Striatal dopamine level contributes to hydroxyl radical generation and subsequent neurodegeneration in the striatum in 3-nitropropionic acid-induced Huntington's disease in rats.
We tested the hypothesis that dopamine contributes significantly to the hydroxyl radical (OH)-induced striatal neurotoxicity caused by 3-nitropropionic acid (3-NP) in a rat model of Huntington's disease. Dopamine (10-100 microM) or 3-NP (10-1000 microM) individually caused a significant increase in the generation of hydroxyl radical (OH) in the mitochondria, which was synergistically enhanced when the lowest dose of the neurotoxin (10 microM) and dopamine (100 microM) were present together. Similarly, systemic administration of l-DOPA (100-250 mg/kg) and a low dose of 3-NP (10 mg/kg) potentiated OH generation in the striatum, and the rats exhibited significant decrease in stride length, a direct indication of neuropathology. The pathology was also evident in striatal sections subjected to NeuN immunohistochemistry. The significant changes in stride length, the production of striatal OH and neuropathological features due to administration of a toxic dose of 3-NP (20 mg/kg) were significantly attenuated by treating the rats with tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine prior to 3-NP administration. These results strongly implicate a major contributory role of striatal dopamine in increased generation of OH, which leads to striatal neurodegeneration and accompanied behavioral changes, in 3-NP model of Huntington's disease.
Indian Institute of Chemical Biology (CSIR), Division of Cell Biology & Physiology, Laboratory of Clinical & Experimental Neuroscience, Kolkata 700032, India.
Mritunjay
M
Pandey
Anupom
A
Borah
Merina
M
Varghese
Pijus Kanti
PK
Barman
Kochupurackal P
KP
Mohanakumar
Rajamma
R
Usha
D000818:Animals; D003292:Convulsants / Q000633:toxicity; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006816:Huntington Disease / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D017665:Hydroxyl Radical / Q000378:metabolism*; D007794:Lameness, Animal / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D009498:Neurotoxins / Q000633:toxicity; D009574:Nitro Compounds / Q000633:toxicity; D010085:Oxidative Phosphorylation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011422:Propionates / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism
D003292:Convulsants; D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D017665:Hydroxyl Radical; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase; C015392:3-nitropropionic acid; D004298:Dopamine