NMDA RECEPTOR-DEPENDENT NITRIC-OXIDE AND CGMP SYNTHESIS IN BRAIN HEMISPHERES AND CEREBELLUM DURING REPERFUSION AFTER TRANSIENT FOREBRAIN ISCHEMIA IN GERBILS - EFFECT OF 7-NITROINDAZOLE

In this study, the N-Methyl-D-Aspartate (NMDA) receptor-dependent nitr ic oxide and cyclic GMP (cGMP) synthesis in the course of reperfusion after 5 min of ischemia in gerbil brain hemispheres and cerebellum wer e investigated, Moreover, the role of the neuronal isoform of nitric o xide (NO) synthase (nNOS) in liberation of NO in postischemic brain an d the involvement of NO in membrane lipoperoxidations activated during reperfusion were evaluated, Enhancement of Ca2+/calmodulin-regulated NOS activity and cGMP level in brain hemispheres and in cerebellum dur ing reperfusion was found to be coupled to the activation of the NMDA receptor, cGMP concentration 40% above the control level was observed to persist up to 7 days after ischemia, The amount of conjugated doubl e bounds in membrane lipids and the level of thiobarbituric acid react ive substances were increased exclusively in brain hemispheres, indica ting activation of lipid peroxidation, The NMDA receptor antagonist, M K-801, eliminated, and a rather selective nNOS inhibitor, 7-Nitroindaz ole (7-NI) attenuated, NMDA receptor-evoked enhancement of NOS activit y and cGMP level in brain hemispheres and in cerebellum during reperfu sion, Moreover, 7-NI decreased significantly membrane lipid peroxidati on during the early time of reperfusion, Histological examination demo nstrated that 7-NI protects against death a selected population of neu ronal cells in CA(1) layer of hippocampus, It is suggested that NMDA r eceptor dependence of NO release during reperfusion is responsible for the degeneration of some populations of neurons and that the effect i s mediated by activation of free radical formation and lipid peroxidat ion. Moreover, in cerebellum, ischemia-evoked activation of glutamater gic system stimulates NO-dependent signal transmission. Our results in dicated that 7-NI has a significant ameliorating effect on biochemical alterations evoked by ischemia, suggesting nNOS inhibitors as a poten tial therapeutic agents in reperfusion injury. (C) 1998 Wiley-Liss, In c.