TY - JOUR
T1 - Striatal dopamine level contributes to hydroxyl radical generation and subsequent neurodegeneration in the striatum in 3-nitropropionic acid-induced Huntington's disease in rats
AU - Pandey, Mritunjay
AU - Borah, Anupom
AU - Varghese, Merina
AU - Barman, Pijus Kanti
AU - Mohanakumar, Kochupurackal P.
AU - Usha, Rajamma
N1 - Funding Information:
The financial support from Department of Science and Technology, Govt. of India vide Grant No. SR/FTP/LS-A-61/2001 (to UR) and from SIP program of IICB, CSIR are gratefully acknowledged. MP, AB and MV are recipients of Senior Research Fellowships from the Council of Scientific and Industrial Research, Government of India.
PY - 2009/11
Y1 - 2009/11
N2 - We tested the hypothesis that dopamine contributes significantly to the hydroxyl radical ({radical dot}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 ({radical dot}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 {radical dot}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 {radical dot}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 {radical dot}OH, which leads to striatal neurodegeneration and accompanied behavioral changes, in 3-NP model of Huntington's disease.
AB - We tested the hypothesis that dopamine contributes significantly to the hydroxyl radical ({radical dot}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 ({radical dot}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 {radical dot}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 {radical dot}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 {radical dot}OH, which leads to striatal neurodegeneration and accompanied behavioral changes, in 3-NP model of Huntington's disease.
KW - Dopamine synthesis inhibition
KW - Hydroxyl radical generation
KW - Mitochondria
KW - NeuN
KW - Succinate dehydrogenase inhibition
KW - Synergistic increase in oxidative stress
UR - http://www.scopus.com/inward/record.url?scp=67650248280&partnerID=8YFLogxK
U2 - 10.1016/j.neuint.2009.04.013
DO - 10.1016/j.neuint.2009.04.013
M3 - Article
C2 - 19410615
AN - SCOPUS:67650248280
SN - 0197-0186
VL - 55
SP - 431
EP - 437
JO - Neurochemistry International
JF - Neurochemistry International
IS - 6
ER -