NEUROPROTECTION OF LUBELUZOLE IS MEDIATED THROUGH THE SIGNAL-TRANSDUCTION PATHWAYS OF NITRIC-OXIDE

Neuronal survival after ischemic injury is determined through the indu ction of several biological pathways. We examined whether lubeluzole, an agent efficacious in both clinical and experimental models of cereb ral ischemia, modulated the signal transduction mechanisms of nitric o xide (NO), a downstream mediator of anoxic neurodegeneration. Both pre treatment [NO survival = 23 +/- 3%, NO/lubeluzole (750 nM) survival = 63 +/- 2%, p < 0.001] and coadministration [NO survival = 25 +/- 3%, N O/lubeluzole (750 nM) survival = 59 +/- 3%, p < 0.001] of lubeluzole w ith NO generators equally protected cultured hippocampal neurons in a dose-dependent manner against the toxic effects of NO, suggesting that the agent protects by acutely modifying toxic cellular pathways rathe r than preconditioning the neuron before injury. The protection observ ed with lubeluzole was stereospecific but was not limited to pre- or c oadministration. Lubeluzole also was found to significantly protect ag ainst the toxicity of NO for a period of 4-6 h after NO exposure [NO s urvival = 31 +/- 2%, NO/lubeluzole (750 nM) survival at 6 h = 56 +/- 3 %, p < 0.001]. We conclude that the neuroprotective ability of lubeluz ole is unique and involves the direct modulation of the NO pathway, In addition, the mechanisms of NO toxicity are dynamic and reversible pr ocesses that, if left unaltered, will lead to neuronal injury, Further investigation of the downstream signal transduction mechanisms below the level of NO generation may elucidate the specific cellular events responsible for neurodegeneration.