The non-steroidal anti-inflammatory drug tepoxalin inhibits interleukin-6 and alpha1-anti-chymotrypsin synthesis in astrocytes by preventing degradation of IkappaB-alpha.
Tepoxalin is a structurally and functionally novel non-steroidal anti-inflammatory 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 CNS. No data, however, are available concerning the effects of this drug in the CNS. Since cytokines such as interleukin-1 (IL-1) or interleukin-6 (IL-6) as well as acute-phase proteins such as alpha1-anti-chymotrypsin (ACT) participate in the etiopathology of Alzheimer's disease (AD), we were interested whether tepoxalin is able to inhibit the synthesis of these immunomodulators in primary rat microglia and astrocytes as well as in the human astrocytoma cell line U373 MG. We found that tepoxalin markedly inhibits IL-1beta-induced IL-6 and ACT synthesis in astrocytes and the synthesis of IL-1beta and IL-6 in lipopolysaccharide (LPS)-stimulated microglial cells. Electrophoretic mobility shift and reporter gene assays revealed that tepoxalin exerts its inhibitory effect through the inhibition of nuclear factor kappaB (NF-kappaB), a transcription factor involved in the induction of IL-1, IL-6 and ACT gene expression. We show that inhibition of NF-kappaB activation by tepoxalin is mediated by preventing IkappaB-alpha degradation. Based on this inhibitory effect of tepoxalin on cytokine and ACT synthesis and the documented therapeutic efficacy of NSAIDs in AD, we conclude that tepoxalin may be of therapeutic benefit for the treatment of AD patients and should therefore be tested in clinical trials.
Fiebich
B L
BL
Department of Psychiatry and Psychotherapy, University of Freiburg Medical School, Germany. bernd_fiebich@psyallg.ukl.uni-freiburg.de
Hofer
T J
TJ
Lieb
K
K
Huell
M
M
Butcher
R D
RD
Schumann
G
G
Schulze-Osthoff
K
K
Bauer
J
J
D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000276:immunology; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000514:alpha 1-Antichymotrypsin / Q000096:biosynthesis*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606206:Nfkbia protein, rat; D011720:Pyrazoles; D000514:alpha 1-Antichymotrypsin; D000072000:NF-KappaB Inhibitor alpha; C073135:tepoxalin