Striatal dopamine level contributes to hydroxyl radical generation and subsequent neurodegeneration in the striatum in 3-nitropropionic acid-induced Huntington's disease in rats |
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Authors: | Mritunjay Pandey Anupom Borah Merina Varghese Pijus Kanti Barman Kochupurackal P Mohanakumar Rajamma Usha |
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Institution: | aIndian Institute of Chemical Biology (CSIR), Division of Cell Biology & Physiology, Laboratory of Clinical & Experimental Neuroscience, 4, Raja S. C. Mullick Road, Kolkata 700032, India;bManovikas Biomedical Research and Diagnostic Centre, 482, Madudah, Plot I-24, Sector-J, E. M. Bypass, Kolkata 700107, India |
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Abstract: | 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 μM) or 3-NP (10–1000 μM) 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 μM) and dopamine (100 μM) 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 α-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. |
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Keywords: | Hydroxyl radical generation Dopamine synthesis inhibition Succinate dehydrogenase inhibition NeuN Mitochondria Synergistic increase in oxidative stress |
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