Microglia-mediated neuroinflammation plays an important role in the pathogenesis of Parkinson's disease (PD). Uncontrolled microglia activation produces major proinflammatory factors including cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS) that may cause dopaminergic neurodegeneration. Peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone has potent antiinflammatory property. We hypothesize pioglitazone protects dopaminergic neuron from lipopolysaccharide (LPS)-induced neurotoxicity by interacting with relevant signal pathways, inhibiting microglial activation and decreasing inflammatory mediators.
First, the neuroprotection of pioglitazone was explored. Second, the signaling transductions such as jun N-terminal kinase (JNK) and the interference with these pathways by pioglitazone were investigated. Third, the effect of pioglitazone on these pathways-mediated PGE2 / nitric oxide (NO) generation was investigated. Finally, the effect of PPARγ antagonist on the inhibition of PGE2 / NO by pioglitazone was explored. The results show that LPS neurotoxicity is microglia-dependent, and pioglitazone protects neurons against LPS insult possibly by suppressing LPS-induced microglia activation and proliferation. Second, pioglitazone protects neurons from COX-2 / PGE2 mediated neuronal loss by interfering with the NF-κB and JNK, in PPARγ-independent mechanisms. Third, pioglitazone significantly inhibits LPS-induced iNOS / NO production, and inhibition of LPS-induced iNOS protects neuron. Fourth, inhibition p38 MAPK reduces LPS-induced NO generation but no effect is found upon JNK inhibition, and pioglitazone inhibits p38 MAPK phosphorylation induced by LPS. In addition, pioglitazone increases PPARγ phosphorylation, followed by the increased PI3K/Akt phosphorylation. Nevertheless, inhibition of PI3K increases LPS-induced p38 MAPK phosphorylation. Inhibition of PI3K eliminates the inhibitive effect of pioglitazone on the LPS-induced NO production, suggesting that the inhibitive effect of pioglitazone on the LPS-induced iNOS and NO might be PI3K-dependent.
| Identifer | oai:union.ndltd.org:uky.edu/oai:uknowledge.uky.edu:gradschool_diss-1632 |
| Date | 01 January 2008 |
| Creators | Xing, Bin |
| Publisher | UKnowledge |
| Source Sets | University of Kentucky |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | University of Kentucky Doctoral Dissertations |
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