Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine damages dopaminergic neu rons as seen in Parkinson disease. Here we show that after administration o f MPTP to mice, there was a robust gliosis in the substantia nigra pars com pacta associated with significant upregulation of inducible nitric oxide sy nthase (iNOS). These changes preceded or paralleled MPTP-induced dopaminerg ic neurodegeneration. We also show that mutant mice lacking the iNOS gene w ere significantly more resistant to MPTP than their wild-type littermates. This study demonstrates that iNOS is important in the MPTP neurotoxic proce ss and indicates that inhibitors of iNOS may provide protective benefit in the treatment of Parkinson disease.