Sustained, long-lasting inhibition of nitric oxide synthase aggravates theneural damage in some models of excitotoxic brain injury

Brain nitric oxide (NO) can be a mediator of physiological and neuroprotect ive actions and an effector of neural damage. The effectiveness of acute or chronic inhibition of NO production in in vivo experiments of neurotoxicit y/neuroprotection is controversial. We report here on the effects of a chro nic, sustained inhibition of nitric oxide synthase (NOS) on the neurodegene rative damage caused by three different excitotoxic lesions. The damage cau sed by intrastriatal injection of ibotenic or kainic acid was aggravated in rats subjected to chronic NOS inhibition. On the contrary, the drop of cor tical cholinergic input consequent to ibotenic acid-mediated degeneration o f basal forebrain neurons was not altered by chronic NOS inhibition. The wo rsening of the damage was not related to any overt differential sensitivity to excitotoxicity of NOS-containing striatal neurons under conditions of N OS inhibition. These results suggest that, contrary to what has been often reported for short-term, mild inhibition of NO production, chronic and sust ained NOS inhibition may exacerbate neuropathology. Thus, long-lasting shor tage of NO may be detrimental when neuroprotective mechanisms related to th e physiological action of this free radical are severely impaired. Although we cannot exclude that inhibition of the endothelial NOS isoform could hav e contributed to the worsening of neuropathology, differences among the par adigms of neurotoxicity used in the present study suggest a primary involve ment of the neuronal NOS isoform. In view of the potential therapeutic use of NOS inhibitors, the effects of a too drastic alteration of the balance b etween neuroprotective and neurodegenerative actions of NO should be carefu lly considered. (C) 2001 Elsevier Science Inc.