Neuronal death/survival signaling pathways in cerebral ischemia

Abstract

Summary:Cumulative evidence suggests that apoptosis plays a pivotal role in cell death in vitro after hypoxia. Apoptotic cell death pathways have also been implicated in ischemic cerebral injury in in vivo ischemia models. Experimental ischemia and reperfusion models, such as transient focal/global ischemia in rodents, have been thoroughly studied and the numerous reports suggest the involvement of cell survival/death signaling pathways in the pathogenesis of apoptotic cell death in ischemic lesions. In these models, reoxygenation during reperfusion provides a substrate for numerous enzymatic oxidation reactions. Oxygen radicals damage cellular lipids, proteins and nucleic acids, and initiate cell signaling pathways after cerebral ischemia. Genetic manipulation of intrinsic antioxidants and factors in the signaling pathways has provided substantial understanding of the mechanisms involved in cell death/survival signaling pathways and the role of oxygen radicals in ischemic cerebral injury. Future studies of these pathways may provide novel therapeutic strategies in clinical stroke.

Apoptosis: Future Targets for Neuroprotective Strategies

“…Several studies with transgenic and knockout mice have shown that overexpression of SOD1 (cytosolic, copper/zinc superoxide dismutase) is associated with a marked reduction in infarct volume following permanent focal ischemia [64, 65]. SOD1 overexpression is also neuroprotective following global ischemia.…”

Role of Continuous High Thoracic Epidural Anesthesia in Hippocampal Apoptosis after Global Cerebral Ischemia in Rats

“…The superoxide radicals in hippocampal CA1 neurons returned to the basal level after 3 days in the global cerebral ischemia model, but in the SOD1 transgenic rats, the complete return of the superoxide radical level to the basal level within 1 day correlates well with the rapid normalization of CBF within 1 day [45]. SOD 1 overexpression confers protection by blocking the caspase activation in the mitochondrial signaling pathway of apoptotic cell death in hippocampal CA1 neurons after global ischemia [2]. In addition, lipid peroxidation due to ischemia reperfusion injury is among the primary causes of tissue injury.…”

“…The mitochondrial-mediated pathway of apoptosis is regulated by the Bcl-2 family of antiapoptotic and proapoptotic proteins, which play a crucial role in intracellular apoptotic signal transduction by regulating permeability of the mitochondrial membrane [2]. The Bax/Bcl-2 ratio is a measure of a cell's vulnerability to apoptosis, and the ratio may be more important than either promoter alone in determining apoptosis [46].…”

“…As for cerebral ischemic injury, it is generally accepted that apoptosis plays a pivotal role in cell death after hypoxia [2]. Pyramidal neurons in cornu ammonis area 1 (CA1) of the hippocampus are selectively vulnerable to GCI, and it has been suggested that the delayed neuronal death 3 or 4 days after ischemic insult is apoptosis [3].…”

“…In global ischemia/reperfusion model, oxygen radicals initiate the mitochondrial pathway of apoptosis with the release of mitochondrial cytochrome c to the cytoplasm, followed by the activation of the cytochrome c -dependent caspase cascade. The downstream caspases cleave many substrate proteins, including PARP [2]. PARP proteolytic cleavage provides an important early marker for apoptosis, and it might be directly responsible for the characteristic changes associated with apoptosis [5].…”