[The precise characterization and the crucial mechanism of NO-induced cytotoxicity].
NO is believed to be involved in neurotoxicity after various neuronal stresses. NO donors are toxic and cause changes in cellular morphology such as condensed and fragmented chromatin, shriveled nuclei, apoptotic bodies and membrane blebbing. These observations are consistent with the overall description of apoptosis. The crucial mechanism of NO-induced cytotoxicity is still unclear. Several mechanisms for NO-induced cytotoxicity in neurons have been proposed. It has been reported that NO enhances ADP-ribosylation or S-nitrosylation of an increasing number of proteins, and two of these proteins were identified as NO-target proteins. One is glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a key enzyme of glycolytic conversion, which is S-nitrosylated by NO inhibiting the enzyme activity. Hence, inhibition of GAPDH activity by NO would decrease the amount of ATP. NO also activates poly (ADP-ribose) polymerase (PARP) in the presence of DNA damage. The activation of PARP results in depletion of NAD and ATP. The energy depletion by NO could cause cell death. Recently, several factors such as Fas, the caspases (interleukin-1 beta-converting enzyme (ICE)-like proteases), Bcl-2 and the tumor suppressor gene product p53 have been shown to be involved in apoptotic cell death. We here discuss the crucial mechanisms of NO-induced cytotoxicity and also discuss recent findings about the protective effect of NO on cell death.
Okuma
Y
Y
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Uehara
T
T
Nomura
Y
Y
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000502:physiology; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology
D009569:Nitric Oxide; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases