LUBELUZOLE, A NOVEL LONG-TERM NEUROPROTECTANT, INHIBITS THE GLUTAMATE-ACTIVATED NITRIC-OXIDE SYNTHASE PATHWAY

The novel drug lubeluzole, but not its (-)-R-isomer, protects against sensorimotor deficits provoked by photochemical stroke in rats. We stu died the mechanism of protection of lubeluzole against glutamate toxic ity in primary hippocampal cell cultures. In a model for glutamate ant agonism, i.e., treatment of the cultures with compound during the glut amate trigger, lubeluzole was not protective. In contrast, after prolo nged pretreatment, i.e., administration of compound to the culture for 7 days before glutamate, lubeluzole was neuroprotective. It had an IC 50 of 48 nM and its R-isomer was nine times less active. Under these c onditions, lubeluzole inhibited glutamate-stimulated guanosine 3',5'-c yclic monophosphate production (IC50 37 nM). Again the R-isomer was se ven times less active. The compounds did not affect nitric oxide synth ase activity, guanylate cyclase activity or arginine uptake. After pro longed pretreatment, lubeluzole attenuated citrulline production in th e culture, which could not be compensated for by excess arginine. Beca use prolonged lubeluzole treatment does not inhibit glutamate-activate d [Ca++](i) rise in these cultures, the findings may indicate that exp ression of nitric oxide synthase or levels of its cofactors were reduc ed. Treatment of C6 glioma cells with lubeluzole did not affect lipopo lysaccharide/gamma interferon induced guanosine 3',5'-cyclic monophosp hate levels, suggesting that lubeluzole does not inhibit the glial nit ric oxide synthase pathway. In conclusion, the long-term neuroprotecti ve property of lubeluzole against glutamate toxicity in hippocampal cu ltures is reflected by the fact of interference with the glutamate-act ivated nitric oxide synthase pathway. Prolonged treatment may reduce e xpression of nitric oxide synthase or levels of its cofactors.