Microglia Activation Induces Parkinsonism in Rats

Grants and Contracts Details


Parkinson's disease (PD) is a movement disorder characterized by the progressive loss of dopamine-containing neurons in the substantia nigra pars compacta (SNpc). Loss of SNpc dopaminergic neurons results in the depletion of striatal dopamine levels and produces symptoms such as tremor, muscle rigidity, and bradykinesia. The etiology of PD is unknown, but chronic inflammatory processes, microglial activation, and oxidative stress are thought to play prominent roles in the degeneration of dopaminergic neurons in the SNpc. Microglia are thought to contribute to neurodegeneration by releasing cytotoxic agents such as pro-inflammatory cytokines and reactive oxygen species that increase inflammation and oxidative stress. N-Methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) is a neurotoxin found to mimic many of the features of PD in animal models, including loss of dopaminergic neurons in SNpc and activation of microglia. Recent observations indicate that cyclooxygenase-2 (COX-2) deficiency in mice reduces the susceptibility of SNpc dopaminergic neurons to MPTP toxicity and diminishes MPTP-induced microglial activation. The purpose of this study is to test the hypothesis that COX-2-regulated inflammatory processes exacerbate MPTP neurotoxicity by activating microglia and increasing oxidative stress that contributes to the degeneration of dopaminergic neurons in the SNpc. To test this hypothesis, mice deficient in the COX-2 gene will be treated with MPTP to determine the role of COX-2 in MPTP-induced neurodegeneration. Furthermore, wild-type mice will be administered exogenous COX-2 inhibitors prior to MPTP treatment to evaluate the protective effects of COX-2 inhibitors against MPTP neurotoxicity. Following these experiments, dopaminergic neuron survival, microglial activation, striatal dopamine levels, and functional recovery will be assessed. In addition, protein modification, generation of reactive oxygen species, expression of inflammatory cytokines and apoptosis-related genes, and activation of specific signaling molecules will be evaluated to determine the molecular mechanisms by which COX-2 exacerbates MPTP neurotoxicity. The goals of this study are to elucidate the changes in inflammatory processing affected by COX-2 deficiency, to explore the etiology and molecular mechanisms underlying Parkinsonian symptoms in the experimental MPTP model, and to develop novel therapeutic treatments for PD and other neurodegenerative diseases.
Effective start/end date8/1/008/31/04


  • National Institute on Aging: $625,240.00


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