| Co-Investigator(Kenkyū-buntansha) |
NISHI Katsunori Tokyo Metropolitan Institute for Neuroscience, Department of Neurology, Chief Researcher, 副参事 (00138257)
KONDO Tomoyoshi Wakayama Medical University, Department of Neurology, Associate Professor, 医学部, 教授 (50103891)
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| Budget Amount *help |
¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2004: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2003: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2002: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Research Abstract |
The present study aimed to study behavioral or histological effects of intraventricular or intrastriatal injections of proteasome inhibitor in rats.
Following intraventricular injection of lactacystin, a potent inhibitor of proteasome, induced behavioral disinhibition and exaggerated startle reactions in rats. Histological studies revealed a degeneration of the nigrostriataldopaminergic system. However, notonludopaminergicsystembutalso the other sites of the brain, particularly those around the ventricular system were found damaged, possibly due to non-specific neurotoxic effects of proteasome inhibition. Thus, it was considered that this model might not be suitable one for analysis of dopamine neuron degeneration by proteasome inhibition.
Next, we studied effects of direct injection of lactacystin into the substantia nigra in rats. Following, intranigral injection of lactacystin, dopamine neurons were prominently lost, and alpha-synuclein-immunopositive inclusions were observed in the r
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emaining neurons. However, there was a nonspecific damage of the brain tissue, possibly because of toxicity of proteasome inhibition. Then, it was also found that injections of protasome inhibitor into not only subtantia nigra but also striatum sufficiently induced dopaminergic neuron degeneration in the sunstantia nigra. In addition, alpha-synuclein-immunopositive inclusions were also observed in the dopaminergic neurons. Simultaneously, an oxidative stree marker was also found increased during the degenerative process in the dopaminergic neurons following intrastriatal injection of proteasome inhibitor. Microglial activation was also prominent in the substantia nigra. Therefore, in this model, dopaminergic neuron degeneration, an increase of oxidative stress marker, and neuroinflammation, all of them were histological characteristics of Parkinson's disease brains, were induced. It is suggested that this retrogaradedopamineneurondegenerationmodel may be a useful one for examining the basic mechanisms underlying dopamine neuron degeneration buanimpairmentof ubiquitin-proteasome function in rats. Less
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