title: Moderate ethanol preconditioning of rat brain cultures engenders neuroprotection against dementia-inducing neuroinflammatory proteins: possible signaling mechanisms.
abstract: There is no question that chronic alcohol (ethanol) abuse, a leading worldwide problem, causes neuronal dysfunction and brain damage. However, various epidemiologic studies in recent years have indicated that in comparisons with abstainers or never-drinkers, light/moderate alcohol consumers have lower risks of age-dependent cognitive decline and/or dementia, including Alzheimer's disease (AD). Such reduced risks have been variously attributed to favorable circulatory and/or cerebrovascular effects of moderate ethanol intake, but they could also involve ethanol "preconditioning" phenomena in brain glia and neurons. Here we summarize our experimental studies showing that moderate ethanol preconditioning (MEP; 20-30 mM ethanol) of rat brain cultures prevents neurodegeneration due to beta-amyloid, an important protein implicated in AD, and to other neuroinflammatory proteins such as gp120, the human immunodeficiency virus 1 envelope protein linked to AIDS dementia. The MEP neuroprotection is associated with suppression of neurotoxic protein-evoked initial increases in [Ca(+2)](i) and proinflammatory mediators--e.g., superoxide anion, arachidonic acid, and glutamate. Applying a sensor --> transducer --> effector model to MEP, we find that onset of neuroprotection correlates temporally with elevations in "effector" heat shock proteins (HSP70, HSP27, and phospho-HSP27). The effector status of HSPs is supported by the fact that inhibiting HSP elevations due to MEP largely restores gp120-induced superoxide potentiation and subsequent neurotoxicity. As upstream mediators, synaptic N-methyl-d-aspartate receptors may be initial prosurvival sensors of ethanol, and protein kinase C epsilon and focal adhesion kinase are likely transducers during MEP that are essential for protective HSP elevations. Regarding human consumption, we speculate that moderate ethanol intake might counter incipient cognitive deterioration during advanced aging or AD by exerting preconditioning-like suppression of ongoing neuroinflammation related to amyloidogenic protein accumulation.
authors.affiliation: Biochemistry Division, Department of Pharmacology, Loyola University Medical School, Maywood, IL 60153, USA. mcollin@lumc.edu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Collins
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Neafsey
authors.forename: Kewei
authors.initials: K
authors.lastname: Wang
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Achille
authors.forename: Robert M
authors.initials: RM
authors.lastname: Mitchell
authors.forename: Sreevidya
authors.initials: S
authors.lastname: Sivaswamy
mesh_terms: D000428:Alcohol Drinking; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects*; D003704:Dementia / Q000473:pathology / Q000503:physiopathology; D000431:Ethanol / Q000494:pharmacology*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D015699:HIV Envelope Protein gp120; D018696:Neuroprotective Agents; D000431:Ethanol; D051416:Focal Adhesion Protein-Tyrosine Kinases; D011493:Protein Kinase C