Reduction of Nuclear Peroxisome Proliferator-Activated Receptor γ Expression in Methamphetamine-Induced Neurotoxicity and Neuroprotective Effects of Ibuprofen
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We examined changes in nuclear peroxisome proliferator-activated receptor γ (PPARγ) in the striatum in methamphetamine (METH)-induced dopaminergic neurotoxicity, and also examined effects of treatment with drugs possessing PPARγ agonistic properties. The marked reduction of nuclear PPARγ-expressed cells was seen in the striatum 3 days after METH injections (4 mg/kg × 4, i.p. with 2-h interval). The reduction of dopamine transporter (DAT)-positive signals and PPARγ expression, and accumulation of activated microglial cells were significantly and dose-dependently attenuated by four injections of a nonsteroidal anti-inflammatory drug and a PPARγ ligand, ibuprofen (10 or 20 mg/kg × 4, s.c.) given 30 min prior to each METH injection, but not by either a low or high dose of aspirin. Either treatment of ibuprofen or aspirin, that showed no effects on METH-induced hyperthermia, significantly blocked the METH-induced striatal cyclooxygenase (COX) expression. Furthermore, the treatment of an intrinsic PPARγ ligand 15d-PG J2 also attenuated METH injections-induced reduction of striatal DAT. Therefore, the present study suggests the involvement of reduction of PPARγ expression in METH-induced neurotoxicity. Taken together with the previous report showing protective effects of other PPARγ ligand, these results imply that the protective effects of ibuprofen against METH-induced neurotoxicity may be based, in part, on its anti-inflammatory PPARγ agonistic properties, but not on its COX-inhibiting property or hypothermic effect.
KeywordsMethamphetamine Neurotoxicity Ibuprofen Nonsteroidal anti-inflammatory drug 15d-PG J2 PPARγ
This work was supported in part by Health and Labour Sciences Research Grants for Research on Regulatory Science of Pharmaceuticals and Medical Devices, for Research on Measures for Intractable Diseases, from the Japanese Ministry of Health, Labour and Welfare (M.A.), and by Grants-in-Aid for Scientific Research (C) (M.A.) and for Young Scientists (B) (I.M.) from the Japanese Ministry of Education, Culture, Sports, Science, and Technology.
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