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

2002 ◽  
Vol 97 (4) ◽  
pp. 896-901 ◽  
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.

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

1999 ◽  
Vol 19 (1) ◽  
pp. 39-43 ◽  
Author(s):  
Miguel A. Pérez-Pinzón ◽  
Guang Ping Xu ◽  
James Born ◽  
José Lorenzo ◽  
Raul Busto ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Cytochrome C ◽  
Mitochondrial Dysfunction ◽  
Neuronal Death ◽  
Hippocampal Slices ◽  
Neuronal Cell Death ◽  
Brain Slices ◽  
Neuronal Cell ◽  
Severe Hypoxia ◽  
Delayed Neuronal Death

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.

Does remote ischemic preconditioning prevent delayed hippocampal neuronal death following transient global cerebral ischemia in rats?

Perfusion ◽  
2009 ◽  
Vol 24 (3) ◽  
pp. 207-211 ◽  
Author(s):  
Pankaj Saxena ◽  
Arul Bala ◽  
Kym Campbell ◽  
Bruno Meloni ◽  
Yves d'Udekem ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
General Anesthesia ◽  
Ischemic Preconditioning ◽  
Neuronal Death ◽  
Limb Ischemia ◽  
Global Cerebral Ischemia ◽  
Sham Procedure ◽  
Transient Global Cerebral Ischemia ◽  
Hippocampal Ca1 ◽  
Ischemia Group

Objective: To determine if remote ischemic preconditioning (RIPC) induced by transient limb ischemia is protective against delayed hippocampal neuronal death in rats undergoing transient global cerebral ischemia (GCI). Method: Animals were randomized into 3 groups: Group I (Control, n = 5) underwent sham procedure, namely, general anesthesia x 2, without cerebral ischemia; Group II (RIPC + GCI, n = 5) was subjected to RIPC, induced by transient left hind limb ischemia under general anesthesia prior to GCI; Group III (GCI only, n = 5) underwent sham procedure under general anesthesia prior to GCI. Twenty-four hours after the RIPC or sham procedure, a transient GCI was induced for 8 minutes in Groups II and III by means of bilateral common carotid artery occlusion and hypotension. Hippocampal CA1 neurons were histologically examined at 7 days after ischemia. Results: There was no significant difference between the RIPC group and the ischemia only group. The number of neurons in the RIPC group were 0.90 (95% CI 0.20, 4.08) times the number in the ischemia group (p=0.89). The number of neurons in the RIPC group were 0.03 (95% CI 0.01, 0.10) times the number in the Control group (p=0.0001). Conclusion: Second window of the RIPC does not prevent hippocampal CA1 neuronal death at 7 days after transient global cerebral ischemia.

scholarly journals Both Caspase-Dependent and Caspase-Independent Pathways May Be Involved in Hippocampal CA1 Neuronal Death Because of Loss of Cytochrome c from Mitochondria in a Rat Forebrain Ischemia Model

2001 ◽  
Vol 21 (5) ◽  
pp. 529-540 ◽  
Author(s):  
Ren-Zhi Zhan ◽  
Chaoran Wu ◽  
Hideyoshi Fujihara ◽  
Kiichiro Taga ◽  
Sihua Qi ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Ischemic Preconditioning ◽  
Neuronal Death ◽  
Late Phase ◽  
Mitochondrial Cytochrome ◽  
Forebrain Ischemia ◽  
Ca1 Neurons ◽  
Hippocampal Ca1 ◽  
Rat Forebrain ◽  
Mitochondrial Cytochrome C

In a rat forebrain ischemia model, the authors examined whether loss of cytochrome c from mitochondria correlates with ischemic hippocampal CA1 neuronal death and how cytochrome c release may shape neuronal death. Forebrain ischemia was induced by bilateral common carotid artery occlusion with simultaneous hypotension for 10 minutes. After reperfusion, an early rapid depletion of mitochondrial cytochrome c and a late phase of diffuse redistribution of cytochrome c occurred in the hippocampal CA1 region, but not in the dentate gyrus and CA3 regions. Intracerebroventricular administration of Z-DEVD-FMK, a relatively selective caspase-3 inhibitor, provided limited but significant protection against ischemic neuronal damage on day 7 after reperfusion. Treatment with 3 minutes of ischemia (ischemic preconditioning) 48 hours before the 10-minute ischemia attenuated both the early and late phases of cytochrome c redistribution. In another subset of animals treated with cycloheximide, a general protein synthesis inhibitor, the late phase of cytochrome c redistribution was inhibited, whereas most hippocampal CA1 neurons never regained mitochondrial cytochrome c. Examination of neuronal survival revealed that ischemic preconditioning prevents, whereas cycloheximide only delays, ischemic hippocampal CA1 neuronal death. DNA fragmentation detected by terminal deoxytransferase-mediated dUTP-nick end labeling (TUNEL) in situ was largely attenuated by ischemic preconditioning and moderately reduced by cycloheximide. These results indicate that the loss of cytochrome c from mitochondria correlates with hippocampal CA1 neuronal death after transient cerebral ischemia in relation to both caspase-dependent and -independent pathways. The amount of mitochondrial cytochrome c regained may determine whether ischemic hippocampal CA1 neurons survive or succumb to late-phase death.

Mitochondrial translocation of p53 underlies the selective death of hippocampal CA1 neurons after global cerebral ischaemia

2006 ◽  
Vol 34 (6) ◽  
pp. 1283-1286 ◽  
Author(s):  
H. Endo ◽  
A. Saito ◽  
P.H. Chan
Keyword(s):  
Cytochrome C ◽  
Cerebral Ischaemia ◽  
Neuronal Death ◽  
Cytochrome C Release ◽  
P53 Pathway ◽  
Ca1 Neurons ◽  
Mitochondrial Translocation ◽  
Hippocampal Ca1 Neurons ◽  
Hippocampal Ca1 ◽  
Global Cerebral Ischaemia

p53, a tumour suppressor, is involved in DNA repair and cell death processes and mediates apoptosis in response to death stimuli by transcriptional activation of pro-apoptotic genes and by transcription-independent mechanisms. In the latter process, p53 induces permeabilization of the outer mitochondrial membrane by forming an inhibitory complex with a protective Bcl-2 family protein, resulting in cytochrome c release in several cell line systems. However, it is unclear how the mitochondrial p53 pathway mediates neuronal apoptosis after cerebral ischaemia. We examined interaction between the mitochondrial p53 pathway and vulnerable hippocampal CA1 neurons using a tGCI (transient global cerebral ischaemia) rat model. We showed mitochondrial translocation of p53 and its binding to Bcl-XL. Mitochondrial p53 translocation, interaction between p53 and Bcl-XL, and cytochrome c release from mitochondria and subsequent CA1 neuronal death were prevented by pifithrin-α, a p53-specific inhibitor. These results suggest that the mitochondrial p53 pathway plays a role in delayed CA1 neuronal death after tGCI.

Sign in / Sign up

Export Citation Format

Share Document