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Piroxicam and NS‐398 rescue neurones from hypoxia/reoxygenation damage by a mechanism independent of cyclo‐oxygenase inhibition
Author(s) -
Vartiainen Nina,
Huang ChiungYing,
Salminen Antero,
Goldsteins Gundars,
Chan Pak H.,
Koistinaho Jari
Publication year - 2001
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2001.00065.x
Subject(s) - piroxicam , hypoxia (environmental) , mapk/erk pathway , pharmacology , kinase , phosphorylation , chemistry , neuroprotection , lactate dehydrogenase , biochemistry , biology , medicine , enzyme , pathology , alternative medicine , organic chemistry , oxygen
We studied whether NS‐398, a selective cyclo‐oxygenase‐2 (COX‐2) enzyme inhibitor, and piroxicam, an inhibitor of COX‐2 and the constitutively expressed COX‐1, protect neurones against hypoxia/reoxygenation injury. Rat spinal cord cultures were exposed to hypoxia for 20 h followed by reoxygenation. Hypoxia/reoxygenation increased lactate dehydrogenase (LDH) release, which was inhibited by piroxicam (180–270 µ m ) and NS‐398 (30 µ m ). Cell counts confirmed the neuroprotection. Western blotting revealed no COX‐1 or COX‐2 proteins even after hypoxia/reoxygenation. Production of prostaglandin E 2 (PGE 2 ), a marker of COX activity, was barely measurable and piroxicam and NS‐398 had no effect on the negligible PGE 2 production. Hypoxia/reoxygenation increased nuclear factor‐kappa B (NF‐κB) binding activity, which was inhibited by piroxicam but not by NS‐398. AP‐1 binding activity after hypoxia/reoxygenation was inhibited by piroxicam but strongly enhanced by NS‐398. However, both COX inhibitors induced activation of extracellular signal‐regulated kinase (ERK) in neurones and phosphorylation of heavy molecular weight neurofilaments, cytoskeletal substrates of ERK. It is concluded that piroxicam and NS‐398 protect neurones against hypoxia/reperfusion. The protection is independent of COX activity and not solely explained by modulation of NF‐κB and AP‐1 binding activity. Instead, piroxicam and NS‐398‐induced phosphorylation through ERK pathway may contribute to the increased neuronal survival.