Neuronal apoptosis and protection: effects of nitric oxide and endoplasmic reticulum-related proteins.
This review presents recent findings with regard to the cellular and molecular mechanisms of neuronal apoptosis induced by cerebral ischemia/hypoxia. The protection of neuronal death by hypoxia-induced proteins in the endoplasmic reticulum (ER) is also reviewed. The excess amount of nitric oxide (NO) generated by inducible NO synthase (iNOS) up-regulated in response to ischemic stress causes neuronal apoptosis through following processes; 1) reduction in mitochondrial membrane potential, 2) release of cytochrome c from mitochondria, and 3) activation of caspase-9 and -3, although low concentrations of NO protect against neuronal death. In contrast, hypoxia induces expression of several proteins such as protein disulfide isomerase (PDI), ubiquilin and HRD1 in the endoplasmic reticulum (ER). PDI and ubiquilin are involved in the protection against neuronal apoptosis probably by interacting with each other and enhancing the effects of PDI as a molecular chaperon. HRD1 is also up-regulated by hypoxia in the ER and induces protection against hypoxia-induced neuronal apoptosis by activating the protein degradation system. The present review hopefully gives pertinent suggestions for further studies on the development of novel prophylactic/therapeutics for neuronal apoptosis-related diseases.
Nomura
Yasuyuki
Y
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan. nomura@pharm.hokudai.ac.jp
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology
D006360:Heat-Shock Proteins; D018696:Neuroprotective Agents; D009569:Nitric Oxide