Cytochrome C Is Released from Mitochondria Into the Cytosol after Cerebral Anoxia or Ischemia

Mitochondrial dysfunction may underlie both acute and delayed neuronal cell death resulting from cerebral ischemia. Specifically, postischemic release of mitochondrial constituents such as the pro-apoptotic respiratory chain component cytochrome c could contribute acutely to further mitochondrial dysfunction and to promote delayed neuronal death. Experiments reported here tested the hypothesis that ischemia or severe hypoxia results in release of cytochrome c from mitochondria. Cytochrome c was measured spectrophotometrically from either the cytosolic fraction of cortical brain homogenates after global ischemia plus reperfusion, or from brain slices subjected to severe hypoxia plus reoxygenation. Cytochrome c content in cytosol derived from cerebral cortex was increased after ischemia and reperfusion. In intact hippocampal slices, there was a loss of reducible cytochrome c after hypoxia/reoxygenation, which is consistent with a decrease of this redox carrier in the mitochondrial pool. These results suggest that cytochrome c is lost to the cytosol after cerebral ischemia in a manner that may contribute to postischemic mitochondrial dysfunction and to delayed neuronal death.

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Ischemic Preconditioning Is Capable of Inducing Mitochondrial Tolerance in the Rat Brain

Anesthesiology ◽

10.1097/00000542-200210000-00022 ◽

2002 ◽

Vol 97 (4) ◽

pp. 896-901 ◽

Cited By ~ 23

Author(s):

Ren-Zhi Zhan ◽

Hideyoshi Fujihara ◽

Hiroshi Baba ◽

Tomohiro Yamakura ◽

Koki Shimoji

Keyword(s):

Cerebral Ischemia ◽

Cytochrome C ◽

Mitochondrial Dysfunction ◽

Ischemic Preconditioning ◽

Neuronal Death ◽

Brain Mitochondria ◽

Sham Operation ◽

Cytochrome C Release ◽

Hippocampal Ca1 ◽

Ischemic Episode

Background Preconditioning to ischemia is a phenomenon whereby a brief episode of sublethal ischemia and other nonlethal stressors produce protection against a subsequent detrimental ischemic insult. As mitochondrial dysfunction is related to necrotic and apoptotic neuronal death after cerebral ischemia, the authors examined if ischemic preconditioning is capable of inducing mitochondrial tolerance. Methods Forebrain ischemia was induced by bilateral common carotid artery occlusion with simultaneous hypotension for 8 min in Wistar rats (275-300 g). A 3-min ischemic episode performed 48 h before the 8-min ischemia was used for preconditioning. The extents of hippocampal CA1 neuronal damage were evaluated 7 days after reperfusion by neuro-specific nuclear protein immunostaining. Brain mitochondria were isolated 48 h after animals were subjected to the sham operation or the 3-min conditioning ischemia. Loss of cytochrome c from mitochondria after cerebral ischemia in vivo and after exposure of brain mitochondria to calcium in vitro was used as an indication of mitochondrial dysfunction. Results Results showed that ischemic preconditioning induced by a 3-min ischemic episode dramatically reduced the loss of hippocampal CA1 neurons resulting from a subsequent 8-min ischemia 7 days after reperfusion, and this protection was associated with a preservation of mitochondrial cytochrome c as examined after early reperfusion. Exposure of isolated brain mitochondria to calcium produced a dose-dependent increase in cytochrome c release either at 30 degrees C or at 37 degrees C. Compared with those animals receiving only sham operation, cytochrome c release caused by 100 microm calcium was significantly reduced in conditioned animals. Conclusion Regarding the importance of mitochondrial dysfunction in mediating ischemic neuronal death, the above results indicate that mitochondria may serve as end-effecting organelles to ischemic preconditioning.

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Role of P2X7 Receptors in Ischemic and Excitotoxic Brain Injury In Vivo

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/01.wcb.0000048519.34839.97 ◽

2003 ◽

Vol 23 (3) ◽

pp. 381-384 ◽

Cited By ~ 45

Author(s):

Rosalind A. Le Feuvre ◽

David Brough ◽

Omar Touzani ◽

Nancy J. Rothwell

Keyword(s):

Cell Death ◽

Cerebral Ischemia ◽

Neuronal Death ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

P2x7 Receptors ◽

Excitotoxic Cell Death ◽

Experimentally Induced

Purinergic P2X7 receptors may affect neuronal cell death through their ability to regulate the processing and release of interleukin-1β (IL-1β), a key mediator in neurodegeneration. The authors tested the hypothesis that ATP, acting at P2X7 receptors, contributes to experimentally induced neuronal death in rodents in vivo. Deletion of P2X7 receptors (P2X7 knockout mice) did not affect cell death induced by temporary cerebral ischemia, which was reduced by treatment with IL-1 receptor antagonist (IL-1RA). Treatment of mice with P2X antagonists did not affect ischemic or excitotoxic cell death, suggesting that P2X7 receptors are not primary mediators of experimentally induced neuronal death.

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The Effects of Sodium Dichloroacetate on Mitochondrial Dysfunction and Neuronal Death Following Hypoglycemia-Induced Injury

Cells ◽

10.3390/cells8050405 ◽

2019 ◽

Vol 8 (5) ◽

pp. 405 ◽

Cited By ~ 5

Author(s):

A Ra Kho ◽

Bo Young Choi ◽

Song Hee Lee ◽

Dae Ki Hong ◽

Jeong Hyun Jeong ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Pyruvate Dehydrogenase ◽

Neuronal Death ◽

Therapeutic Potential ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Pyruvate Dehydrogenase Kinase ◽

Histological Evaluation ◽

Glucose Levels ◽

Blood Brain Barrier Disruption

Our previous studies demonstrated that some degree of neuronal death is caused by hypoglycemia, but a subsequent and more severe wave of neuronal cell death occurs due to glucose reperfusion, which results from the rapid restoration of low blood glucose levels. Mitochondrial dysfunction caused by hypoglycemia leads to increased levels of pyruvate dehydrogenase kinase (PDK) and suppresses the formation of ATP by inhibiting pyruvate dehydrogenase (PDH) activation, which can convert pyruvate into acetyl-coenzyme A (acetyl-CoA). Sodium dichloroacetate (DCA) is a PDK inhibitor and activates PDH, the gatekeeper of glucose oxidation. However, no studies about the effect of DCA on hypoglycemia have been published. In the present study, we hypothesized that DCA treatment could reduce neuronal death through improvement of glycolysis and prevention of reactive oxygen species production after hypoglycemia. To test this, we used an animal model of insulin-induced hypoglycemia and injected DCA (100 mg/kg, i.v., two days) following hypoglycemic insult. Histological evaluation was performed one week after hypoglycemia. DCA treatment reduced hypoglycemia-induced oxidative stress, microglial activation, blood–brain barrier disruption, and neuronal death compared to the vehicle-treated hypoglycemia group. Therefore, our findings suggest that DCA may have the therapeutic potential to reduce hippocampal neuronal death after hypoglycemia.

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Apoptosis inducing factor (AIF) is essential for neuronal cell death following transient focal cerebral ischemia

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9591524.0466 ◽

2005 ◽

Vol 25 (1_suppl) ◽

pp. S466-S466

Author(s):

Carsten Culmsee ◽

Changlian Zhu ◽

Miriam Höhn ◽

Stefan Landshamer ◽

Uta Mamrak ◽

...

Keyword(s):

Cell Death ◽

Cerebral Ischemia ◽

Focal Cerebral Ischemia ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Transient Focal Cerebral Ischemia ◽

Apoptosis Inducing Factor

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Oxidative Stress: Major Threat in Traumatic Brain Injury

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527317666180627120501 ◽

2018 ◽

Vol 17 (9) ◽

pp. 689-695 ◽

Cited By ~ 37

Author(s):

Nidhi Khatri ◽

Manisha Thakur ◽

Vikas Pareek ◽

Sandeep Kumar ◽

Sunil Sharma ◽

...

Keyword(s):

Oxidative Stress ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Mitochondrial Dysfunction ◽

Calcium Influx ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Physical Assault ◽

Mortality And Morbidity ◽

Primary Injury

Background & Objective: Traumatic Brain Injury (TBI) is one of the major causes of mortality and morbidity worldwide. It represents mild, moderate and severe effects of physical assault to brain which may cause sequential, primary or secondary ramifications. Primary injury can be due to the first physical hit, blow or jolt to one of the brain compartments. The primary injury is then followed by secondary injury which leads to biochemical, cellular, and physiological changes like blood brain barrier disruption, inflammation, excitotoxicity, necrosis, apoptosis, mitochondrial dysfunction and generation of oxidative stress. Apart from this, there is also an immediate increase in glutamate at the synapses following severe TBI. Excessive glutamate at synapses in turn activates corresponding NMDA and AMPA receptors that facilitate excessive calcium influx into the neuronal cells. This leads to the generation of oxidative stress which further leads to mitochondrial dysfunction, lipid peroxidation and oxidation of proteins and DNA. As a consequence, neuronal cell death takes place and ultimately people start facing some serious disabilies. Conclusion: In the present review we provide extensive overview of the role of reactive oxygen species (ROS)-induced oxidative stress and its fatal effects on brain after TBI.

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miR-380-5p facilitates NRF2 and attenuates cerebral ischemia/reperfusion injury-induced neuronal cell death by directly targeting BACH1

Translational Neuroscience ◽

10.1515/tnsci-2020-0172 ◽

2021 ◽

Vol 12 (1) ◽

pp. 210-217

Author(s):

Yibiao Wang ◽

Min Xu

Keyword(s):

Cell Death ◽

Cerebral Ischemia ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Luciferase Assay ◽

Neuroprotective Effects ◽

Cerebral Ischemia Reperfusion

Abstract Background This study aimed to explore the role of miR-380-5p in cerebral ischemia/reperfusion (CIR) injury-induced neuronal cell death and the potential signaling pathway involved. Methodology Human neuroblastoma cell line SH-SY5Y cells were used in this study. Oxygen and glucose deprivation/reperfusion (OGD/R) model was used to mimic ischemia/reperfusion injury. CCK-8 assay and flow cytometry were used to examine cell survival. Quantitative real time PCR (RT-qPCR) assay and Western blotting were used to measure the change of RNA and protein expression, respectively. TargetScan and Luciferase assay was used to confirm the target of miR-380-5p. Malondialdehyde (MDA) superoxide dismutase (SOD) and glutathione peroxidase (GSHPx) were measured using commercial kits. Results miR-380-5p was downregulated in SH-SY5Y cells after OGD/R. Cell viability was increased by miR-380-5p, while cell apoptosis was reduced by miR-380-5p mimics. MDA was reduced by miR-380-5p mimics, while SOD and GSHPx were increased by miR-380-5p. Results of TargetScan and luciferase assay have showed that BACH1 is the direct target of miR-380-5p. Expression of NRF2 was upregulated after OGD/R, but was not affected by miR-380-5p. mRNA expression of HO-1 and NQO1 and ARE activity were increased by miR-380-5p. Overexpression of BACH1 reversed the antioxidant and neuroprotective effects of miR-380-5p. Conclusion miR-380-5p inhibited cell death induced by CIR injury through target BACH1 which also facilitated the activation of NRF2, indicating the antioxidant and neuroprotective effects of miR-380-5p.

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