NITRIC OXIDE-DEPENDENT PRODUCTION OF CGMP SUPPORTS THE SURVIVAL OF RAT EMBRYONIC MOTOR-NEURONS CULTURED WITH BRAIN-DERIVED NEUROTROPHIC FACTOR

Trophic factor deprivation induces neuronal nitric oxide synthase (NOS ) and apoptosis of rat embryonic motor neurons in culture. We report h ere that motorneurons constitutively express endothelial NOS that help s support the survival of motor neurons cultured with brain-derived ne urotrophic factor (BDNF) by activating the nitric oxide-dependent solu ble guanylate cyclase. Exposure of BDNF-treated motor neurons to nitro -L-arginine methyl ester (L-NAME) decreased cell survival 40-50% 24 hr after plating. Both low steady-state concentrations of exogenous nitr ic oxide (<0.1 mu M) and cGMP analogs protected BDNT-treated motor neu rons from death induced by L-NAME. Equivalent concentrations of cAMP a nalogs did not affect cell survival. Inhibition of nitric oxide-sensit ive guanylate cyclase with 2 mu M 1H-[1,2,4]oxadiazolo[4,3-a]quinoxali n-1-one (ODQ) reduced the survival of BDNF-treated motor neurons by 35 %. cGMP analogs also protected from ODQ-induced motor neuron death, wh ereas exogenous nitric oxide did not. In all cases, cell death was pre vented with caspase inhibitors. Our results suggest that nitric oxide- stimulated cGMP synthesis helps to prevent apoptosis in BDNF-treated m otor neurons.