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Nitric oxide synthase inhibitors protect against rotenone-induced, oxidative stress mediated parkinsonism in rats
- Source :
- Neurochemistry International. 62:674-683
- Publication Year :
- 2013
- Publisher :
- Elsevier BV, 2013.
-
Abstract
- Rotenone is known to cause progressive dopaminergic neuronal loss in rodents, but it remains unclear how this mitochondrial complex-I inhibitor mediates neurodegeneration specific to substantia nigra pars compacta (SNpc). One of the proposed mechanisms is increased free radical generation owing to mitochondrial electron transport chain dysfunction following complex-I inhibition. The present study examined the role of nitric oxide (NO) and hydroxyl radicals (OH) in mediating rotenone-induced dopaminergic neurotoxicity. Indications of NO involvement are evidenced by inducible nitric oxide synthase (NOS) over-expression, and increased NADPH-diaphorase staining in SNpc neurons 96h following rotenone administration. Treatment of these animals with specific neuronal NOS inhibitor, 7-nitroindazole (7-NI) and non-specific NOS inhibitor, N-ω-nitro-l-argenine methyl ester (l-NAME) caused reversal of rotenone-induced striatal dopamine depletion, and attenuation of the neurotoxin-induced decrease in the number of tyrosine hydroxylase immunoreactive neurons in SNpc, as well as in apomorphine and amphetamine-induced unilateral rotations. Interestingly, the study also demonstrated the contribution of OH in mediating rotenone nigral toxicity since there appeared a significant generation of the reactive oxygen species in vivo 24h following rotenone administration, a copious loss of reduced and oxidized glutathione, and increased superoxide dismutase and catalase activities in the cytosolic fractions of the ipsilateral SNpc area on the 5th day. An OH scavenging capacity of 7-NI and l-NAME in a Fenton-like reaction, as well as complete reversal of the rotenone-induced increases in the antioxidant enzyme activities, and the loss in reduced and oxidized glutathione contents in the SNpc supported OH involvement in rotenone-induced dopaminergic neurotoxicity. While these results strongly suggest the contribution of both OH and NO, resulting in acute oxidative stress culminating in dopaminergic neurodegeneration caused by rotenone, the course of events indicated generation of OH as the primary event in the neurotoxic processes.
- Subjects :
- Male
Dopamine
Nitric Oxide Synthase Type II
Substantia nigra
Pharmacology
medicine.disease_cause
Antioxidants
Nitric oxide
Rats, Sprague-Dawley
Cellular and Molecular Neuroscience
chemistry.chemical_compound
Parkinsonian Disorders
Rotenone
medicine
Animals
Enzyme Inhibitors
DNA Primers
Base Sequence
biology
Reverse Transcriptase Polymerase Chain Reaction
Pars compacta
Dopaminergic
Neurotoxicity
Cell Biology
medicine.disease
Rats
Nitric oxide synthase
Oxidative Stress
Biochemistry
chemistry
biology.protein
Oxidative stress
Subjects
Details
- ISSN :
- 01970186
- Volume :
- 62
- Database :
- OpenAIRE
- Journal :
- Neurochemistry International
- Accession number :
- edsair.doi.dedup.....e8c159f0adc4b8f2f06f5791ddff00a0