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 toxicity. The teratogenic effect of ethanol may result from its action on prostaglandins. Prostaglandins are generated through the release of arachidonic acid (AA) by the action of cytosolic phospholipase A2 (cPLA2) on membrane‐bound phospholipids and the catalytic conversion of AA to prostaglandin E2 (PGE2) by cyclo‐oxygenase (COX). COX is expressed in two isoforms, constitutive COX1 and inducible COX2. Cultured astrocytes and neurons from immature 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 astrocytes and neurons. Ethanol (200–400 mg/dL for 24 h) significantly increased 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 activity was up‐regulated by ethanol in astrocytes and neurons, and indomethacin, a nonselective blocker for COX, eliminated the ethanol‐induced increases of COX activity in both cell types. Increased COX activity in astrocytes resulted from an increase in COX2 expression. NS‐398, a selective COX2 blocker, completely inhibited ethanol‐induced alterations in COX activity. In neurons, however, ethanol had a direct effect on COX activity in the absence of a change in COX expression. NS‐398 only partially blocked ethanol‐induced increases in neuronal COX activity. Thus, astrocytes are a primary target of ethanol and ethanol‐induced increases in glial PGE2 synthesis are mediated by COX, principally COX2. Ethanol toxicity may be mediated through PGE2 in immature cortical cells.