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 [I]. However, when synthesized excessively in neurones, cell death may occur [2]. An Impairment of mitochondrial cytochrome oxidase and subsequent cellular energy depletion seems to be a likely mechanism for this neurotoxicity [3]. Within neurones, nitric oxide is synthesized by the constitutive, Ca2+-dependent form of nitric oxide synthase (nNOS) [4]. Astrocytes, however, possess both the constitutive [5] and the inducible Ca2+-independent NOS (iNOS) [6,7], which is expressed by endotoxin and/or cytokines [5]. In vitro, activation of nNOS rapidly produces neuronal cell death [2]. In contrast to neurones, following induction of iNOS, astrocytes synthesize large quantities of nitric oxide [3,9], but cell death is not apparent despite marked damage to mitochondrial cytochrome oxidase [3]. 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 [3]. 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 [10].