Piroxicam and NS-398 rescue neurones from hypoxia/reoxygenation damage by a mechanism independent of cyclo-oxygenase inhibition

Citation
N. Vartiainen et al., Piroxicam and NS-398 rescue neurones from hypoxia/reoxygenation damage by a mechanism independent of cyclo-oxygenase inhibition, J NEUROCHEM, 76(2), 2001, pp. 480-489
Citations number
76
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Neurosciences & Behavoir
Journal title
JOURNAL OF NEUROCHEMISTRY
ISSN journal
0022-3042 → ACNP
Volume
76
Issue
2
Year of publication
2001
Pages
480 - 489
Database
ISI
SICI code
0022-3042(200101)76:2<480:PANRNF>2.0.ZU;2-1
Abstract
We studied whether NS-398, a selective cyclo-oxygenase-2 (COX-2) enzyme inh ibitor, and piroxicam, an inhibitor of COX-2 and the constitutively express ed 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 muM) and NS-398 (30 muM). Cell counts c onfirmed the neuroprotection. Western blotting revealed no COX-1 or COX-2 p roteins 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/reoxygena tion increased nuclear factor-kappa B (NF-kappaB) binding activity, which w as inhibited by piroxicam but not by NS-398. AP-1 binding activity after hy poxia/reoxygenation was inhibited by piroxicam but strongly enhanced by NS- 398. However, both COX inhibitors induced activation of extracellular signa l-regulated kinase (ERK) in neurones and phosphorylation of heavy molecular weight neurofilaments, cytoskeletal substrates of ERK. It is concluded tha t piroxicam and NS-398 protect neurones against hypoxia/reperfusion. The pr otection is independent of COX activity and not solely explained by modulat ion of NF-KB and AP-1 binding activity. Instead, piroxicam and NS-398-induc ed phosphorylation through ERK pathway may contribute to the increased neur onal survival.