| Summary: | 碩士 === 國防醫學院 === 藥理學研究所 === 96 === Abstract
The PPAR-γ (peroxisome proliferators-activated receptor γ) agonists such as Thiazolidinediones (TZDs), exhibit potent anti-inflammatory and anti-apoptosis effects and appear to have direct neuroprotective actions. TZDs are already used to improve insulin resistance and treat type 2 diabetes. Recent evidence indicates that TZDs have been shown to be efficacious in animal models of Alzheimer’s disease, stroke, multiple sclerosis, Parkinson’s disease and amyotrophic lateral sclerosis. Methamphetamine (METH) is an addictive drug that can cause a progressive and fatal neurodegenerative disorder characterized by multiple apoptotic pathways in the rodent brain. The aim of this study was to evaluate whether the direct modulation of Wnt signaling and tau phosphorylation pathways by TZDs prevents the toxic effects induced by METH in rat cortical cells. We report here that (1) PPAR-γ is present in rat cortical cell in culture. (2) Activation of PPAR-γ by rosiglitazone or pioglitazone (0.01~ 10 μM) protects rat cortical cells against METH-induced neurodegeneration, as shown by immunohistochemistry using anti-NeuN and anti-GFAP antibodies. (3) PPAR-γ activation prevents the excitotoxic METH-induced rise in bulk-free Ca2+ using Furo-3 detected by flowcytometry. (4) TZDs regulates tau phosphorylation through a PPAR-γ dependent mechanism involving an AKT/glycogen synthase kinase-3 (GSK-3) –dependent signaling cascade. (5) PPAR-γ activation of TZDs results in the modulation of Wnt signaling components, including an increase of the -catenin levels. We conclude that the TZDs prevent METH-induced neurogeneration by a mechanism that may involve a cross talk between taupathy and the Wnt signaling pathways. More important, the fact that the activation of PPAR-γ attenuated METH-dependent neurodengenation opens a new therapeutic perspective.
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