Roles of nitric oxide in brain hypoxia-ischemia

A large body of evidence has appeared over the last 6 years suggesting that nitric oxide biosynthesis is a key factor in the pathophysiological respon se of the brain to hypoxia-ischemia. Whilst studies on the influence of nit ric oxide in this phenomenon initially offered conflicting conclusions, the use of better biochemical tools, such as selective inhibition of nitric ox ide synthase (NOS) isoforms or transgenic animals, is progressively clarify ing the precise role of nitric oxide in brain ischemia. Brain ischemia trig gers a cascade of events, possibly mediated by excitatory amino acids, yiel ding the activation of the Ca2+-dependent NOS isoforms, i.e. neuronal NOS ( nNOS) and endothelial NOS (eNOS). However, whereas the selective inhibition of nNOS is neuroprotective, selective inhibition of eNOS is neurotoxic. Fu rthermore, mainly in glial cells, delayed ischemia or reperfusion after an ischemic episode induces the expression of Ca2+-independent inducible NOS ( iNOS), and its selective inhibition is neuroprotective. In conclusion, it a ppears that activation of nNOS or induction of iNOS mediates ischemic brain damage, possibly by mitochondrial dysfunction and energy depletion. Howeve r, there is a simultaneous compensatory response through eNOS activation wi thin the endothelium of blood vessels, which mediates vasodilation and henc e increases blood flow to the damaged brain area. (C) 1999 Elsevier Science B.V. All rights reserved.