Mitochondria and neuronal death/survival signaling pathways in cerebral ischemia.
Apoptotic cell death pathways have been implicated in acute brain injuries, including cerebral ischemia, brain trauma, and spinal cord injury, and in chronic neurodegenerative diseases. Experimental ischemia and reperfusion models, such as transient focal/global ischemia in rodents, have been thoroughly studied and suggest the involvement of mitochondria and the cell survival/death signaling pathways in cell death/survival cascades. Recent studies have implicated mitochondria-dependent apoptosis involving pro- and antiapoptotic protein binding, the release of cytochrome c and second mitochondria-derived activator of caspase, the activation of downstream caspases-9 and -3, and DNA fragmentation. Reactive oxygen species are known to be significantly generated in the mitochondrial electron transport chain in the dysfunctional mitochondria during reperfusion after ischemia, and are also implicated in the survival signaling pathway that involves phosphatidylinositol-3-kinase (PI3-K), Akt, and downstream signaling molecules, like Bad, 14-3-3, and the proline-rich Akt substrate (PRAS), and their bindings. Further studies of these survival pathways may provide novel therapeutic strategies for clinical stroke.
Chan
Pak H
PH
Department of Neurosurgery, Stanford University School of Medicine, Stanford, California 94305-5487, USA. phchan@stanford.edu
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002545:Brain Ischemia / Q000473:pathology*; D002470:Cell Survival / Q000502:physiology; D006801:Humans; D008928:Mitochondria / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*