Evaluation of the efficacy of potential therapeutic agents at protecting against nitric oxide synthase-mediated mitochondrial damage in activated astrocytes.
Within the central nervous system, nitric oxide is an important physiological messenger. However, when synthesized excessively in neurones, cell death may occur. An impairment of mitochondrial cytochrome oxidase and subsequent cellular energy depletion seems to be a likely mechanism for this neurotoxicity. Within neurones, nitric oxide is synthesized by the constitutive, Ca(2+)-dependent form of nitric oxide synthase (nNOS). Astrocytes, however, possess both the constitutive and the inducible Ca(2+)-independent NOS (iNOS), which is expressed by endotoxin and/or cytokines. In vitro, activation of nNOS rapidly produces neuronal cell death. In contrast to neurones, following induction of iNOS, astrocytes synthesize large quantities of nitric oxide, but cell death is not apparent despite marked damage to mitochondrial cytochrome oxidase. The resistance of astrocytes to nitric oxide synthase-mediated cell damage may be due to their ability to increase their glycolytic rate when mitochondrial ATP synthesis is compromised. On the basis of this phenomenon, we propose that activated astrocytes represent a suitable system for studying the efficacy of potential therapeutic agents at protecting from nitric oxide synthase-mediated mitochondrial damage.
Bolaños
J P
JP
Department of Neurochemistry, Institute of Neurology, London, UK. jbolanos@gugu.usal.es
Peuchen
S
S
Land
J M
JM
Clark
J B
JB
Heales
S J
SJ
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D002839:Chromans / Q000494:pharmacology; D003576:Electron Transport Complex IV / Q000378:metabolism; D004790:Enzyme Induction / Q000502:physiology; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009488:Neurosciences / Q000379:methods; D019001:Nitric Oxide Synthase / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
D000975:Antioxidants; D002839:Chromans; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D003576:Electron Transport Complex IV; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid