L-deprenyl protects against rotenone-induced, oxidative stress-mediated dopaminergic neurodegeneration in rats.
The present study investigated oxidative damage and neuroprotective effect of the antiparkinsonian drug, L-deprenyl in neuronal death produced by intranigral infusion of a potent mitochondrial complex-I inhibitor, rotenone in rats. Unilateral stereotaxic intranigral infusion of rotenone caused significant decrease of striatal dopamine levels as measured employing HPLC-electrochemistry, and loss of tyrosine hydroxylase immunoreactivity in the perikarya of ipsilateral substantia nigra (SN) neurons and their terminals in the striatum. Rotenone-induced increases in the salicylate hydroxylation products, 2,3- and 2,5-dihydroxybenzoic acid indicators of hydroxyl radials in mitochondrial P2 fraction were dose-dependently attenuated by L-deprenyl. L-deprenyl (0.1-10mg/kg; i.p.) treatment dose-dependently attenuated rotenone-induced reductions in complex-I activity and glutathione (GSH) levels in the SN, tyrosine hydroxylase immunoreactivity in the striatum or SN as well as striatal dopamine. Amphetamine-induced stereotypic rotations in these rats were also significantly inhibited by deprenyl administration. The rotenone-induced elevated activities of cytosolic antioxidant enzymes superoxide dismutase and catalase showed further significant increase following L-deprenyl. Our findings suggest that unilateral intranigral infusion of rotenone reproduces neurochemical, neuropathological and behavioral features of PD in rats and L-deprenyl can rescue the dopaminergic neurons from rotenone-mediated neurodegeneration in them. These results not only establish oxidative stress as one of the major causative factors underlying dopaminergic neurodegeneration as observed in Parkinson's disease, but also support the view that deprenyl is a potent free radical scavenger and an antioxidant.
Saravanan
Karuppagounder S
KS
Division of Clinical and Experimental Neuroscience, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Calcutta 700032, India.
Sindhu
Kizhakke M
KM
Senthilkumar
Karuppagounder S
KS
Mohanakumar
Kochupurackal P
KP
D000661:Amphetamine / Q000009:adverse effects / Q000037:antagonists & inhibitors; D000818:Animals; D002374:Catalase / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000187:drug effects / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism; D008297:Male; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000037:antagonists & inhibitors / Q000633:toxicity; D012642:Selegiline / Q000494:pharmacology* / Q000627:therapeutic use; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects / Q000378:metabolism; D014475:Uncoupling Agents / Q000037:antagonists & inhibitors / Q000633:toxicity; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D015259:Dopamine Agents; D018696:Neuroprotective Agents; D014475:Uncoupling Agents; D012402:Rotenone; D012642:Selegiline; D017665:Hydroxyl Radical; D000661:Amphetamine; D002374:Catalase; D014446:Tyrosine 3-Monooxygenase; D013482:Superoxide Dismutase; D042967:Electron Transport Complex I; D004298:Dopamine