Prendergast M A, Harris B R, Blanchard J A, Mayer S, Gibson D A, Littleton J M
Department of Psychology, University of Kentucky, Lexington 40506-0044, USA.
Alcohol Clin Exp Res. 2000 Dec;24(12):1855-61.
Long-term ethanol dependence results in neuronal adaptation that likely contributes to ethanol withdrawal-induced central nervous system excitability and, potentially, neurotoxicity. This has been suggested to result, in part, from increased release of or response to endogenous polyamines. Furthermore, it has been reported that neurological difficulties related to ethanol dependence and withdrawal may be more severe in female than in male alcoholics. Thus, we designed this study to examine effects of the polyamine spermidine on neurotoxicity associated with withdrawal from long-term ethanol exposure by using organotypic hippocampal slice cultures derived from male and female rats.
Twenty-four hours of withdrawal after continuous 10 day ethanol exposure (100 mM in culture medium) resulted in cytotoxicity in hippocampal slice explants obtained from both sexes. This was most evident in pyramidal cell layers of the CA1 region, and no sex differences were observed in the severity of damage. Exposure of explants from both sexes to the NMDA blocker MK-801 during ethanol withdrawal significantly reduced this toxicity. In control cultures, exposure to spermidine (100 microM) alone produced significant and similar cytotoxicity in hippocampal explants of male and female rats. Exposure to spermidine (100 microM) during ethanol withdrawal significantly increased cytotoxicity in all regions of explants. In the CA3 region, spermidine-potentiation of ethanol withdrawal damage was significantly greater in explants from female rats compared with those from male rats.
These data demonstrate the presence of significant hippocampal neurotoxicity during withdrawal from long-term ethanol exposure that is mediated, in part, by overactivation of NMDA receptors. Furthermore, these findings suggest that the central nervous system of females may be more susceptible than that of males to polyamine-mediated neuronal damage during withdrawal from long-term ethanol exposure.
长期乙醇依赖会导致神经元适应性改变，这可能导致乙醇戒断引起的中枢神经系统兴奋性增加，并可能导致神经毒性。有人认为，这部分是由于内源性多胺的释放增加或对其反应增强所致。此外，据报道，与乙醇依赖和戒断相关的神经功能障碍在女性酗酒者中可能比男性更为严重。因此，我们设计了这项研究，通过使用来自雄性和雌性大鼠的海马脑片培养物，来研究多胺亚精胺对长期乙醇暴露戒断相关神经毒性的影响。
连续10天在培养基中暴露于乙醇（100 mM）后24小时戒断，导致两性海马脑片外植体出现细胞毒性。这在CA1区的锥体细胞层最为明显，损伤严重程度未观察到性别差异。在乙醇戒断期间，将两性的脑片外植体暴露于NMDA拮抗剂MK-801可显著降低这种毒性。在对照培养物中，单独暴露于亚精胺（100 μM）会在雄性和雌性大鼠的海马脑片外植体中产生显著且相似的细胞毒性。在乙醇戒断期间暴露于亚精胺（100 μM）会显著增加外植体所有区域的细胞毒性。在CA3区，与雄性大鼠的脑片外植体相比，雌性大鼠脑片外植体中乙醇戒断损伤的亚精胺增强作用显著更大。
这些数据表明，长期乙醇暴露戒断期间存在显著的海马神经毒性，部分是由NMDA受体过度激活介导的。此外，这些发现表明，在长期乙醇暴露戒断期间，女性的中枢神经系统可能比男性更容易受到多胺介导的神经元损伤。
