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Zhu Y, Zhou H, Chen D, Zhou D, Zhao N, Xiong L, Deng I, Zhou X, Zhu Z. New progress of isoflurane, sevoflurane and propofol in hypoxic-ischemic brain injury and related molecular mechanisms based on p75 neurotrophic factor receptor. IBRAIN 2021; 7:132-140. [PMID: 37786902 PMCID: PMC10528789 DOI: 10.1002/j.2769-2795.2021.tb00075.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 05/17/2021] [Accepted: 06/10/2021] [Indexed: 10/04/2023]
Abstract
Hypoxic ischemic brain injury (HIBI) is one of the most common clinical disorders, especially in neonates. The complex pathophysiology of HIBI is an important cause of disability and even death of patients, however, being without effective clinical treatments. Common anesthetics (such as isoflurane, propofol and sevoflurane) have an adverse impact on neuronal cells for HIBI via the regulation of p75 neurotrophic factor receptor (P75NTR). In order to protect the injured brains and study the effect of underlying treatments, it is particularly significant to understand and master the developmental mechanism of anesthetics for the occurrence of HIBI related molecular mechanisms. Therefore, this paper will mainly review the corresponding pathogenic and protective mechanisms about HIBI binding to the research progress of the role of P75NTR. In conclusion, the effects of neuroprotection and injured nerves are involved in the expression and activation of P75NTR, mainly increased P75NTR mRNA, protein levels and calpain-dependent for propofol, and inducing neuronal apoptosis for isoflurane and sevoflurane, and we look forward to that connection with P75NTR, common anaesthetic and HIBI may be a new direction of research and gain perfect outcomes in the future.
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Affiliation(s)
- Yi Zhu
- School of AnesthesiologyZunyi Medical UniversityZunyiGuizhouChina
| | - Hong‐Su Zhou
- School of AnesthesiologyZunyi Medical UniversityZunyiGuizhouChina
| | - Dong‐Qin Chen
- School of AnesthesiologyZunyi Medical UniversityZunyiGuizhouChina
| | - Di Zhou
- School of AnesthesiologyZunyi Medical UniversityZunyiGuizhouChina
| | - Nan Zhao
- Department of AnesthesiaHospital of Stomatology, Zunyi Medical UniversityZunyiGuizhouChina
| | - Liu‐Lin Xiong
- Clinical and Health Sciences, University of South AustraliaAdelaide5000South AustraliaAustralia
| | - Issac Deng
- Clinical and Health Sciences, University of South AustraliaAdelaide5000South AustraliaAustralia
| | - Xin‐Fu Zhou
- Clinical and Health Sciences, University of South AustraliaAdelaide5000South AustraliaAustralia
| | - Zhao‐Qiong Zhu
- School of AnesthesiologyZunyi Medical UniversityZunyiGuizhouChina
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Feng L, Sun ZG, Liu QW, Ma T, Xu ZP, Feng ZG, Yuan WX, Zhang H, Xu LH. Propofol inhibits the expression of Abelson nonreceptor tyrosine kinase without affecting learning or memory function in neonatal rats. Brain Behav 2020; 10:e01810. [PMID: 32869521 PMCID: PMC7667295 DOI: 10.1002/brb3.1810] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 07/17/2020] [Accepted: 08/04/2020] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE Propofol is one of the most commonly used intravenous drugs to induce and maintain general anesthesia. In vivo and in vitro studies have shown that propofol can affect neuronal growth, leading to apoptosis and impairing cognitive function. The Abelson nonreceptor tyrosine kinase (c-Abl) is associated with both neuritic plaques and neurofibrillary tangles in the brains of patients with Alzheimer's disease and other neurodegenerative diseases. This study aimed to explore the effect of propofol on apoptosis and neurocognition through its regulation of c-Abl expression in vivo and in vitro. MATERIALS AND METHODS In this study, primary hippocampal neurons were cultured and exposed to propofol at different concentrations. Protein expression was measured by Western blotting and coimmunoprecipitation. The c-Abl transcription level was verified by fluorescence quantitative PCR. Reactive oxygen species (ROS) levels were detected by flow cytometry. In addition, an animal experiment was conducted to assess neuronal apoptosis by immunofluorescence staining for caspase-3 and to evaluate behavioral changes by the Morris water maze (MWM) test. RESULTS The in vitro experiment showed that propofol significantly decreased c-Abl expression and ROS levels. In addition, propofol has no cytotoxic effect and does not affect cell activity. Moreover, in the animal experiment, intraperitoneal injection of 50 mg/kg propofol for 5 days obviously decreased the expression of c-Abl in the neonatal rat brain (p < .05) but did not significantly increase the number of caspase-3-positive cells. Propofol treatment did not significantly reduce the number of platform crossings (p > .05) or prolong the escape latency of neonatal rats (p > .05) in the MWM test. CONCLUSIONS The present data suggest that reduced expression of this nonreceptor tyrosine kinase through consecutive daily administration of propofol did not impair learning or memory function in neonatal rats.
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Affiliation(s)
- Long Feng
- Anesthesia and Operation Center, Chinese PLA Medical School, Beijing, China.,PLA general hospital of Hainan Hospital, Hainan, China
| | - Zhi-Gao Sun
- PLA general hospital of Hainan Hospital, Hainan, China
| | - Qiang-Wei Liu
- Anesthesia and Operation Center, Chinese PLA Medical School, Beijing, China
| | - Tao Ma
- Department of Anesthesiology, PLA Rocket Force Characteristic Medical Center, Beijing, China
| | - Zhi-Peng Xu
- Anesthesia and Operation Center, Chinese PLA Medical School, Beijing, China
| | - Ze-Guo Feng
- Anesthesia and Operation Center, Chinese PLA Medical School, Beijing, China
| | - Wei-Xiu Yuan
- PLA general hospital of Hainan Hospital, Hainan, China
| | - Hong Zhang
- Anesthesia and Operation Center, Chinese PLA Medical School, Beijing, China
| | - Long-He Xu
- Anesthesia and Operation Center, Chinese PLA Medical School, Beijing, China.,PLA general hospital of Hainan Hospital, Hainan, China
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Gürkan G, Sayin M, Kizmazoglu C, Erdogan MA, Yigitturk G, Erbak Yilmaz H, Uzunoglu I, Kaya I, Yuceer N. Evaluation of the neuroprotective effects of ozone in an experimental spine injury model. J Neurosurg Spine 2020; 33:406-414. [PMID: 32413852 DOI: 10.3171/2020.2.spine191439] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 02/20/2020] [Indexed: 11/06/2022]
Abstract
OBJECTIVE The pathophysiology of spine injury consists of primary and secondary damage mechanisms. The vast majority of treatments aim to prevent or at least stop the progression of secondary neurotoxic events during the acute period. Ozone has been found to have potent antiinflammatory effects, to activate the immune system, and to have a substantial impact on the antioxidant system. In this study the authors aimed to evaluate the neuroprotective effects of ozone and their possible roles in recovery from spine injury, assessed based on biochemical, histological, and neurological parameters using an experimental spine injury model in rats. METHODS The study included 31 female Wistar albino rats. The rats were divided randomly into 5 groups, with 7 rats in each group except the sham group, which contained 3 rats, as follows: group 1 (sham), laminectomy; group 2 (control), laminectomy and spinal trauma with no medical treatment (0.5 ml isotonic saline applied 1 hour postsurgery); group 3, single medical treatment with 30 mg/kg methylprednisolone applied intraperitoneally 1 hour after laminectomy and trauma; group 4, single medical treatment with 60 μg/ml ozone at 0.7 mg/kg applied intraperitoneally 1 hour after laminectomy and trauma; and group 5, double medical treatment with 30 mg/kg methylprednisolone and 60 μg/ml ozone at 0.7 mg/kg applied intraperitoneally 1 hour after laminectomy and trauma. After neurosurgery, neurobehavioral tests were performed in all groups. After 7 days of follow-up, all the rats were killed. Biopsy specimens obtained from trauma sites were examined using H & E, cresyl violet, immunohistochemical (anticonnexin-43), and TUNEL staining processes. Levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) and total oxidant status (TOS) and total antioxidant status (TAS) were measured in blood samples. RESULTS The level of neurobehavioral healing was the highest in the double-treatment group (group 5), and the difference between the groups was significant. The minimum IL-6 level was found in group 5, indicating that the antiinflammatory impact was the most significant in this group (p = 0.01). Additionally, ozone was found to reduce oxidant stress more effectively than methylprednisolone (p = 0.03). Although methylprednisolone was superior to ozone in terms of the antiinflammatory effect, this effect was greater in group 5. Nevertheless, the number of neurons in group 5 was close to that of the control group, and the number of apoptotic cells was the least in group 5 (p < 0.001). CONCLUSIONS In acute spinal injury, the combined application of methylprednisolone and ozone was found to have a greater antiinflammatory effect, hasten clinical recovery, and increase histological recovery compared with methylprednisolone therapy alone. This study showed that this combination therapy of methylprednisolone with the addition of ozone might have a more beneficial effect in the treatment of spinal injury than methylprednisolone therapy alone.
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Affiliation(s)
- Gokhan Gürkan
- 1Department of Neurosurgery, Katip Celebi University Atatürk Training and Research Hospital, Izmir
| | - Murat Sayin
- 1Department of Neurosurgery, Katip Celebi University Atatürk Training and Research Hospital, Izmir
| | - Ceren Kizmazoglu
- 2Department of Neurosurgery, Dokuz Eylul University Hospital, Izmir
| | | | | | - Huriye Erbak Yilmaz
- 5Department of Medical Biochemistry, Katip Celebi University Atatürk Training and Research Hospital, Izmir; and
| | - Inan Uzunoglu
- 1Department of Neurosurgery, Katip Celebi University Atatürk Training and Research Hospital, Izmir
| | - Ismail Kaya
- 6Department of Neurosurgery, Dumlupinar University Kutahya Evliya Celebi Training and Research Hospital, Kutahya, Turkey
| | - Nurullah Yuceer
- 1Department of Neurosurgery, Katip Celebi University Atatürk Training and Research Hospital, Izmir
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Zhao DA, Bi LY, Huang Q, Zhang FM, Han ZM. [Isoflurane provides neuroprotection in neonatal hypoxic ischemic brain injury by suppressing apoptosis]. Rev Bras Anestesiol 2016; 66:613-621. [PMID: 27637994 DOI: 10.1016/j.bjan.2016.08.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 04/22/2015] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Isoflurane is halogenated volatile ether used for inhalational anesthesia. It is widely used in clinics as an inhalational anesthetic. Neonatal hypoxic ischemia injury ensues in the immature brain that results in delayed cell death via excitotoxicity and oxidative stress. Isoflurane has shown neuroprotective properties that make a beneficial basis of using isoflurane in both cell culture and animal models, including various models of brain injury. We aimed to determine the neuroprotective effect of isoflurane on hypoxic brain injury and elucidated the underlying mechanism. METHODS A hippocampal slice, in artificial cerebrospinal fluid with glucose and oxygen deprivation, was used as an in vitro model for brain hypoxia. The orthodromic population spike and hypoxic injury potential were recorded in the CA1 and CA3 regions. Amino acid neurotransmitters concentration in perfusion solution of hippocampal slices was measured. RESULTS Isoflurane treatment caused delayed elimination of population spike and improved the recovery of population spike; decreased frequency of hypoxic injury potential, postponed the onset of hypoxic injury potential and increased the duration of hypoxic injury potential. Isoflurane treatment also decreased the hypoxia-induced release of amino acid neurotransmitters such as aspartate, glutamate and glycine induced by hypoxia, but the levels of γ-aminobutyric acid were elevated. Morphological studies showed that isoflurane treatment attenuated edema of pyramid neurons in the CA1 region. It also reduced apoptosis as evident by lowered expression of caspase-3 and PARP genes. CONCLUSIONS Isoflurane showed a neuro-protective effect on hippocampal neuron injury induced by hypoxia through suppression of apoptosis.
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Affiliation(s)
- De-An Zhao
- The First Affiliated Hospital of Xinxiang Medical University, Department of Pediatrics, Weihui, China.
| | - Ling-Yun Bi
- The First Affiliated Hospital of Xinxiang Medical University, Department of Pediatrics, Weihui, China
| | - Qian Huang
- The First Affiliated Hospital of Xinxiang Medical University, Department of Pediatrics, Weihui, China
| | - Fang-Min Zhang
- The First Affiliated Hospital of Xinxiang Medical University, Department of Pediatrics, Weihui, China
| | - Zi-Ming Han
- The First Affiliated Hospital of Xinxiang Medical University, Department of Pediatrics, Weihui, China
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Wang H, Zheng S, Liu M, Jia C, Wang S, Wang X, Xue S, Guo Y. The Effect of Propofol on Mitochondrial Fission during Oxygen-Glucose Deprivation and Reperfusion Injury in Rat Hippocampal Neurons. PLoS One 2016; 11:e0165052. [PMID: 27788177 PMCID: PMC5082830 DOI: 10.1371/journal.pone.0165052] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Accepted: 10/05/2016] [Indexed: 11/18/2022] Open
Abstract
The neuroprotective role of propofol in transient global and focal cerebral ischemia reperfusion (I/R) animal model has recently been highlighted. However, no studies have conducted to explore the relationship between mitochondrial fission/fusion and I/R injury under the intervention of propofol. Moreover, neuroprotective mechanism of propofol is yet unclear. Culturing primary hippocampal cells were subjected to oxygen-glucose deprivation and re-oxygenation (OGD/R) model, as a model of cerebral I/R in vitro. Methods CCK-8 assay was used to test the effect of propofol on cell viability. We examined the effect of propofol on mitochondrial ultrastructure and mitochondrial fission evoked by OGD/R with transmission electron microscopy and immunofluorescence assay. To investigate possible neuroprotective mechanisms, the authors then examined whether propofol could inhibit calcium-overload, calcineurin (CaN) activation and the phosphorylation of dynamin-related protein 1 (Drp1) during the period of OGD/R, as well as the combination of Drp1-ser 637 and fission 1 (Fis1) protein by immunofluorescence assay, ELISA and double-labeling immunofluorescence analysis. Finally, the expression of Drp1-ser 637 and Fis1, apoptosis inducing factor (AIF) and cytochrome C (Cyt C) were detected by western blot. When added in culture media during OGD period, propofol (0.1μM-50μM) could alleviate neurons injury and protect mitochondrial ultrastructure, meanwhile inhibit mitochondrial fission. Furthermore, the concentration of intracellular free Ca2+, CaN activition and the phosphorylation of Drp1-ser637 were suppressed, as well as the translocation and combination of Drp1-ser 637 and Fis1. The authors also found that the expression of Cyt C, AIF, Drp1-ser637 and Fis1 were down-regulated. Notably, high dose of propofol (100μM-200μM) were confirmed to decrease the survival of neurons based on results of cell viability. Propofol could inhibit mitochondrial fission and mitochondrial apoptotic pathway evoked by OGD/R in rat hippocampal neurons, which may be via depressing calcium-overload.
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Affiliation(s)
- Haibin Wang
- Department of Anesthesiology, the Affiliated Hospital of Qingdao University, Huangdao, Qingdao, Shandong Province, China
| | - Shengfa Zheng
- Institute of Cerebrovascular Diseases, Affiliated Hospital of Qingdao University, Huangdao, Qingdao, Shandong Province, China
| | - Maodong Liu
- Department of Anesthesiology, the Affiliated Hospital of Qingdao University, Huangdao, Qingdao, Shandong Province, China
| | - Changxin Jia
- Department of Anesthesiology, the Affiliated Hospital of Qingdao University, Huangdao, Qingdao, Shandong Province, China
| | - Shilei Wang
- Department of Anesthesiology, the Affiliated Hospital of Qingdao University, Huangdao, Qingdao, Shandong Province, China
- * E-mail:
| | - Xue Wang
- Department of Anesthesiology, the Affiliated Hospital of Qingdao University, Huangdao, Qingdao, Shandong Province, China
| | - Sha Xue
- Department of Anesthesiology, the Affiliated Hospital of Qingdao University, Huangdao, Qingdao, Shandong Province, China
| | - Yunliang Guo
- Department of Anesthesiology, People's Hospital of Rizhao, Rizhao, Shandong Province, China
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Yuan J, Cui G, Li W, Zhang X, Wang X, Zheng H, Zhang J, Xiang S, Xie Z. Propofol Enhances Hemoglobin-Induced Cytotoxicity in Neurons. Anesth Analg 2016; 122:1024-30. [PMID: 26771264 DOI: 10.1213/ane.0000000000001123] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND It has been increasingly suggested that propofol protects against hypoxic-/ischemic-induced neuronal injury. As evidenced by hemorrhage-induced stroke, hemorrhage into the brain may also cause brain damage. Whether propofol protects against hemorrhage-induced brain damage remains unknown. Therefore, in this study, we investigated the effects of propofol on hemoglobin-induced cytotoxicity in cultured mouse cortical neurons. METHODS Neurons were prepared from the cortex of embryonic 15-day-old mice. Hemoglobin was used to induce cytotoxicity in the neurons. The neurons were then treated with propofol for 4 hours. Cytotoxicity was determined by lactate dehydrogenase release assay. Caspase-3 activation was examined by Western blot analysis. Finally, the free radical scavenger U83836E was used to examine the potential involvement of oxidative stress in propofol's effects on hemoglobin-induced cytotoxicity. RESULTS We found that treatment with hemoglobin induced cytotoxicity in the neurons. Propofol enhanced hemoglobin-induced cytotoxicity. Specifically, there was a significant difference in the amount of lactate dehydrogenase release between hemoglobin plus saline (19.84% ± 5.38%) and hemoglobin plus propofol (35.79% ± 4.41%) in mouse cortical neurons (P = 0.00058, Wilcoxon Mann-Whitney U test, n = 8 in the control group or the treatment group). U83836E did not attenuate the enhancing effects of propofol on hemoglobin-induced cytotoxicity in the neurons, and propofol did not significantly affect caspase-3 activation induced by hemoglobin. These data suggested that caspase-3 activation and oxidative stress might not be the underlying mechanisms by which propofol enhanced hemoglobin-induced cytotoxicity. Moreover, these data suggested that the neuroprotective effects of propofol would be dependent on the condition of the brain injury, which will need to be confirmed in future studies. CONCLUSIONS These results from our current proof-of-concept study should promote more research in vitro and in vivo to develop better anesthesia care for patients with hemorrhagic stroke.
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Affiliation(s)
- Jing Yuan
- From the *Key Laboratory of Protein Biochemistry and Developmental Biology of State Education Ministry, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China; †Neuroprotection Research Laboratory, Massachusetts General Hospital, Charlestown, Massachusetts; Departments of ‡Radiology and §Neurology, Massachusetts General Hospital, Charlestown, Massachusetts; ‖Program in Neuroscience, Harvard Medical School, Boston, Massachusetts; ¶Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China; #Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts; and **Massachusetts General Hospital Biostatistics Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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Zhao DA, Bi LY, Huang Q, Zhang FM, Han ZM. Isoflurane provides neuroprotection in neonatal hypoxic ischemic brain injury by suppressing apoptosis. Braz J Anesthesiol 2016; 66:613-621. [PMID: 27793236 DOI: 10.1016/j.bjane.2015.04.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 04/22/2015] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND AND OBJECTIVES Isoflurane is halogenated volatile ether used for inhalational anesthesia. It is widely used in clinics as an inhalational anesthetic. Neonatal hypoxic ischemia injury ensues in the immature brain that results in delayed cell death via excitotoxicity and oxidative stress. Isoflurane has shown neuroprotective properties that make a beneficial basis of using isoflurane in both cell culture and animal models, including various models of brain injury. We aimed to determine the neuroprotective effect of isoflurane on hypoxic brain injury and elucidated the underlying mechanism. METHODS A hippocampal slice, in artificial cerebrospinal fluid with glucose and oxygen deprivation, was used as an in vitro model for brain hypoxia. The orthodromic population spike and hypoxic injury potential were recorded in the CA1 and CA3 regions. Amino acid neurotransmitters concentration in perfusion solution of hippocampal slices was measured. RESULTS Isoflurane treatment caused delayed elimination of population spike and improved the recovery of population spike; decreased frequency of hypoxic injury potential, postponed the onset of hypoxic injury potential and increased the duration of hypoxic injury potential. Isoflurane treatment also decreased the hypoxia-induced release of amino acid neurotransmitters such as aspartate, glutamate and glycine induced by hypoxia, but the levels of γ-aminobutyric acid were elevated. Morphological studies showed that isoflurane treatment attenuated edema of pyramid neurons in the CA1 region. It also reduced apoptosis as evident by lowered expression of caspase-3 and PARP genes. CONCLUSIONS Isoflurane showed a neuro-protective effect on hippocampal neuron injury induced by hypoxia through suppression of apoptosis.
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Affiliation(s)
- De-An Zhao
- The First Affiliated Hospital of Xinxiang Medical University, Department of Pediatrics, Weihui, China.
| | - Ling-Yun Bi
- The First Affiliated Hospital of Xinxiang Medical University, Department of Pediatrics, Weihui, China
| | - Qian Huang
- The First Affiliated Hospital of Xinxiang Medical University, Department of Pediatrics, Weihui, China
| | - Fang-Min Zhang
- The First Affiliated Hospital of Xinxiang Medical University, Department of Pediatrics, Weihui, China
| | - Zi-Ming Han
- The First Affiliated Hospital of Xinxiang Medical University, Department of Pediatrics, Weihui, China
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Abstract
Organotypic hippocampal slice cultures (OHSCs) have been used as a powerful ex vivo model for decades. They have been used successfully in studies of neuronal death, microglial activation, mossy fiber regeneration, neurogenesis, and drug screening. As a pre-animal experimental phase for physiologic and pathologic brain research, OHSCs offer outcomes that are relatively closer to those of whole-animal studies than outcomes obtained from cell culture in vitro. At the same time, mechanisms can be studied more precisely in OHSCs than they can be in vivo. Here, we summarize stroke and traumatic brain injury research that has been carried out in OHSCs and review classic experimental applications of OHSCs and its limitations.
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Sun W, Pei L. microRNA Expression Profiling of Propofol-Treated Developing Rat Hippocampal Astrocytes. DNA Cell Biol 2015; 34:511-23. [PMID: 26083276 DOI: 10.1089/dna.2015.2831] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Although propofol exerts toxic effects on the developing central nervous system (CNS), it remains a first-choice anesthetic in the pediatric population. Astrocytes represent a major glial cell population whose role in CNS development is widely appreciated and that has been recently shown to be mediated in large part by microRNAs (miRNAs). In contrast, relatively little is known about the roles of miRNAs in developing astrocytes during propofol treatment. Here, miRNA microarray was used to profile fluctuations in miRNA expression in immature hippocampal astrocytes in response to propofol treatment, and results were subsequently validated using quantitative real-time polymerase chain reaction. Predictive analysis of genes targeted by propofol-regulated miRNAs indicated enrichment of genes in the gene ontology (GO) nervous system development and differentiation category, and in the Kyoto encyclopedia of genes and genomes (KEGG) apoptotic pathway category. A total of 24 (10 short-term dosage and 14 long-term dosage) miRNAs were significantly regulated, one of which was rno-miR-665. Ectopic overexpression and silencing of rno-miR-665 demonstrated its role in the neurotoxic effects of propofol on hippocampal immature astrocytes. We present evidence that the role of rno-miR-665 in anesthesia-induced disturbances in astroglia development may involve direct downregulation of the anti-apoptotic gene Bcl2l1, and subsequent increased caspase-3-mediated apoptosis. Our results shed light on the anesthetic mechanism of propofol and have implications for its use in the clinical setting.
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Affiliation(s)
- Wenchong Sun
- Department of Anesthesiology, The First Affiliated Hospital, China Medical University , Shenyang, China
| | - Ling Pei
- Department of Anesthesiology, The First Affiliated Hospital, China Medical University , Shenyang, China
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Liu G, Liu C, Zhang XN. Comparison of the neuropsychological mechanisms of 2,6-diisopropylphenol and N-methyl-D-aspartate receptor antagonist against electroconvulsive therapy-induced learning and memory impairment in depressed rats. Mol Med Rep 2015; 12:3297-3308. [PMID: 25998151 PMCID: PMC4526078 DOI: 10.3892/mmr.2015.3803] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2014] [Accepted: 04/14/2015] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to examine the neurophysiological mechanisms of the 2,6-diisopropylphenol and N-methyl-D-aspartate (NMDA) receptor antagonist against learning and memory impairment, induced by electroconvulsive therapy (ECT). A total of 48 adult depressed rats without olfactory bulbs were randomly divided into six experimental groups: i) saline; ii) 10 mg/kg MK‑801; iii) 10 mg/kg MK‑801 and a course of ECT; iv) 200 mg/kg 2,6‑diisopropylphenol; v) 200 mg/kg 2,6‑diisopropylphenol and a course of ECT; and vi) saline and a course of ECT. The learning and memory abilities of the rats were assessed using a Morris water maze 1 day after a course of ECT. The hippocampus was removed 1 day after assessment using the Morris water maze assessment. The content of glutamate in the hippocampus was detected using high‑performance liquid chromatography. The expression levels of p‑AT8Ser202 and GSK‑3β1H8 in the hippocampus were determined using immunohistochemical staining and western blot analysis. The results demonstrated that the 2,6‑diisopropylphenol NMDA receptor antagonist, MK‑801 and ECT induced learning and memory impairment in the depressed rats. The glutamate content was significantly upregulated by ECT, reduced by 2,6‑diisopropylphenol, and was unaffected by the NMDA receptor antagonist in the hippocampus of the depressed rats. Tau protein hyperphosphorylation in the hippocampus was upregulated by ECT, but was reduced by 2,6‑diisopropylphenol and the MK‑801 NMDA receptor antagonist. It was also demonstrated that 2,6‑diisopropylphenol prevented learning and memory impairment and reduced the hyperphosphorylation of the Tau protein, which was induced by eECT. GSK‑3β was found to be the key protein involved in this signaling pathway. The ECT reduced the learning and memory impairment, caused by hyperphosphorylation of the Tau protein, in the depressed rats by upregulating the glutamate content.
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Affiliation(s)
- Gang Liu
- Department of Anesthesiology, General Hospital of Beijing Military Area of PLA, Beijing 100700, P.R. China
| | - Chao Liu
- Department of Anesthesiology, Tianjin Chest Hospital, Tianjin 300222, P.R. China
| | - Xue-Ning Zhang
- Department of Radiology, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
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Dalbayrak S, Yaman O, Yılmaz T. Current and future surgery strategies for spinal cord injuries. World J Orthop 2015; 6:34-41. [PMID: 25621209 PMCID: PMC4303788 DOI: 10.5312/wjo.v6.i1.34] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Accepted: 05/14/2014] [Indexed: 02/06/2023] Open
Abstract
Spinal cord trauma is a prominent cause of mortality and morbidity. In developed countries a spinal cord injury (SCI) occurs every 16 min. SCI occurs due to tissue destruction, primarily by mechanical and secondarily ischemic. Primary damage occurs at the time of the injury. It cannot be improved. Following the primary injury, secondary harm mechanisms gradually result in neuronal death. One of the prominent causes of secondary harm is energy deficit, emerging from ischemia, whose main cause in the early stage, is impaired perfusion. Due to the advanced techniques in spinal surgery, SCI is still challenging for surgeons. Spinal cord doesn’t have a self-repair property. The main damage occurs at the time of the injury primarily by mechanical factors that cannot be improved. Secondarily mechanisms take part in the following sections. Spinal compression and neurological deficit are two major factors used to decide on surgery. According to advanced imaging techniques the classifications systems for spinal injury has been changed in time. Aim of the surgery is to decompress the spinal channel and to restore the spinal alinement and mobilize the patient as soon as possible. Use of neuroprotective agents as well as methods to achieve cell regeneration in addition to surgery would contribute to the solution.
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Alasia S, Cocito C, Merighi A, Lossi L. Real-time visualization of caspase-3 activation by fluorescence resonance energy transfer (FRET). Methods Mol Biol 2015; 1254:99-113. [PMID: 25431060 DOI: 10.1007/978-1-4939-2152-2_8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
As apoptosis occurs via a complex signaling cascade that is tightly regulated at multiple cell points, different methods exist to evaluate the activity of the proteins involved in the intracellular apoptotic pathways and the phenotype of apoptotic neurons. Detention of the activity of the enzyme caspase-3, the key executioner caspase in programmed cell death, by laser scanning confocal fluorescence microscopy and the fluorescence resonance energy transfer technology is an alternative approach to classical standard techniques, such as Western blotting, activity assays, or histological techniques, and allows working with both fixed and living cells. This technique combined with the organotypic culture approach ex vivo represents a valid tool for the study of the mechanisms of neuronal survival /death and neuroprotection.
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Affiliation(s)
- Silvia Alasia
- Department of Veterinary Sciences, University of Turin, Via Leonardo da Vinci 44, Turin, Grugliasco, 10095, Italy
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Ogura T, Hamada T, Matsui T, Tanaka S, Okabe S, Kazama T, Kobayashi Y. Neuroprotection by JM-1232(−) against oxygen–glucose deprivation-induced injury in rat hippocampal slice culture. Brain Res 2015; 1594:52-60. [DOI: 10.1016/j.brainres.2014.10.038] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Revised: 07/01/2014] [Accepted: 10/21/2014] [Indexed: 10/24/2022]
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Tasca CI, Dal-Cim T, Cimarosti H. In vitro oxygen-glucose deprivation to study ischemic cell death. Methods Mol Biol 2015; 1254:197-210. [PMID: 25431067 DOI: 10.1007/978-1-4939-2152-2_15] [Citation(s) in RCA: 108] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Oxygen-glucose deprivation (OGD ) is widely used as an in vitro model for stroke, showing similarities with the in vivo models of brain ischemia. In order to perform OGD, cell or tissue cultures, such as primary neurons or organotypic slices, and acutely prepared tissue slices are usually incubated in a glucose-free medium under a deoxygenated atmosphere, for example in a hypoxic chamber. Here, we describe the step-by-step procedure to expose cultures and acute slices to OGD, focusing on the most suitable methods for assessing cellular death and/or viability. OGD is a simple yet highly useful technique, not only for the elucidation of the role of key cellular and molecular mechanisms underlying brain ischemia, but also for the development of novel neuroprotective strategies.
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Affiliation(s)
- Carla I Tasca
- Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário - Trindade 88040-900, Florianópolis, SC, Brazil
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15
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Allard J, Paci P, Vander Elst L, Ris L. Regional and time-dependent neuroprotective effect of hypothermia following oxygen-glucose deprivation. Hippocampus 2014; 25:197-207. [DOI: 10.1002/hipo.22364] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/05/2014] [Indexed: 11/08/2022]
Affiliation(s)
- Justine Allard
- Department of Neurosciences; Research Institute for Health Sciences and Technology, University of Mons; Mons Belgium
| | - Paula Paci
- Department of Neurosciences; Research Institute for Health Sciences and Technology, University of Mons; Mons Belgium
| | - Luce Vander Elst
- Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory; Research Institute for Health Sciences and Technology, University of Mons; Mons Belgium
| | - Laurence Ris
- Department of Neurosciences; Research Institute for Health Sciences and Technology, University of Mons; Mons Belgium
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Zhang DX, Ding HZ, Jiang S, Zeng YM, Tang QF. Anin vitrostudy of the neuroprotective effect of propofol on hypoxic hippocampal slice. Brain Inj 2014; 28:1758-65. [DOI: 10.3109/02699052.2014.947624] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Yaman O, Yaman B, Aydın F, Var A, Temiz C. Hyperbaric oxygen treatment in the experimental spinal cord injury model. Spine J 2014; 14:2184-94. [PMID: 24530437 DOI: 10.1016/j.spinee.2014.02.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2012] [Revised: 01/03/2014] [Accepted: 02/03/2014] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT Spinal cord trauma is a major cause of mortality and morbidity. Although no known treatment for spinal cord injury exists, a limited number of effective treatment modalities and procedures are available that improve secondary injury. Hyperbaric oxygen (HBO) treatment has been used to assist in neurologic recovery after cranial injury or ischemic stroke. PURPOSE To report the findings on the effectiveness of HBO treatment on rats with experimental traumatic spinal cord injury. Improvement was evaluated through motor strength assessment and nitrite level assay testing. STUDY DESIGN We randomly distributed 40 rats among 5 groups of 8 rats each: sham incurable trauma, induced trauma, HBO treatment begun at the 1st hour, HBO treatment begun at the 6th hour, and HBO treatment begun at the 24th hour. METHOD The HBO treatment was administered to rats in three of the groups and conducted in two 90-minute sessions, under an absolute atmospheric pressure of 2.4 at 100% oxygen for 5 days. In the motor strength evaluations, all the rats were observed during the inclined plane test and clinical motor examination on the first, third, and fifth days. In addition, the nitrite levels of spinal cord tissues on the sixth day were also studied. RESULTS Results from the inclined plane levels and motor strength test from all the three groups undergoing HBO treatment were higher than those from Group 2. It was also determined that early HBO treatment resulted in higher recovery rates (groups 3 and 4). The highest levels were seen in the group in which the HBO treatments were started in the first hour (Group 3). It was noted that nitrite levels of rats in the group exposed to trauma increased, compared with the sham group, but increased levels also diminished after HBO treatments. Again, the greatest decrease in nitrite levels was evident in the group where the HBO treatment was started the earliest (Group 3). CONCLUSIONS Prompt HBO treatment after trauma significantly contributed to the clinical, histopathologic, and biochemical recovery of the rats.
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Affiliation(s)
- Onur Yaman
- Department of Neurosurgery, Tepecik Education and Training Hospital, 35110 Yenişehir, Konak, Izmir, Turkey.
| | - Banu Yaman
- Department of Pathology, Faculty of Medicine, Aegean University, 35040 Bornova, Izmir, Turkey
| | - Figen Aydın
- Hyperbaric Oxygen Treatment Center, 1587/1 Street No:1/D 35040 Bornova, Izmir, Turkey
| | - Ahmet Var
- Department of Biochemistry, Faculty of Medicine, University of Celal Bayar, Manisa, Turkey
| | - Cüneyt Temiz
- Department of Neurosurgery, Faculty of Medicine, University of Celal Bayar, 45030 Manisa, Turkey
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Xu SY, Hu YF, Li WP, Wu YM, Ji Z, Wang SN, Li K, Pan SY. Intermittent hypothermia is neuroprotective in an in vitro model of ischemic stroke. Int J Biol Sci 2014; 10:873-81. [PMID: 25170301 PMCID: PMC4147221 DOI: 10.7150/ijbs.8868] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Accepted: 07/14/2014] [Indexed: 01/05/2023] Open
Abstract
OBJECTIVE To investigate whether the intermittent hypothermia (IH) protects neurons against ischemic insult and the potential molecular targets using an in vitro ischemic model of oxygen glucose deprivation (OGD). METHODS Fetal rat cortical neurons isolated from Day E18 rat embryos were subjected to 90-min OGD and hypothermia treatments during reoxygenation before examining the changes in microscopic morphology, cell viability, microtubule- associated protein 2 (MAP-2) release, intracellular pH value and calcium, reactive oxygen species (ROS) generation, mitochondrial membrane potential (△Ψm) and neuronal death using cell counting kit (CCK-8), enzyme-linked immunosorbent assay (ELISA), BCECF AM, Fluo-3 AM, DCFH-DA and dihydroethidium (DHE), JC-1 staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), respectively. RESULTS 90-min OGD induced morphologic abnormalities, cell viability decline, MAP-2 release, intracellular acidosis, calcium overload, increased ROS generation, △Ψm decrease and cell death in primary neurons, which was partially inhibited by continuous hypothermia (CH) and intermittent hypothermia (IH). Interestingly, 6-h CH was insufficient to reduce intracellular calcium overload and stabilize mitochondrial membrane potential (△Ψm), while 12-h CH was effective in reversing the above changes. All IH treatments (6×1 h, 4×1.5 h or 3×2 h) effectively attenuated intracellular free calcium overload, inhibited ROS production, stabilized mitochondrial membrane potential (△Ψm) and reduced delayed cell death in OGD-treated cells. However, only IH intervals longer than 1.5 h appeared to be effective in preventing cell viability loss and intracellular pH decline. CONCLUSION Both CH and IH were neuroprotective in an in vitro model of ischemic stroke, and in spite of shorter hypothermia duration, IH could provide a comparable neuroprotection to CH.
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Affiliation(s)
- Sui-yi Xu
- 1. Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; ; 2. Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, Shenzhen Second People's Hospital, Shenzhen University 1st Affiliated Hospital, Shenzhen 518035, China
| | - Ya-fang Hu
- 1. Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Wei-pin Li
- 2. Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, Shenzhen Second People's Hospital, Shenzhen University 1st Affiliated Hospital, Shenzhen 518035, China
| | - Yong-ming Wu
- 1. Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Zhong Ji
- 1. Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Sheng-nan Wang
- 1. Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Ke Li
- 3. Research Center of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Su-yue Pan
- 1. Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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Antonic A, Dottori M, Leung J, Sidon K, Batchelor PE, Wilson W, Macleod MR, Howells DW. Hypothermia protects human neurons. Int J Stroke 2014; 9:544-52. [PMID: 24393199 PMCID: PMC4235397 DOI: 10.1111/ijs.12224] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Accepted: 10/14/2013] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND AIMS Hypothermia provides neuroprotection after cardiac arrest, hypoxic-ischemic encephalopathy, and in animal models of ischemic stroke. However, as drug development for stroke has been beset by translational failure, we sought additional evidence that hypothermia protects human neurons against ischemic injury. METHODS Human embryonic stem cells were cultured and differentiated to provide a source of neurons expressing β III tubulin, microtubule-associated protein 2, and the Neuronal Nuclei antigen. Oxygen deprivation, oxygen-glucose deprivation, and H2 O2 -induced oxidative stress were used to induce relevant injury. RESULTS Hypothermia to 33°C protected these human neurons against H2 O2 -induced oxidative stress reducing lactate dehydrogenase release and Terminal deoxynucleotidyl transferase dUTP nick end labeling-staining by 53% (P ≤ 0·0001; 95% confidence interval 34·8-71·04) and 42% (P ≤ 0·0001; 95% confidence interval 27·5-56·6), respectively, after 24 h in culture. Hypothermia provided similar protection against oxygen-glucose deprivation (42%, P ≤ 0·001, 95% confidence interval 18·3-71·3 and 26%, P ≤ 0·001; 95% confidence interval 12·4-52·2, respectively) but provided no protection against oxygen deprivation alone. Protection (21%) persisted against H2 O2 -induced oxidative stress even when hypothermia was initiated six-hours after onset of injury (P ≤ 0·05; 95% confidence interval 0·57-43·1). CONCLUSION We conclude that hypothermia protects stem cell-derived human neurons against insults relevant to stroke over a clinically relevant time frame. Protection against H2 O2 -induced injury and combined oxygen and glucose deprivation but not against oxygen deprivation alone suggests an interaction in which protection benefits from reduction in available glucose under some but not all circumstances.
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Affiliation(s)
- Ana Antonic
- Florey Institute of Neuroscience and Mental HealthHeidelberg, Vic, Australia
- Department of Medicine, University of MelbourneHeidelberg, Vic, Australia
| | - Mirella Dottori
- Centre for Neuroscience Research, Department of Anatomy and Neuroscience, University of MelbourneMelbourne, Vic, Australia
| | - Jessie Leung
- Centre for Neuroscience Research, Department of Anatomy and Neuroscience, University of MelbourneMelbourne, Vic, Australia
| | - Kate Sidon
- Florey Institute of Neuroscience and Mental HealthHeidelberg, Vic, Australia
- Department of Medicine, University of MelbourneHeidelberg, Vic, Australia
| | - Peter E Batchelor
- Department of Medicine, University of MelbourneHeidelberg, Vic, Australia
| | - William Wilson
- CSIRO Mathematics, Informatics and Statistics, Riverside Life Sciences PrecinctNorth Ryde, NSW, Australia
| | - Malcolm R Macleod
- Department of Clinical Neurosciences, Western General Hospital, University of EdinburghEdinburgh, UK
| | - David W Howells
- Florey Institute of Neuroscience and Mental HealthHeidelberg, Vic, Australia
- Department of Medicine, University of MelbourneHeidelberg, Vic, Australia
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Bao L, Xu F. Fundamental research progress of mild hypothermia in cerebral protection. SPRINGERPLUS 2013; 2:306. [PMID: 23888277 PMCID: PMC3710408 DOI: 10.1186/2193-1801-2-306] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Accepted: 07/03/2013] [Indexed: 11/27/2022]
Abstract
Through the years, the clinical application of mild hypothermia has been carried out worldwide and is built from the exploration and cognition of neuroprotection mechanisms by hypothermia. However, within the last decade, extensive and fundamental researches in this area have been conducted. In addition to aspects of the previous findings, scholars have discovered several new contents and uncertain results. This article reviews and summarizes this decade’s progression of mild hypothermia in lowering the cerebral oxygen metabolism, protecting the blood–brain-barrier, regulating the inflammatory response, regulating the excessive release of neurotransmitters, inhibiting calcium overload, and reducing neuronal apoptosis. In many aspects, particularly in regulating inflammatory reverse reaction, various results have been reported and therefore guide scholars to conduct more detailed analysis and investigation in order to discover the inherent theories surrounding the effect of mild hypothermia, and for better clinical services.
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Affiliation(s)
- Long Bao
- Department of Emergency medicine, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China
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Sall JW, Leong J. Technical communication: stability of propofol in polystyrene-based tissue culture plates. Anesth Analg 2013; 117:65-7. [PMID: 23632056 DOI: 10.1213/ane.0b013e318292f32e] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Propofol has been reported to have high stability in glass and relatively high stability up to 24 hours in polyvinyl chloride-based medical plastics. Recent publications have observed the effects of propofol on cells and tissues grown in culture. Many cell culture plastics are formulated from polystyrene but we could find little information on the stability of propofol exposed to these products. We observed very little change in the concentration of propofol diluted in cell culture medium over 24 hours when exposed to glass, but substantial loss of the drug when exposed to 96-well polystyrene cell culture plates. This decrease was most rapid in the first hour but continued until 24 hours. The type of plastic used in cell and tissue culture experiments with propofol may influence the results by increasing the apparent dose required to see an effect.
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Affiliation(s)
- Jeffrey W Sall
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, S255, Box 0542, 513 Parnassus Ave., San Francisco, CA 94143-0542, USA.
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Cui D, Wang L, Qi A, Zhou Q, Zhang X, Jiang W. Propofol prevents autophagic cell death following oxygen and glucose deprivation in PC12 cells and cerebral ischemia-reperfusion injury in rats. PLoS One 2012; 7:e35324. [PMID: 22509406 PMCID: PMC3324553 DOI: 10.1371/journal.pone.0035324] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2012] [Accepted: 03/12/2012] [Indexed: 12/11/2022] Open
Abstract
Background Propofol exerts protective effects on neuronal cells, in part through the inhibition of programmed cell death. Autophagic cell death is a type of programmed cell death that plays elusive roles in controlling neuronal damage and metabolic homeostasis. We therefore studied whether propofol could attenuate the formation of autophagosomes, and if so, whether the inhibition of autophagic cell death mediates the neuroprotective effects observed with propofol. Methodology/Principal Findings The cell model was established by depriving the cells of oxygen and glucose (OGD) for 6 hours, and the rat model of ischemia was introduced by a transient two-vessel occlusion for 10 minutes. Transmission electron microscopy (TEM) revealed that the formation of autophagosomes and autolysosomes in both neuronal PC12 cells and pyramidal rat hippocampal neurons after respective OGD and ischemia/reperfusion (I/R) insults. A western blot analysis revealed that the autophagy-related proteins, such as microtubule-associated protein 1 light chain 3 (LC3-II), Beclin-1 and class III PI3K, were also increased accordingly, but cytoprotective Bcl-2 protein was decreased. The negative effects of OGD and I/R, including the formation of autophagosomes and autolysosomes, the increase in LC3-II, Beclin-1 and class III PI3K expression and the decline in Bcl-2 production were all inhibited by propofol and specific inhibitors of autophagy, such as 3-methyladenine (3-MA), LY294002 and Bafilomycin A1 (Baf),. Furthermore, in vitro OGD cultures and in vivo I/R rats showed an increase in cell survival following the administration of propofol, as assessed by an MTT assay or histochemical analyses. Conclusions/Significance Our data suggest that propofol can markedly attenuate autophagic processes via the decreased expression of autophagy-related proteins in vitro and in vivo. This inhibition improves cell survival, which provides a novel explanation for the pleiotropic effects of propofol that benefit the nervous system.
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Affiliation(s)
- Derong Cui
- Department of Anesthesiology, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiaotong University, Shanghai, China
| | - Li Wang
- Department of Anesthesiology, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiaotong University, Shanghai, China
| | - Aihua Qi
- Department of Postgraduate School, Soochow University, Suzhou, China
| | - Quanhong Zhou
- Department of Anesthesiology, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiaotong University, Shanghai, China
| | - Xiaoli Zhang
- Department of Anesthesiology, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiaotong University, Shanghai, China
| | - Wei Jiang
- Department of Anesthesiology, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiaotong University, Shanghai, China
- * E-mail:
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Patel RV, Stygall J, Harrington J, Newman SP, Haddad FS. Cerebral microembolization during primary total hip arthroplasty and neuropsychologic outcome: a pilot study. Clin Orthop Relat Res 2010; 468:1621-9. [PMID: 19838644 PMCID: PMC2865620 DOI: 10.1007/s11999-009-1140-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2009] [Accepted: 10/02/2009] [Indexed: 01/31/2023]
Abstract
BACKGROUND Intraoperative cerebral microembolization occurs in a substantial proportion of patients undergoing THA. Historically, postoperative cognitive dysfunction has been attributed to different factors, including anesthesia, but the influence of the surgery has not been thoroughly examined. QUESTIONS/PURPOSES We conducted a prospective, controlled clinical trial to assess intraoperative cerebral microembolization during THA and neuropsychologic outcome. METHODS The presence of a patent foramen ovale (PFO) also was investigated, using transcranial Doppler, to determine whether this affected cerebral microembolic incidence and load and whether microemboli occurred as a result of specific surgical activity. Forty-five patients were recruited who underwent THA and neuropsychologic assessment; a battery of tests was administered preoperatively and at 6 weeks and 6 months postoperatively. RESULTS Overall, patients showed improvement in total neuropsychologic change scores at both postoperative intervals. The incidence of cerebral microembolization for THA was 23%. The prevalence of PFO was 37%. PFO did not appear to influence microemboli load or incidence. More microemboli were seen during femoral component insertion and impaction. CONCLUSIONS Intraoperative cerebral microembolization occurs in a substantial proportion of patients during THA recorded by transcranial Doppler. The microemboli load is low and is not influenced by the presence of PFO. Certain surgical activities seem responsible for greater cerebral microemboli generation. However, neuropsychologic outcome was not affected postoperatively by microemboli or other operative or patient variables.
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MESH Headings
- Aged
- Arthroplasty, Replacement, Hip/adverse effects
- Arthroplasty, Replacement, Hip/psychology
- Cognition Disorders/diagnosis
- Cognition Disorders/epidemiology
- Cognition Disorders/etiology
- Female
- Foramen Ovale, Patent/complications
- Foramen Ovale, Patent/diagnostic imaging
- Foramen Ovale, Patent/epidemiology
- Humans
- Incidence
- Intracranial Embolism/diagnostic imaging
- Intracranial Embolism/epidemiology
- Intracranial Embolism/etiology
- Male
- Middle Aged
- Neuropsychological Tests
- Osteoarthritis, Hip/surgery
- Pilot Projects
- Prevalence
- Prospective Studies
- Risk Assessment
- Risk Factors
- Time Factors
- Treatment Outcome
- Ultrasonography, Doppler, Transcranial
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Affiliation(s)
- Rahul V Patel
- Department of Trauma & Orthopaedics, University College London Hospitals Trust, Flat 3, 39 Priory Terrace, NW6 4DG London, UK.
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Cell death and proliferation in acute slices and organotypic cultures of mammalian CNS. Prog Neurobiol 2009; 88:221-45. [DOI: 10.1016/j.pneurobio.2009.01.002] [Citation(s) in RCA: 112] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2008] [Revised: 12/09/2008] [Accepted: 01/07/2009] [Indexed: 11/24/2022]
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Rossaint J, Rossaint R, Weis J, Fries M, Rex S, Coburn M. Propofol: neuroprotection in an in vitro model of traumatic brain injury. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2009; 13:R61. [PMID: 19397790 PMCID: PMC2689510 DOI: 10.1186/cc7795] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2009] [Revised: 03/18/2009] [Accepted: 04/27/2009] [Indexed: 02/01/2023]
Abstract
Introduction The anaesthetic agent propofol (2,6-diisopropylphenol) has been shown to be an effective neuroprotective agent in different in vitro models of brain injury induced by oxygen and glucose deprivation. We examined its neuroprotective properties in an in vitro model of traumatic brain injury. Methods In this controlled laboratory study organotypic hippocampal brain-slice cultures were gained from six- to eight-day-old mice pups. After 14 days in culture, hippocampal brain slices were subjected to a focal mechanical trauma and subsequently treated with different molar concentrations of propofol under both normo- and hypothermic conditions. After 72 hours of incubation, tissue injury assessment was performed using propidium iodide (PI), a staining agent that becomes fluorescent only when it enters damaged cells via perforated cell membranes. Inside the cell, PI forms a fluorescent complex with nuclear DNA. Results A dose-dependent reduction of both total and secondary tissue injury could be observed in the presence of propofol under both normo- and hypothermic conditions. This effect was further amplified when the slices were incubated at 32°C after trauma. Conclusions When used in combination, the dose-dependent neuroprotective effect of propofol is additive to the neuroprotective effect of hypothermia in an in vitro model of traumatic brain injury.
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Affiliation(s)
- Jan Rossaint
- Department of Anesthesiology, RWTH Aachen University Hospital, Pauwelsstrasse 30, 52074 Aachen, Germany
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Dalen ML, Frøyland E, Saugstad OD, Mollnes TE, Rootwelt T. Post-hypoxic hypothermia is protective in human NT2-N neurons regardless of oxygen concentration during reoxygenation. Brain Res 2009; 1259:80-9. [DOI: 10.1016/j.brainres.2008.12.055] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2008] [Revised: 12/22/2008] [Accepted: 12/22/2008] [Indexed: 01/08/2023]
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Vasileiou I, Xanthos T, Koudouna E, Perrea D, Klonaris C, Katsargyris A, Papadimitriou L. Propofol: A review of its non-anaesthetic effects. Eur J Pharmacol 2009; 605:1-8. [DOI: 10.1016/j.ejphar.2009.01.007] [Citation(s) in RCA: 173] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Sigaut S, Jannier V, Rouelle D, Gressens P, Mantz J, Dahmani S. The Preconditioning Effect of Sevoflurane on the Oxygen Glucose-Deprived Hippocampal Slice: The Role of Tyrosine Kinases and Duration of Ischemia. Anesth Analg 2009; 108:601-8. [DOI: 10.1213/ane.0b013e31818e2018] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Cimarosti H, Henley JM. Investigating the mechanisms underlying neuronal death in ischemia using in vitro oxygen-glucose deprivation: potential involvement of protein SUMOylation. Neuroscientist 2008; 14:626-36. [PMID: 19029060 PMCID: PMC3310903 DOI: 10.1177/1073858408322677] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
It is well established that brain ischemia can cause neuronal death via different signaling cascades. The relative importance and interrelationships between these pathways, however, remain poorly understood. Here is presented an overview of studies using oxygen-glucose deprivation of organotypic hippocampal slice cultures to investigate the molecular mechanisms involved in ischemia. The culturing techniques, setup of the oxygen-glucose deprivation model, and analytical tools are reviewed. The authors focus on SUMOylation, a posttranslational protein modification that has recently been implicated in ischemia from whole animal studies as an example of how these powerful tools can be applied and could be of interest to investigate the molecular pathways underlying ischemic cell death.
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Affiliation(s)
- Helena Cimarosti
- MRC Centre for Synaptic Plasticity, Department of Anatomy, University Walk, University of Bristol, Bristol, UK
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Adembri C, Venturi L, Pellegrini-Giampietro DE. Neuroprotective effects of propofol in acute cerebral injury. CNS DRUG REVIEWS 2008; 13:333-51. [PMID: 17894649 PMCID: PMC6494151 DOI: 10.1111/j.1527-3458.2007.00015.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Propofol (2,6-diisopropylphenol) is one of the most popular agents used for induction of anesthesia and long-term sedation, owing to its favorable pharmacokinetic profile, which ensures a rapid recovery even after prolonged administration. A neuroprotective effect, beyond that related to the decrease in cerebral metabolic rate for oxygen, has been shown to be present in many in vitro and in vivo established experimental models of mild/moderate acute cerebral ischemia. Experimental studies on traumatic brain injury are limited and less encouraging. Despite the experimental results and the positive effects on cerebral physiology (propofol reduces cerebral blood flow but maintains coupling with cerebral metabolic rate for oxygen and decreases intracranial pressure, allowing optimal intraoperative conditions during neurosurgical operations), no clinical study has yet indicated that propofol may be superior to other anesthetics in improving the neurological outcome following acute cerebral injury. Therefore, propofol cannot be indicated as an established clinical neuroprotectant per se, but it might play an important role in the so-called multimodal neuroprotection, a global strategy for the treatment of acute injury of the brain that includes preservation of cerebral perfusion, temperature control, prevention of infections, and tight glycemic control.
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Affiliation(s)
- Chiara Adembri
- Section of Anesthesiology and Intensive Care, Department of Critical Care, University of Florence, Italy.
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Kotani Y, Shimazawa M, Yoshimura S, Iwama T, Hara H. The experimental and clinical pharmacology of propofol, an anesthetic agent with neuroprotective properties. CNS Neurosci Ther 2008; 14:95-106. [PMID: 18482023 PMCID: PMC6494023 DOI: 10.1111/j.1527-3458.2008.00043.x] [Citation(s) in RCA: 166] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Propofol (2,6-diisopropylphenol) is a versatile, short-acting, intravenous (i.v.) sedative-hypnotic agent initially marketed as an anesthetic, and now also widely used for the sedation of patients in the intensive care unit (ICU). At the room temperature propofol is an oil and is insoluble in water. It has a remarkable safety profile. Its most common side effects are dose-dependent hypotension and cardiorespiratory depression. Propofol is a global central nervous system (CNS) depressant. It activates gamma-aminobutyric acid (GABA A) receptors directly, inhibits the N-methyl-d-aspartate (NMDA) receptor and modulates calcium influx through slow calcium-ion channels. Furthermore, at doses that do not produce sedation, propofol has an anxiolytic effect. It has also immunomodulatory activity, and may, therefore, diminish the systemic inflammatory response believed to be responsible for organ dysfunction. Propofol has been reported to have neuroprotective effects. It reduces cerebral blood flow and intracranial pressure (ICP), is a potent antioxidant, and has anti-inflammatory properties. Laboratory investigations revealed that it might also protect brain from ischemic injury. Propofol formulations contain either disodium edetate (EDTA) or sodium metabisulfite, which have antibacterial and antifungal properties. EDTA is also a chelator of divalent ions such as calcium, magnesium, and zinc. Recently, EDTA has been reported to exert a neuroprotective effect itself by chelating surplus intracerebral zinc in an ischemia model. This article reviews the neuroprotective effects of propofol and its mechanism of action.
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Affiliation(s)
- Yoshinori Kotani
- Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Gifu 502-8585, Japan
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Gressens P, Dingley J, Plaisant F, Porter H, Schwendimann L, Verney C, Tooley J, Thoresen M. Analysis of neuronal, glial, endothelial, axonal and apoptotic markers following moderate therapeutic hypothermia and anesthesia in the developing piglet brain. Brain Pathol 2007; 18:10-20. [PMID: 17924981 DOI: 10.1111/j.1750-3639.2007.00095.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Hypothermia (HT) by whole body (WBC) or selective head cooling (SHC) reduces hypoxic-ischemic (HI) brain injury; however, whether prolonged hypothermia and/or anesthesia disrupts immature brain development, eg, increases apoptosis, is unknown. Anesthesia increases apoptosis in immature animals. We investigated whether neuroprotective hypothermia and anesthesia disrupts normal brain development. Thirty-eight pigs <24 h old were randomized between five groups and were killed after 72 h: eighteen received a global hypoxic-ischemic insult under anesthesia, eight subsequently cooled by SHC with WBC to T(rectal) 34.5 degrees C for 24 h, followed by 48 h normothermia (NT) at T(rectal) 39.0 degrees C, while 10 remained normothermic. Sixteen underwent anesthetized sham hypoxic-ischemic, six then following normothermia and 10 following hypothermia protocols. There were four normothermic controls. The hypothermia groups demonstrated significant brain hypothermia. In the hypoxic-ischemic groups this conferred approximately 60% neuroprotection reducing histological injury scores in all brain areas. Immunohistochemical/histochemical analyses of neuronal, glial, endothelial, axonal, transcriptional apoptotic markers in areas devoid of histological lesions revealed no hypothermia/normothermia group and differences whether exposed to hypoxic-ischemic or not. Neither 36-h anesthesia nor 24-h hypothermia produced adverse effects at 4-day survival on a panel of brain maturation/neural death markers in newborn pigs. Longer survival studies are necessary to verify the safety of hypothermia in the developing brain.
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Abstract
Carotid endarterectomy (CEA) is performed to prevent embolic stroke in patients with atheromatous disease at the carotid bifurcation. There is now substantial evidence to support early operation in symptomatic patients, ideally within 2 weeks of the last neurological symptoms. Thus, the anaesthetist may be faced with a high risk patient in whom there has been limited time for preoperative preparation. The operation may be performed under local or general anaesthesia. The advantages and disadvantages of both are explored in this review. Carotid shunting may offer a degree of cerebral protection, but carries its own risks and has not been proved to reduce morbidity and mortality. The use of carotid shunts is based on clinical judgement, awake neurological monitoring, and the use of monitors of cerebral perfusion. There is no ideal monitor of cerebral perfusion in the patient receiving general anaesthesia. Both the intraoperative and postoperative periods may be witness to dramatic haemodynamic changes that may compromise the cerebral or myocardial circulations. In particular, postoperative hypotension may compromise both myocardial and cerebral perfusion, and severe hypertension can cause cerebral hyperperfusion. There is as yet limited evidence to guide the management of these problems. In summary, CEA can yield significant benefit, but those with the most to gain from the operation also present the greatest challenge to the anaesthetist.
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Affiliation(s)
- S J Howell
- Academic Unit of Anaesthesia, The General Infirmary at Leeds, Great George Street, Leeds LS1 3EX, UK.
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Abstract
PURPOSE OF REVIEW Patients at risk for perioperative stroke, or those who have suffered recent cerebral injury, may benefit from neuroprotective properties of anesthetic agents during surgery. This manuscript reviews recent clinical and experimental evidence for neuroprotective effects of common anesthetic agents, and presents potential mechanisms involved in anesthetic neuroprotection. RECENT FINDINGS Although strong experimental data support a neuroprotective potential of several anesthetic agents, specifically isoflurane and xenon, consistent long-term protection by either agent has not been demonstrated. Unfortunately, there is a lack of clinical studies that would support the use of any one anesthetic agent over the others. Mechanisms of neuroprotection by anesthetic agents appear to involve suppression of excitatory neurotransmission, and potentiation of inhibitory activity, which may contribute to the reduction of excitotoxic injury. Activation of intracellular signaling cascades that lead to altered expression of protective genes may also be involved. SUMMARY Solid experimental evidence supports neuroprotection by anesthetic agents. It is too early to recommend any specific agent for clinical use as a neuroprotectant, however. Further study is warranted to unravel relevant mechanisms and to appreciate the potential clinical relevance of experimental findings.
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Affiliation(s)
- Ines P Koerner
- Department of Anesthesiology and Peri-Operative Medicine, Oregon Health and Science University, Portland, Oregon 97239, USA
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Al-Jahdari WS, Saito S, Goto F, Nakano T. Propofol induces growth cone collapse and neurite retractions in chick explant culture[Le propofol provoque un collapsus des cônes de croissance et des rétractions des neurites de poussin embryonnaire en culture]. Can J Anaesth 2006; 53:1078. [DOI: 10.1007/bf03022874] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/13/2006] [Indexed: 10/20/2022] Open
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