TY - JOUR
T1 - Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease
AU - Liberatore, Gabriel T.
AU - Jackson-Lewis, Vernice
AU - Vukosavic, Slobodanka
AU - Mandir, Allen S.
AU - Vila, Miquel
AU - Mcauliffe, W. Geoffrey
AU - Dawson, Valina L.
AU - Dawson, Ted M.
AU - Przedborski, Serge
N1 - Funding Information:
Acknowledgments We thank V.H. Perry and J. Goldman for their advice on the glial studies; H. Ischiropoulos for his guidance on the nitrotyrosine studies; and N. Romero and D. Guestella for their assistance in maintaining and genotyping the iNOS mutant mice. This study was supported by National Institute of Neurological Disorders and Stroke grant R29 NS37345, RO1 NS38586 and P50 NS38370, and US Department of Defense contract number DAMD 17-99-1-9474 (S.P.); the Lowenstein Foundation and the Parkinson’s Disease Foundation (G.L., V.J-L., S.P.); National Institutes of Health/National Institute of Neurological Disorders and Stroke grant P50 NS38377; the Mitchell Family foundation (A.S.M, V.L.D, T.M.D); Public Health Service/Career Investigator Development Award grant NS 1K08N2035; and the American Parkinson Disease Association (A.S.M). M.V. is recipient of a fellowship from the Human Frontier Science Program Organization, and S.P. is recipient of the Cotzias Award from the American Parkinson Disease Association.
PY - 1999/12
Y1 - 1999/12
N2 - 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.
AB - 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.
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U2 - 10.1038/70978
DO - 10.1038/70978
M3 - Article
C2 - 10581083
AN - SCOPUS:0032710609
SN - 1078-8956
VL - 5
SP - 1403
EP - 1409
JO - Nature medicine
JF - Nature medicine
IS - 12
ER -