Mitchell Robert M, Neafsey Edward J, Collins Michael A
Department of Pharmacology, Division of Biochemistry, Loyola University Stritch School of Medicine, Maywood, Illinois 60153, USA.
J Neurochem. 2009 Oct;111(2):580-8. doi: 10.1111/j.1471-4159.2009.06351.x. Epub 2009 Aug 19.
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.
在多项流行病学研究中，适度饮酒与认知能力下降风险降低或患阿尔茨海默病性痴呆的风险降低有关。具有潜在相关性的是，用适度乙醇浓度预处理的脑培养物对神经毒性阿尔茨海默病β淀粉样蛋白（Aβ）肽具有抗性。我们使用大鼠小脑混合培养物研究了某些膜受体是否是适度乙醇预处理（MEP）中的早期“传感器”。在为期6天的MEP方案（30 mM乙醇）中，在腺苷A(1)或Gα(i/o)蛋白偶联受体的前3天进行拮抗作用，对Aβ25 - 35的神经保护作用并未减弱。然而，用美金刚或DL - 2 - 氨基 - 5 - 膦酰基戊酸（AP - 5）（NMDA受体（NMDAR）拮抗剂）进行类似的联合处理则消除了神经保护作用，表明这种离子型谷氨酸受体在早期起关键作用。同样在这些培养物中，使用亚兴奋性毒性NMDA预处理直接激活NMDAR可预防Aβ神经毒性。到MEP的第2天，我们观察到NMDAR亚基NR1、NR2B和NR2C的水平升高，并持续到第6天。有趣的是，美金刚共同暴露可阻止必需的NR1亚基升高。此外，2天的MEP显著增加了突触NMDAR定位的两个指标，即NR2B磷酸化酪氨酸1472和突触后致密蛋白95支架蛋白。结果表明，乙醇预处理依赖性神经保护作用与NR亚基的早期增加有关，同时伴随着NMDAR突触定位和活性的增强。
