Selective increase of neuronal cyclooxygenase-2 (COX-2) expression in vulnerable brain regions of rats with experimental Wernicke's encephalopathy: effect of nimesulide.
Thiamine deficiency (TD) in both humans and experimental animals results in severe mitochondrial dysfunction and leads to selective neuronal cell death in diencephalic and cerebellar structures. We have investigated cyclooxygenase-2 (COX-2) expression in vulnerable (medial thalamus, inferior colliculus) and spared (frontal cortex) regions of rats with thiamine deficiency. Expression of COX-2 mRNA was selectively increased (twofold, p < 0.001) in vulnerable regions at symptomatic stages of encephalopathy (14 days) of TD compared to pair-fed controls or presymptomatic (days 12) rats. Induction of COX-2 expression was accompanied by a significant increase (two- to threefold, p < 0.001) in prostanglandin E2 (PGE2) synthesis in vulnerable regions at symptomatic stages of TD. COX-2 immunolabeling revealed a neuronal localization and COX-2 immunoreactive neurons were significantly increased at symptomatic stages of encephalopathy. Administration of nimesulide, a highly specific COX-2 inhibitor, significantly reduced PGE-2 levels in vulnerable regions but, rather than being neuroprotective, precipitated encephalopathy and exacerbated neuronal cell death due to TD. These findings suggest that newly synthesized prostanoids exert a neuroprotective role in TD.
Gu
Baoying
B
Neuroscience Research Unit, CHUM/Campus Saint-Luc, 1058 St-Denis Street, Montreal, Quebec, Canada, H2X 3J4.
Desjardins
Paul
P
Butterworth
Roger F
RF
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D015232:Dinoprostone / Q000096:biosynthesis; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000009:adverse effects; D007150:Immunohistochemistry; D008297:Male; D009410:Nerve Degeneration / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000009:adverse effects*; D013832:Thiamine Deficiency / Q000201:enzymology* / Q000503:physiopathology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014899:Wernicke Encephalopathy / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D015232:Dinoprostone; C012655:nimesulide