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Bilateral Common Carotid Artery Occlusion as an Adequate Preconditioning Stimulus to Induce Early Ischemic Tolerance to Focal Cerebral Ischemia
Published on: May 9, 2013
Effect of ischemic preconditioning on mitochondrial dysfunction and mitochondrial p53 translocation after transient
Peter Racay1, Zuzana Tatarkova, Anna Drgova
1Institute of Biochemistry, Jessenius Faculty of Medicine, Comenius University, Mala Hora 4, Martin 03601, Slovak Republic. racay@jfmed.uniba.sk
Abstract:
Transient global brain ischemia induces dysfunctions of mitochondria including disturbance in mitochondrial protein synthesis and inhibition of respiratory chain complexes. Due to capacity of mitochondria to release apoptogenic proteins, ischemia-induced mitochondrial dysfunction is considered to be a key event coupling cerebral blood flow arrest to neuronal cell death. Ischemic preconditioning (IPC) represents an important phenomenon of adaptation of central nervous system (CNS) to sub-lethal short-term ischemia, which results in increased tolerance of CNS to the lethal ischemia. In this study we have determined the effect of ischemic preconditioning on ischemia/reperfusion-associated inhibition of mitochondrial protein synthesis and activity of mitochondrial respiratory chain complexes I and IV in the hippocampus of rats. Global brain ischemia was induced by 4-vessel occlusion in duration of 15 min. Rats were preconditioned by 5 min of sub-lethal ischemia and 2 days later, 15 min of lethal ischemia was induced. Our results showed that IPC affects ischemia-induced dysfunction of hippocampal mitochondria in two different ways. Repression of mitochondrial translation induced during reperfusion of the ischemic brain is significantly attenuated by IPC. Slight protective effect of IPC was documented for complex IV, but not for complex I. Despite this, protective effect of IPC on ischemia/reperfusion-associated changes in integrity of mitochondrial membrane and membrane proteins were observed. Since IPC exhibited also inhibitory effect on translocation of p53 to mitochondria, our results indicate that IPC affects downstream processes connecting mitochondrial dysfunction to neuronal cell death.
Insights
Ischemic preconditioning (IPC) protects brain mitochondria from ischemia/reperfusion injury by attenuating protein synthesis repression and preserving mitochondrial membrane integrity. This adaptation enhances neuronal tolerance to lethal ischemia.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Ischemia Research
Background:
- Transient global brain ischemia causes mitochondrial dysfunction, including impaired protein synthesis and inhibited respiratory chain complexes.
- Mitochondrial release of apoptogenic proteins links ischemia to neuronal cell death.
- Ischemic preconditioning (IPC) is a CNS adaptation that increases tolerance to lethal ischemia.
Purpose of the Study:
- To investigate the effect of IPC on ischemia/reperfusion-induced inhibition of mitochondrial protein synthesis and respiratory chain complex activity in rat hippocampus.
- To determine IPC's impact on mitochondrial membrane integrity and p53 translocation.
Main Methods:
- Global brain ischemia induced via 4-vessel occlusion (15 min).
- IPC applied (5 min sub-lethal ischemia) 2 days prior to lethal ischemia.
- Assessed mitochondrial protein synthesis, respiratory chain complex I and IV activity, membrane integrity, and p53 translocation in rat hippocampus.
Main Results:
- IPC significantly attenuated ischemia-induced repression of mitochondrial translation during reperfusion.
- IPC showed a slight protective effect on Complex IV activity, but not Complex I.
- IPC preserved mitochondrial membrane integrity and membrane proteins, and inhibited p53 translocation to mitochondria.
Conclusions:
- IPC mitigates ischemia/reperfusion-induced mitochondrial dysfunction in the hippocampus.
- IPC's protective effects involve attenuating mitochondrial translation inhibition and preserving membrane integrity.
- IPC may protect neurons by influencing downstream events that link mitochondrial dysfunction to cell death, including p53-mediated pathways.
