Troglitazone inhibits both post-glutamate neurotoxicity and low-potassium-induced apoptosis in cerebellar granule neurons.
Both excitotoxicity and apoptosis contribute to neuronal loss in various neurodegenerative diseases such as Alzheimer's disease as well as stroke, and a drug inhibiting both types of cell death may lead to practical treatment for these diseases. Post-treatment with troglitazone, a potent and specific activator of peroxisome proliferator-activated receptor (PPAR)-gamma attenuated the cell death of cerebellar granule neurons, triggered by glutamate exposure. The inhibitory effect of troglitazone against glutamate excitotoxicity, in vitro, was observed even when added 2.5 h after the end of glutamate exposure, a time when glutamate antagonists are no longer neuroprotective. However, troglitazone did not block the glutamate-induced elevation of calcium influx, suggesting that troglitazone interfered with downstream consequences of excitotoxic glutamate receptor overactivation. In addition, troglitazone also suppressed low-potassium-induced apoptosis in cerebellar granule neurons in a phosphatidylinositol 3-kinase independent manner. In conclusion, although the mechanisms of troglitazone's neuroprotective effects are unknown, the post-treatment-neuroprotective effect and the dual-inhibitory-activity against both excitotoxicity and apoptosis may provide a novel therapy for various neurodegenerative diseases.
Uryu
Shigeko
S
Neuroscience and Immunology Research Laboratories, Sankyo Co., Ltd., 2-58, Hiromachi 1-chome, Shinagawa-ku, Tokyo 140-8710, Japan. shigek@shina.sankyo.co.jp
Harada
Jun
J
Hisamoto
Marie
M
Oda
Tomiichiro
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D002839:Chromans / Q000494:pharmacology*; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000633:toxicity*; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology; D020675:Peroxisomes / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone; D014665:Vasodilator Agents / Q000494:pharmacology*
D002839:Chromans; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D018696:Neuroprotective Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D014665:Vasodilator Agents; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D018698:Glutamic Acid; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D000077288:Troglitazone; D011188:Potassium