014] [Accepted: 11/19/2014] [Indexed: 12/15/2022]
Abstract
Momordica charantia (MC) is a medicinal plant for stroke treatment in Traditional Chinese Medicine, but its active compounds and molecular targets are unknown yet. M. charantia polysaccharide (MCP) is one of the important bioactive components in MC. In the present study, we tested the hypothesis that MCP has neuroprotective effects against cerebral ischemia/reperfusion injury through scavenging superoxide (O2(-)), nitric oxide (NO) and peroxynitrite (ONOO(-)) and inhibiting c-Jun N-terminal protein kinase (JNK3) signaling cascades. We conducted experiments with in vivo global and focal cerebral ischemia/reperfusion rat models and in vitro oxygen glucose deprivation (OGD) neural cells. The effects of MCP on apoptotic cell death and infarction volume, the bioactivities of scavenging O2(-), NO and ONOO(-), inhibiting lipid peroxidation and modulating JNK3 signaling pathway were investigated. Major results are summarized as below: (1) MCP dose-dependently attenuated apoptotic cell death in neural cells under OGD condition in vitro and reduced infarction volume in ischemic brains in vivo; (2) MCP had directing scavenging effects on NO, O2(-) and ONOO(-) and inhibited lipid peroxidation; (3) MCP inhibited the activations of JNK3/c-Jun/Fas-L and JNK3/cytochrome C/caspases-3 signaling cascades in ischemic brains in vivo. Taken together, we conclude that MCP could be a promising neuroprotective ingredient of M. charantia and its mechanisms could be at least in part attributed to its antioxidant activities and inhibiting JNK3 signaling cascades during cerebral ischemia/reperfusion injury.
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Li W, Long JA, Watts LT, Jiang Z, Shen Q, Li Y, Duong TQ. A quantitative MRI method for imaging blood-brain barrier leakage in experimental traumatic brain injury. PLoS One 2014; 9:e114173. [PMID: 25478693 PMCID: PMC4257611 DOI: 10.1371/journal.pone.0114173] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 11/04/2014] [Indexed: 01/21/2023] Open
Abstract
Blood-brain barrier (BBB) disruption is common following traumatic brain injury (TBI). Dynamic contrast enhanced (DCE) MRI can longitudinally measure the transport coefficient Ktrans which reflects BBB permeability. Ktrans measurements however are not widely used in TBI research because it is generally considered to be noisy and possesses low spatial resolution. We improved spatiotemporal resolution and signal sensitivity of Ktrans MRI in rats by using a high-sensitivity surface transceiver coil. To overcome the signal drop off profile of the surface coil, a pre-scan module was used to map the flip angle (B1 field) and magnetization (M0) distributions. A series of T1-weighted gradient echo images were acquired and fitted to the extended Kety model with reversible or irreversible leakage, and the best model was selected using F-statistics. We applied this method to study the rat brain one hour following controlled cortical impact (mild to moderate TBI), and observed clear depiction of the BBB damage around the impact regions, which matched that outlined by Evans Blue extravasation. Unlike the relatively uniform T2 contrast showing cerebral edema, Ktrans shows a pronounced heterogeneous spatial profile in and around the impact regions, displaying a nonlinear relationship with T2. This improved Ktrans MRI method is also compatible with the use of high-sensitivity surface coil and the high-contrast two-coil arterial spin-labeling method for cerebral blood flow measurement, enabling more comprehensive investigation of the pathophysiology in TBI.
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Affiliation(s)
- Wei Li
- Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
- Department of Ophthalmology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
- * E-mail: (WL); (TQD)
| | - Justin Alexander Long
- Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
| | - Lora Talley Watts
- Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
- Department of Cellular and Structure Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
- Department of Neurology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
| | - Zhao Jiang
- Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
| | - Qiang Shen
- Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
| | - Yunxia Li
- Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
| | - Timothy Q. Duong
- Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
- Department of Ophthalmology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
- Department of Neurology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
- South Texas Veterans Health Care System, Department of Veterans Affairs, San Antonio, Texas, United States of America
- * E-mail: (WL); (TQD)
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Fu S, Gu Y, Jiang JQ, Chen X, Xu M, Chen X, Shen J. Calycosin-7-O-β-D-glucoside regulates nitric oxide /caveolin-1/matrix metalloproteinases pathway and protects blood-brain barrier integrity in experimental cerebral ischemia-reperfusion injury. JOURNAL OF ETHNOPHARMACOLOGY 2014; 155:692-701. [PMID: 24930357 DOI: 10.1016/j.jep.2014.06.015] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Revised: 04/28/2014] [Accepted: 06/04/2014] [Indexed: 06/03/2023]
Abstract
ETHNOPHARMACOLOGY RELEVANCE Astragali Radix (AR) has been used for thousands years to treat ischemic stroke. Calycosin and its glycoside form calycosin-7-O-β-D-glucoside (CG) are two representative isoflavones in Astragali Radix. However, its neurological effects and related molecular mechanisms are largely unknown. The present study aims to evaluate the neuroprotective effects of CG on blood-brain barrier (BBB) integrity of ischemic brain tissue and explore the relevant signaling mechanisms. MATERIAL AND METHOD Male adult Sprague-Daweley rats were subjected to 2 h of middle cerebral artery occlusion (MCAO) plus 24 h or 14 days of reperfusion. CG (26.8 mg/kg) was intraperitoneally administered into the rats at 15 min before onset of ischemia. The neuroprotective effects of CG were evaluated by measuring infarct volume, histological damage and BBB permeability. Furthermore, the effects of CG on scavenging nitric oxide (NO), and modulating matrix metalloproteinases (MMPs) and caveolin-1 (cav-1) were investigated with in vitro cultured brain microvascular endothelial cells treated with NO donor or oxygen-glucose deprivation (OGD) and/or in vivo rat model of MCAO cerebral ischemia-reperfusion injury. RESULTS CG treatment significantly reduced infarct volume, histological damage and BBB permeability in the in vivo MCAO ischemia-reperfusion rat model. CG treatment remarkably inhibited the expression and activities of MMPs, and secured the expression of cav-1 and tight junction proteins in the microvessels isolated from ischemic rat cortex. Furthermore, CG was revealed to scavenge NO, inhibit the activities of MMP-2 and MMP-9, and attenuate cell death in the in vitro cultured brain microvascular endothelial cells under OGD condition. CONCLUSION CG could protect BBB integrity in experimental cerebral ischemia-reperfusion injury via regulating NO/cav-1/MMPs pathway.
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Affiliation(s)
- Shuping Fu
- School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong SAR, China
| | - Yong Gu
- School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong SAR, China
| | - Jian-Qin Jiang
- Department of Phytochemistry, China Pharmacology University, 24 Tongjia Alley, Gulou, Nanjing, Jiangsu, 210009, China
| | - Xi Chen
- School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong SAR, China
| | - Mingjing Xu
- School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong SAR, China
| | - Xingmiao Chen
- School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong SAR, China
| | - Jiangang Shen
- School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong SAR, China; Research Center of Heart, Brain, Hormone & Health Aging, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong SAR, China.
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Role of matrix metalloproteinase activity in the neurovascular protective effects of Angiotensin antagonism. Stroke Res Treat 2014; 2014:560491. [PMID: 25147751 PMCID: PMC4134816 DOI: 10.1155/2014/560491] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Revised: 06/23/2014] [Accepted: 07/07/2014] [Indexed: 11/18/2022] Open
Abstract
Background and Purpose. Oxidative stress and matrix metalloproteinase (MMP) activity have been identified as key mediators of early vascular damage after ischemic stroke. Somewhat surprisingly, the angiotensin II type 1 receptor (AT1) blocker, candesartan, has been shown to acutely increase MMP activity while providing neurovascular protection. We aimed to determine the contribution of MMP and nitrative stress to the effects of angiotensin blockade in experimental stroke. Methods. Wistar rats (n = 9–14/group; a total of 99) were treated in a factorial design with candesartan 1 mg/kg IV, alone or in combination with either a peroxynitrite decomposition catalyst, FeTPPs, 30 mg/kg IP or GM6001 50 mg/kg IP (MMP inhibitor). Neurological deficit, infarct, size and hemorrhagic transformation (HT) were measured after 3 h of middle cerebral artery occlusion (MCAO) and 21 h of reperfusion. MMP activity and nitrotyrosine expression were also measured. Results. Candesartan reduced infarct size and HT when administered alone (P = 0.0011) and in combination with FeTPPs (P = 0.0016). GM6001 did not significantly affect HT when administered alone, but the combination with candesartan caused increased HT (P < 0.0001) and worsened neurologic score (P = 0.028). Conclusions. Acute administration of candesartan reduces injury after stroke despite increasing MMP activity, likely by an antioxidant mechanism.
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O'Sullivan S, Medina C, Ledwidge M, Radomski MW, Gilmer JF. Nitric oxide-matrix metaloproteinase-9 interactions: biological and pharmacological significance--NO and MMP-9 interactions. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2014; 1843:603-17. [PMID: 24333402 DOI: 10.1016/j.bbamcr.2013.12.006] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Revised: 12/02/2013] [Accepted: 12/05/2013] [Indexed: 12/24/2022]
Abstract
Nitric oxide (NO) and matrix metalloproteinase 9 (MMP-9) levels are found to increase in inflammation states and in cancer, and their levels may be reciprocally modulated. Understanding interactions between NO and MMP-9 is of biological and pharmacological relevance and may prove crucial in designing new therapeutics. The reciprocal interaction between NO and MMP-9 have been studied for nearly twenty years but to our knowledge, are yet to be the subject of a review. This review provides a summary of published data regarding the complex and sometimes contradictory effects of NO on MMP-9. We also analyse molecular mechanisms modulating and mediating NO-MMP-9 interactions. Finally, a potential therapeutic relevance of these interactions is presented.
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Ectopic expression of human angiopoietin-1 promotes functional recovery and neurogenesis after focal cerebral ischemia. Neuroscience 2014; 267:135-46. [DOI: 10.1016/j.neuroscience.2014.02.036] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Revised: 01/28/2014] [Accepted: 02/24/2014] [Indexed: 11/22/2022]
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