Sustained, long-lasting inhibition of nitric oxide synthase aggravates the neural damage in some models of excitotoxic brain injury.
Brain nitric oxide (NO) can be a mediator of physiological and neuroprotective actions and an effector of neural damage. The effectiveness of acute or chronic inhibition of NO production in in vivo experiments of neurotoxicity/neuroprotection is controversial. We report here on the effects of a chronic, sustained inhibition of nitric oxide synthase (NOS) on the neurodegenerative damage caused by three different excitotoxic lesions. The damage caused by intrastriatal injection of ibotenic or kainic acid was aggravated in rats subjected to chronic NOS inhibition. On the contrary, the drop of cortical cholinergic input consequent to ibotenic acid-mediated degeneration of basal forebrain neurons was not altered by chronic NOS inhibition. The worsening of the damage was not related to any overt differential sensitivity to excitotoxicity of NOS-containing striatal neurons under conditions of NOS inhibition. These results suggest that, contrary to what has been often reported for short-term, mild inhibition of NO production, chronic and sustained NOS inhibition may exacerbate neuropathology. Thus, long-lasting shortage of NO may be detrimental when neuroprotective mechanisms related to the physiological action of this free radical are severely impaired. Although we cannot exclude that inhibition of the endothelial NOS isoform could have contributed to the worsening of neuropathology, differences among the paradigms of neurotoxicity used in the present study suggest a primary involvement 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 between neuroprotective and neurodegenerative actions of NO should be carefully considered.
Ciani
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Department of Biology, University of Bologna, Bologna, Italy.
Baldinotti
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I
Contestabile
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A
D000818:Animals; D020532:Basal Nucleus of Meynert / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D001930:Brain Injuries / Q000139:chemically induced* / Q000201:enzymology / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002795:Choline O-Acetyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D002799:Cholinergic Fibers / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000633:toxicity*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007051:Ibotenic Acid / Q000494:pharmacology; D007150:Immunohistochemistry; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D009252:NADPH Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D017072:Neostriatum / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000201:enzymology / Q000503:physiopathology; D009498:Neurotoxins / Q000633:toxicity*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D009498:Neurotoxins; D007051:Ibotenic Acid; D009569:Nitric Oxide; D014700:Verapamil; D019001:Nitric Oxide Synthase; D009252:NADPH Dehydrogenase; D002795:Choline O-Acetyltransferase; D005968:Glutamate Decarboxylase; D007608:Kainic Acid; D019331:NG-Nitroarginine Methyl Ester