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.

scholarly journals Calcium Movement in Ischemia-Tolerant Hippocampal CA1 Neurons after Transient Forebrain Ischemia in Gerbils

1996 ◽  
Vol 16 (5) ◽  
pp. 915-922 ◽  
Author(s):  
Shinsuke Ohta ◽  
Shigeru Furuta ◽  
Ichiro Matsubara ◽  
Keiji Kohno ◽  
Yoshiaki Kumon ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Neuronal Death ◽  
Pyramidal Neurons ◽  
Forebrain Ischemia ◽  
Electron Microscopic ◽  
Ca1 Neurons ◽  
Hippocampal Ca1 Neurons ◽  
Hippocampal Ca1 ◽  
Before And After ◽  
Intracellular Ca

Hippocampal CA1 neurons exposed to a nonlethal period (2 min) of ischemia, acquired tolerance to a subsequent lethal 5-min period of ischemia, which usually causes delayed-type neuronal death. Intracelluar Ca2+ movements before and after the 5 min of forebrain ischemia were evaluated in gerbil hippocampal CA1 pyramidal neurons, had acquired tolerance in comparison with nonischemia-tolerant CA1 neurons. Evaluation was performed by observing the ultrastructural intracellular Ca2+ distribution and the Ca2+ adenosine triphosphatase (Ca2+-ATPase) activity using electron microscopic cytochemistry. In comparison with nonischemia-tolerant CA1 neurons, mitochondria of ischemia-tolerant CA1 neurons sequestered more Ca2+ from the cytosomal fraction 15 min after the 5-min period of ischemia, and Ca2+ deposits in these mitochondria were rapidly decreased. Plasma membrane Ca2+-ATPase activities were already significantly elevated before the 5 min of ischemia, and remained at a higher level subsequently compared to nonischemia-tolerant CA1 neurons. Changes in the mitochondrial Ca2+ distribution and Ca2+-ATPase activities in ischemia-tolerant CA1 neurons after the 5-min period of ischemia showed a strong resemblance to those in CA3 neurons, which originally possess resistance to such periods of ischemia. These findings suggest that enhanced or maintained activities of mitochondrial Ca2+ sequestration and plasma membrane Ca2+-ATPase reduced Ca2+ toxicity following 5-min ischemia in terms of time, resulting in escape from delayed neuronal death.

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.

Release of cytochrome c from mitochondria to cytosol in gerbil hippocampal CA1 neurons after transient forebrain ischemia

1999 ◽  
Vol 849 (1-2) ◽  
pp. 216-219 ◽  
Author(s):  
Hiroki Nakatsuka ◽  
Shinsuke Ohta ◽  
Junya Tanaka ◽  
Kazuko Toku ◽  
Yoshiaki Kumon ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Forebrain Ischemia ◽  
Ca1 Neurons ◽  
Transient Forebrain Ischemia ◽  
Hippocampal Ca1 Neurons ◽  
Hippocampal Ca1

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.

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