Suppression of heat- and polyglutamine-induced cytotoxicity by nonsteroidal anti-inflammatory drugs.
We have shown that sodium salicylate activates the heat shock promoter and induces the expression of heat shock proteins (hsps), with a concomitant increase in the thermotolerance of cells. To determine whether these effects are generally displayed by nonsteroidal anti-inflammatory drugs (NSAIDs), we examined the effects of a cyclooxygenase inhibitor, indomethacin, and a lipoxygenase inhibitor, nordihydroguaiaretic acid. Both inhibitors up-regulated the hsp promoter at 37 degrees C through the activation of heat shock factors, and increased cellular levels of hsps in mammalian cells, although the degree of the expression of hsps and thermotolerance of cells differed depending on the drugs. Furthermore, NSAIDs such as sodium salicylate and indomethacin suppressed the protein aggregation and apoptosis caused by an expanded polyglutamine tract in a cellular model of polyglutamine disease. These findings suggest that NSAIDs generally induce the expression of hsps in mammalian cells and may be used for the protection of cells against deleterious stressors and neurodegenerative diseases.
Ishihara
Keiichi
K
Department of Biochemistry, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, Japan.
Yamagishi
Nobuyuki
N
Hatayama
Takumi
T
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D019556:COS Cells; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D002843:Chromatin / Q000737:chemistry; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D006358:Hot Temperature; D007213:Indomethacin / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009637:Masoprocol / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D018613:Microscopy, Confocal; D010455:Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012980:Sodium Salicylate / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002843:Chromatin; D016861:Cyclooxygenase Inhibitors; D006360:Heat-Shock Proteins; D016859:Lipoxygenase Inhibitors; D010455:Peptides; C097188:polyglutamine; D009637:Masoprocol; D012980:Sodium Salicylate; D007213:Indomethacin