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 neurons as seen in Parkinson disease. Here we show that after administration of MPTP to mice, there was a robust gliosis in the substantia nigra pars compacta associated with significant upregulation of inducible nitric oxide synthase (iNOS). These changes preceded or paralleled MPTP-induced dopaminergic neurodegeneration. We also show that mutant mice lacking the iNOS gene were significantly more resistant to MPTP than their wild-type littermates. This study demonstrates that iNOS is important in the MPTP neurotoxic process and indicates that inhibitors of iNOS may provide protective benefit in the treatment of Parkinson disease.
Liberatore
G T
GT
Department of Neurology, Columbia University, New York, New York 10032, USA.
Jackson-Lewis
V
V
Vukosavic
S
S
Mandir
A S
AS
Vila
M
M
McAuliffe
W G
WG
Dawson
V L
VL
Dawson
T M
TM
Przedborski
S
S
D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D020267:MPTP Poisoning / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000201:enzymology; D009410:Nerve Degeneration / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology*; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D010300:Parkinson Disease / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D004298:Dopamine