Essential involvement of the NMDA receptor in ethanol preconditioning-dependent neuroprotection from amyloid-betain vitro.
In several epidemiological studies, moderate ethanol consumption has been associated with reduced risks of cognitive decline or Alzheimer's dementia. Of potential relevance is that brain cultures preconditioned with moderate ethanol concentrations are resistant to neurotoxic Alzheimer's amyloid-beta (Abeta) peptides. Using rat cerebellar mixed cultures we investigated whether certain membrane receptors were early 'sensors' in moderate ethanol preconditioning (MEP). In a 6-day MEP protocol (30 mM ethanol), neuroprotection from Abeta25-35 was undiminished by antagonism during the first 3 days of either adenosine A(1) or Galpha(i/o) protein-coupled receptors. However, similar cotreatment with memantine or DL-2-amino-5-phosphono-pentanoic acid (AP-5), antagonists of NMDA receptors (NMDAR), abolished neuroprotection, indicating key early involvement of this ionotropic glutamate receptor. Also in these cultures, directly activating NMDAR using subexcitotoxic NMDA preconditioning prevented Abeta neurotoxicity. By day 2 of MEP, we observed increased levels of NMDAR subunits NR1, NR2B, and NR2C that persisted through day 6. Interestingly, memantine co-exposure blocked elevations in the obligatory NR1 subunit. Furthermore, 2 days of MEP significantly increased two indicators of synaptic NMDAR localization, NR2B phospho-Tyr1472, and post-synaptic density 95 scaffolding protein. The results indicate that ethanol preconditioning-dependent neuroprotection is associated with early increases in NR subunits concomitant with enhancement of synaptic localization and activity of NMDAR.
Mitchell
Robert M
RM
Department of Pharmacology, Division of Biochemistry, Loyola University Stritch School of Medicine, Maywood, Illinois 60153, USA.
Neafsey
Edward J
EJ
Collins
Michael A
MA
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002531:Cerebellum / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D066298:In Vitro Techniques; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism / Q000633:toxicity*; D019000:Phosphotyrosine / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D016229:Amyloid beta-Peptides; D002492:Central Nervous System Depressants; C409466:NR1 NMDA receptor; C121001:NR2B NMDA receptor; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; C074636:amyloid beta-protein (25-35); D019000:Phosphotyrosine; D000431:Ethanol
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