Induction of neuronal nitric oxide synthase by methylmercury in the cerebellum.

A free radical, nitric oxide (NO), besides being a messenger molecule in the brain, becomes a neurotoxin if overproduced. We recently reported that methylmercury (MeHg) induces neuronal NO synthase (nNOS) in Purkinje cells. In the present study, we examined the distribution and the mechanism of nNOS induction by MeHg. Subcutaneous administration of MeHg chloride to mice, 10 mg/kg/day for 9 days, increased calcium-dependent NOS activity to 60% more than the controls only in the cerebellum but not in other brain regions. The Western blots showed a comparable increase in nNOS protein in the cerebellum. A N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, did not block, but rather enhanced, the increase in the nNOS activity. Another NMDA antagonist, 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), did not affect the nNOS activity. The Western blots of protein kinase C (PKC), which is an important cofactor regulating nNOS, did not change after the administration of MeHg. These results show that MeHg induces biologically active nNOS selectively in the cerebellum. The induction is independent of PKC and is not reduced by the blockade of the NMDA receptor.