Inhibition of astroglial cell proliferation by alcohols: interference withthe protein kinase C-phospholipase D signaling pathway

Ethanol inhibits astroglial cell proliferation, an effect that may contribu te to the development of alcoholic embryopathy in humans. In the present st udy, we investigated inhibitory effects of ethanol and butanol isomers (1-, 2- and t-butanol) on astroglial cell proliferation induced by the strongly mitogenic phorbol ester, 4 beta -phorbol-12 alpha ,13 beta -dibutyrate (PD B). 4 beta -Phorbol-12 alpha ,13 beta -dibutyrate (PDB) induced a 10-fold i ncrease of [H-3] thymidine incorporation in cortical astrocytes prepared fr om newborn rats (EC50: 70 nM) which was blocked by Po 31-8220, a cell-perme able protein kinase C (PKC) inhibitor. Ethanol blocked PDB-induced astrogli al proliferation in a concentration-dependent manner; significant effects w ere already seen at 0.1% (v/v). Concomitantly, ethanol caused the formation of phosphatidylethanol (PEth) by phospholipase D (PLD) and reduced PLD-med iated formation of phosphatidic acid (PA). The butanols also inhibited the mitogenic action of phorbol ester; the inhibitory potency of the butanols w as 1-butanol > 2-butanol > t-butanol. The same range of potencies was obser ved for the inhibitory activity of the butanols towards protein kinase C ac tivity measured in vitro. At 0.3% concentration, I-butanol potently suppres sed the PDB-induced formation of phosphatidic acid while 2- and t-butanol w ere less active. Taken together, our results suggest that ethanol and I-but anol exert a specific inhibitory effect on PKC-dependent astroglial cell pr oliferation by synergistically inhibiting PKC activity and the PLD signalin g pathway. (C) 2000 ISDN. Published by Elsevier Science Ltd. All rights res erved.