Differential effects of ethanol on the expression of cyclo-oxygenase in cultured cortical astrocytes and neurons

The developing central nervous system is a primary target of ethanol toxici ty. The teratogenic effect of ethanol may result from its action on prostag landins. Prostaglandins are generated through the release of arachidonic ac id (AA) by the action of cytosolic phospholipase A(2) (cPLA(2)) on membrane -bound phospholipids and the catalytic conversion of AA to prostaglandin E- 2 (PGE(2)) by cyclo-oxygenase (COX). COX is expressed in two isoforms, cons titutive COX1 and inducible COX2. Cultured astrocytes and neurons from imma ture cerebral cortex were used as in vitro models to investigate the effect of ethanol on PGE2 synthesis. In both cell types, neither the activity nor the expression of cPLA2 was affected by ethanol. PGE2 was synthesized by a strocytes and neurons. Ethanol (200-400 mg/dL for 24 h) significantly incre ased PGE2 production in both cell types and the ethanol-induced increase in PGE2 accumulation in astrocytes was significantly greater than in neurons. These increases resulted from the effects of ethanol on COX. Overall COX a ctivity was up-regulated by ethanol in astrocytes and neurons, and indometh acin, a nonselective blocker for COX, eliminated the ethanol-induced increa ses of COX activity in both cell types. Increased COX activity in astrocyte s resulted from an increase in COX2 expression. NS-398, a selective COX2 bl ocker, completely inhibited ethanol-induced alterations in COX activity. In neurons, however, ethanol had a direct effect on COX activity in the absen ce of a change in COX expression. NS-398 only partially blocked ethanol-ind uced increases in neuronal COX activity. Thus, astrocytes are a primary tar get of ethanol and ethanol-induced increases in glial PGE, synthesis are me diated by COX, principally COX2. Ethanol toxicity may be mediated through P GE2 in immature cortical cells.