Human immunodeficiency virus type 1 gp120 and ethanol coexposure in rat organotypic brain slice cultures: Curtailment of gp120-induced neurotoxicity and neurotoxic mediators by moderate but not high ethanol concentrations.
Human immunodeficiency virus type 1 (HIV-1) envelope protein gp120, implicated with other retroviral proteins in acquired immunodeficiency syndrome (AIDS)-related dementia, causes neuronal degeneration by inciting cascades of neurotoxic mediators from glia. It also may facilitate neuronal glutamate (N-methyl-D-aspartate, NMDA) receptor-mediated excitotoxicity by interacting at the glycine coagonist site. The authors reported that preconditioning rat organotypic hippocampal-cortical slice cultures subchronically with ethanol at concentrations occurring during moderate drinking (20 to 30 mM) prevented gp120's induction of neurotoxic mediators and intracellular calcium, as well as neuronal death. The authors now find that the acute copresence of ethanol in moderate as opposed to high concentrations similarly blocks the retroviral protein's neurotoxic effects in brain slice cultures, assessed with lactate dehydrogenase (LDH) release and propidium iodide (PI) labeling. As with ethanol preconditioning, neuroprotection against gp120 by moderate ethanol coexposure appears secondary to abrogation of the retroviral protein's early induction of arachidonic acid (AA), glutamate, and superoxide (but not nitric oxide) elevations/release. Additionally, experiments indicate that 30 mM ethanol is sufficient to inhibit the NMDA receptor, particularly in the presence of added glycine, thus hindering potential direct neuronal stimulation by gp120. However, in contrast to moderate ethanol, 100 mM ethanol, a concentration tolerated only in chronic alcoholics, potentiates gp120-dependent neurotoxicity (PI labeling) in the hippocampal CA1 region, augments LDH release, and fails to curtail gp120's actions on AA, glutamate, and superoxide-but does suppress nitric oxide induction. The results indicate dominant roles for AA, superoxide, and glutamate-mediated oxidative stress in gp120's neurotoxic mechanism, but perhaps a less important role for NMDA receptor stimulation, which would be constrained at both ethanol concentrations employed. We suggest that ethanol's concentration-dependent, two-edged sword behavior could alter the development of dementia in HIV-1-infected individuals during social consumption or abuse. Further studies are needed to elucidate the differing apparently glial effects of the two concentrations of ethanol.
Belmadani
A
A
Department of Cell Biology, Neurobiology and Anatomy, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, USA.
Neafsey
E J
EJ
Collins
M A
MA
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D005998:Glycine / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D016202:N-Methylaspartate / Q000494:pharmacology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism
D002492:Central Nervous System Depressants; D018690:Excitatory Amino Acid Agonists; D015699:HIV Envelope Protein gp120; D013481:Superoxides; D016718:Arachidonic Acid; D000431:Ethanol; D018698:Glutamic Acid; D016202:N-Methylaspartate; D005998:Glycine