Involvement of the mitochondrial apoptotic pathway and nitric oxide synthase in dopaminergic neuronal death induced by 6-hydroxydopamine and lipopolysaccharide.
The primary pathology in Parkinson's disease patients is significant loss of dopaminergic neurons in the substantia nigra through multiple mechanisms. We previously have demonstrated the involvement of nitric oxide (NO) in the dopaminergic neurodegeneration induced by 6-hydroxydopamine (6-OHDA) and lipopolysaccharide (LPS) in rats. The present study was undertaken to investigate further the role of NO in the mitochondria-mediated apoptosis of dopaminergic neurons during the early time period after administration of 6-OHDA and LPS. Measurement of dopamine and its metabolites, TH immunolabeling, cytochrome-c release, mitochondrial complex-I and caspase-3 activity assessment was performed in both the 6-OHDA- and LPS-induced experimental models of Parkinson's disease. Significant decreases in dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), tyrosine hydroxylase (TH) immunolabeling and mitochondrial complex-I activity were observed, with increase in cytochrome-c release and caspase-3 activation. Dopmaine and its metabolite levels, mitochondrial complex-I activity and caspase-3 activity were significantly reversed with treatment of the NOS inhibitor, L-NAME. The reduction in the extent of cytochrome-c release responded variably to NOS inhibition in both the models. The results obtained suggest that NO contributes to mitochondria-mediated neuronal apoptosis in the dopaminergic neurodegeneration induced by 6-OHDA and LPS in rats.
Singh
Sarika
S
Division of Toxicology, Central Drug Research Institute (CSIR), Lucknow 226001, Uttar Pradesh, India. sarika_singh@cdri.res.in
Kumar
Sachin
S
Dikshit
Madhu
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008928:Mitochondria / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016627:Oxidopamine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013565:Sympatholytics / Q000494:pharmacology
D008070:Lipopolysaccharides; D013565:Sympatholytics; D009569:Nitric Oxide; D016627:Oxidopamine; D019001:Nitric Oxide Synthase; D042967:Electron Transport Complex I; D019331:NG-Nitroarginine Methyl Ester; D004298:Dopamine