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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS044157-01A1
Application #
6680072
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Sheehy, Paul A
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
1
Fiscal Year
2003
Total Cost
$253,638
Indirect Cost
Name
University of Kentucky
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Xing, Bin; Xin, Tao; Zhao, Lingling et al. (2010) Glial cell line-derived neurotrophic factor protects midbrain dopaminergic neurons against lipopolysaccharide neurotoxicity. J Neuroimmunol 225:43-51
Choi, Dong-Young; Zhang, Jinlu; Bing, Guoying (2010) Aging enhances the neuroinflammatory response and alpha-synuclein nitration in rats. Neurobiol Aging 31:1649-53
Liu, Mei; Choi, Dong-Young; Hunter, Randy L et al. (2010) Trichloroethylene induces dopaminergic neurodegeneration in Fisher 344 rats. J Neurochem 112:773-83
Nguyen, Xuan V; Liu, Mei; Kim, Hyoung-Chun et al. (2009) Effects of prodynorphin deletion on striatal dopamine in mice during normal aging and in response to MPTP. Exp Neurol 219:228-38
Hunter, Randy L; Cheng, Baohua; Choi, Dong-Young et al. (2009) Intrastriatal lipopolysaccharide injection induces parkinsonism in C57/B6 mice. J Neurosci Res 87:1913-21
Choi, Dong-Young; Liu, Mei; Hunter, Randy L et al. (2009) Striatal neuroinflammation promotes Parkinsonism in rats. PLoS One 4:e5482
Liu, Mei; Hunter, Randy; Nguyen, Xuan V et al. (2008) Microsomal epoxide hydrolase deletion enhances tyrosine hydroxylase phosphorylation in mice after MPTP treatment. J Neurosci Res 86:2792-801
Hunter, Randy L; Choi, Dong-Young; Ross, Stuart A et al. (2008) Protective properties afforded by pioglitazone against intrastriatal LPS in Sprague-Dawley rats. Neurosci Lett 432:198-201
Hunter, Randy L; Liu, Mei; Choi, Dong Young et al. (2008) Inflammation and age-related iron accumulation in F344 rats. Curr Aging Sci 1:112-21
Xing, Bin; Xin, Tao; Hunter, Randy Lee et al. (2008) Pioglitazone inhibition of lipopolysaccharide-induced nitric oxide synthase is associated with altered activity of p38 MAP kinase and PI3K/Akt. J Neuroinflammation 5:4

Showing the most recent 10 out of 15 publications