Details

Autor(en) / Beteiligte

• Mitchell, Robert M
• Neafsey, Edward J
• Collins, Michael A

Titel

Essential involvement of the NMDA receptor in ethanol preconditioning-dependent neuroprotection from amyloid-[beta]in vitro

Ist Teil von

• Journal of neurochemistry, 2009-10, Vol.111 (2), p.580

Ort / Verlag

New York: Blackwell Publishing Ltd

Erscheinungsjahr

2009

Quelle

Wiley Online Library

Beschreibungen/Notizen

• 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] (A[beta]) 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 A[beta]25-35 was undiminished by antagonism during the first 3 days of either adenosine A1 or G[alpha]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 A[beta] 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. [PUBLICATION ABSTRACT]