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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 lipoxyg-enase inhibitor, nordihydroguaiaretic acid. Both inhibitors up-regulated the hsp promoter at 37 C through the acti- | Eur. J. Biochem. 271 4552-4558 2004 FEBS 2004 doi 10.1111 j.1432-1033.2004.04419.x Suppression of heat- and polyglutamine-induced cytotoxicity by nonsteroidal anti-inflammatory drugs Keiichi Ishihara Nobuyuki Yamagishi and Takumi Hatayama Department of Biochemistry Kyoto Pharmaceutical University Misasagi Yamashina-ku Kyoto Japan 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 antiinflammatory 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 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. Keywords heat shock proteins indomethacin nonsteroidal anti-inflammatory drugs nordihydroguaiaretic acid polyglutamine disease. Nonsteroidal anti-inflammatory drugs NSAIDs such as sodium salicylate SA and indomethacin IND are widely used as analgesic or antipyretic agents for the clinical treatment of inflammatory diseases. Most NSAIDs exhibit an inhibitory effect on cyclooxygenases COXs which catalyze the biosynthesis of prostaglandins and thromboxanes from arachidonic acid. On the other hand nordihydroguaiaretic acid NDGA inhibits lipoxygenases LOXs which produce leukotrienes from
