THE NITRIC OXIDE-CYCLIC GMP PATHWAY PLAYS AN ESSENTIAL ROLE IN BOTH PROMOTING CELL-SURVIVAL OF CEREBELLAR GRANULE CELLS IN CULTURE AND PROTECTING THE CELLS AGAINST ETHANOL NEUROTOXICITY

NMDA has two beneficial effects on primary neuronal cultures of cerebe llar granule cells (CGCs) established from 10-day-old rat pups. First, NMDA is neurotrophic and will enhance survival of CGCs in culture in the absence of ethanol. Second, ethanol exposure will induce cell deat h in CGC cultures, and NMDA can lessen this ethanol-induced cell loss, i.e., NMDA is neuroprotective. Because NMDA can stimulate production of nitric oxide (NO), which can in turn enhance synthesis of cyclic GM P, this study tested the hypothesis that the NO-cyclic GMP pathway is essential for NMDA-mediated neurotrophism and neuroprotection. Inhibit ing the synthesis of NO with N-G-nitro-L-arginine methyl ester elimina ted both the NMDA-mediated neurotrophic and neuroprotective effects. S imilarly, inhibiting production of cyclic GMP with the agent LY83583 a lso abolished these effects. The NO generator 2,2'-(hydroxynitrosohydr azono)bisethanamine produced neurotrophic and neuroprotective effects that were similar to those induced by NMDA. Also, 8-bromo-cyclic GMP p roduced neurotrophic and neuroprotective effects that were quite simil ar to the effects produced by NMDA. In conclusion, NMDA enhances survi val of cerebellar granule cells and protects the cells against ethanol -induced cell death by a mechanism(s) that involves the NO-cyclic GMP pathway.