Ethanol pre-exposure suppresses HIV-1 glycoprotein 120-induced neuronal degeneration by abrogating endogenous glutamate/Ca2+-mediated neurotoxicity

The neurotoxic mechanism of HIV-1 envelope glycoprotein 120 (gp120) involve s glutamatergic (NMDA) receptor/Ca2+-dependent excitotoxicity. mediated in part via glia. Pro-inflammatory cytokines also mag; have roles. We have rep orted that pre-exposure of brain cultures to 'physiological' ethanol concen trations (20-30 mM) protects against neuronal damage from HIV-I gp120, but not from the direct receptor agonist, NMDA. Using lactate dehydrogenase ass ays and propidium iodide staining of rat organotypic hippocampal-entorhinal cortical slice cultures we determined that ethanol's suppression of gp120 neurotoxicity required at least 4 days of pretreatment. The gp120-induced n eurotoxicity was accompanied by interleukin-6 elevations that were not affe cted by the pretreatment. However. gp120 induced substantial. early increas es in extracellular glutamate levels that were blocked by ethanol pretreatm ent. conceivably abrogating excitotoxicity. Consistent with abrogation of e xcitotoxic pathways. fura-2 imaging showed selective deficits in gp120-depe ndent intracellular Ca2+ responses in ethanol-pretreated slices. Gp120 is b elieved to increase glutamate levels by both stimulating release and inhibi ting (re)uptake. Results with a labeled glutamate analog, D-[H-3]aspartate, revealed that gp120's inhibition of glutamate uptake, rather than its stim ulation of release. was abolished after ethanol. Further studies indicated that two converging effects of ethanol pretreatment may underlie the abolis hment of gp120-mediated glutamate uptake inhibition: (a) blockade of gp120- induced release (ostensibly from glia) of arachidonic acid, an inhibitor of astroglial glutamate reuptake, and (b) modest proliferation and activation of astroglia upon gp120 stimulation - which are likely to augment glutamat e transporters. Thus. as with gp120 itself. glia and glutamate/arachidonic acid regulation appear to be important targets for ethanol. Since moderate ethanol consumption is as common among HIV-infected individu als as in the general population, this newly recognized neuroprotective (an d apparently anti-excitotoxic) effect of ethanol withdrawal in vitro could be important but it requires further study before its significance. if any, is understood. (C) 2001 IBRO. Published by Elsevier Science Ltd. All right s reserved.