The non-steroidal anti-inflammatory drug tepoxalin inhibits interleukin-6 and alpha(1)-anti-chymotrypsin synthesis in astrocytes by preventing degradation of I kappa B-alpha

Tepoxalin is a structurally and functionally novel non-steroidal anti-infla mmatory drug (NSAID) with potent anti-inflammatory and analgesic properties . Apart from its inhibitory effect on cyclooxygenase activity, tepoxalin is able to inhibit production of cytokines in peripheral cells outside the CN S. No data, however, are available concerning the effects of this drug in t he CNS. Since cytokines such as interleukin-1 (IL-1) or interleukin-6 (IL-6 ) as well as acute-phase proteins such as alpha(1)-anti-chymotrypsin (ACT) participate in the etiopathology of Alzheimer's disease (AD), we were inter ested whether tepoxalin is able to inhibit the synthesis of these immunomod ulators in primary rat microglia and astrocytes as well as in the human ast rocytoma cell line U373 MG. We found that tepoxalin markedly inhibits IL-1 beta-induced IL-6 and ACT synthesis in astrocytes and the synthesis of IL-1 beta and IL-6 in lipopolysaccharide (LPS)-stimulated microglial cells. Ele ctrophoretic mobility shift and reporter gene assays revealed that tepoxali n exerts its inhibitory effect through the inhibition of nuclear factor kap paB (NF-kappa B), a transcription factor involved in the induction of IL-1, IL-6 and ACT gene expression. We show that inhibition of NF-kappa B activa tion by tepoxalin is mediated by preventing I kappa B-alpha degradation. Ba sed on this inhibitory effect of tepoxalin on cytokine and ACT synthesis an d the documented therapeutic efficacy of NSAIDs in AD, we conclude that tep oxalin may be of therapeutic benefit for the treatment of AD patients and s hould therefore be tested in clinical trials. (C) 1999 Elsevier Science Ltd . All rights reserved.