Simvastatin prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced striatal dopamine depletion and protein tyrosine nitration in mice.
Parkinson's disease is a neurological disorder involving the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. There is increasing evidence that inflammation plays a role in the propagation of neurodegenerative processes in Parkinson's disease. We investigated the neuroprotective effects of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor with anti-inflammatory properties, in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Oral administration of simvastatin attenuated the depletion of dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in the striatum caused by MPTP in a dose-dependent manner. Simvastatin also inhibited the formation of 3-nitrotyrosine in striatal proteins in MPTP-treated mice. Simvastatin had no effect on cholesterol concentrations in the plasma or in the striatum. Simvastatin inhibited the production of tumor necrosis factor (TNF)-alpha, nitric oxide, and superoxide in cultured rat microglia stimulated by lipopolysaccharide. The results suggest that simvastatin inhibits the formation of TNF-alpha and peroxynitrite in activated microglia thereby protecting dopaminergic neurons from inflammatory damage. Simvastatin may be a potential new treatment to slow the progression of Parkinson's disease.
Selley
Michael L
ML
Angiogen Pharmaceuticals Pty. Ltd., Level 31, ABN AMRO Tower, 88 Phillip Street, Sydney, N.S.W. 2000, Australia. mlselley@angiogen.com.au
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D006719:Homovanillic Acid / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D009566:Nitrates / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis*; D016877:Oxidants / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism*
D015259:Dopamine Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009566:Nitrates; D016877:Oxidants; D014409:Tumor Necrosis Factor-alpha; D015102:3,4-Dihydroxyphenylacetic Acid; D013481:Superoxides; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D002784:Cholesterol; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D019821:Simvastatin; D004298:Dopamine; D006719:Homovanillic Acid