Neuroprotection of lubeluzole is mediated through the signal transduction pathways of nitric oxide

Abstract

Neuronal survival after ischemic injury is determined through the induction of several biological pathways. We examined whether lubeluzole, an agent efficacious in both clinical and experimental models of cerebral ischemia, modulated the signal transduction mechanisms of nitric oxide (NO), a downstream mediator of anoxic neurodegeneration. Both pretreatment [NO survival = 23 < 3%, NO/lubeluzole (750 nM) survival = 63 ± 2%, p < 0.001] and coadministration [NO survival = 25 ± 3%, NO/lubeluzole (750 nM) survival = 59 ± 3%, p < 0.001] of lubeluzole with 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 rather than preconditioning the neuron before injury. The protection observed with lubeluzole was stereospecific but was not limited to pre- or coadministration. Lubeluzole also was found to significantly protect against the toxicity of NO for a period of 4-6 h after NO exposure [NO survival = 31 ± 2%, NO/lubeluzole (750 nM) survival at 6 h = 56 ± 3%, p < 0.001]. We conclude that the neuroprotective ability of lubeluzole is unique and involves the direct modulation of the NO pathway. In addition, the mechanisms of NO toxicity are dynamic and reversible processes 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.