title: Selective increase of neuronal cyclooxygenase-2 (COX-2) expression in vulnerable brain regions of rats with experimental Wernicke's encephalopathy: effect of nimesulide.
abstract: 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.
authors.affiliation: Neuroscience Research Unit, CHUM/Campus Saint-Luc, 1058 St-Denis Street, Montreal, Quebec, Canada, H2X 3J4.
authors.forename: Baoying
authors.initials: B
authors.lastname: Gu
authors.forename: Paul
authors.initials: P
authors.lastname: Desjardins
authors.forename: Roger F
authors.initials: RF
authors.lastname: Butterworth
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D015232:Dinoprostone; C012655:nimesulide