磷酸二酯酶4抑制剂咯利普兰逆转慢性酒精中毒及戒断诱导的小鼠抑郁样行为

发布时间：2018-07-07 23:38

本文选题：咯利普兰 + 抑郁　；参考：《中国病理生理杂志》2017年02期

【摘要】：目的:研究磷酸二酯酶4(PDE4)抑制剂咯利普兰对酒精中毒戒断诱导的抑郁样行为的作用及对小鼠海马和前额叶皮质脑区环磷酸腺苷(cAMP)、蛋白激酶A(PKA)、cAMP反应元件结合蛋白(CREB)、磷酸化CREB(p-CREB)和脑源性神经营养因子(BDNF)表达的影响。方法:取60只雄性ICR小鼠,随机分为空白对照组、空白+咯利普兰组、慢性酒精模型组和咯利普兰治疗组(0.1、0.5和1 mg/kg)。给予酒精28 d期间每周进行酒精戒断处理。慢性酒精处理后,进行强迫游泳测试(FST)和悬尾测试(TST),观察小鼠抑郁样行为;ELISA检测小鼠海马和前额叶皮质cAMP含量,Western blot检测小鼠海马和额叶皮质PKA、CREB、p-CREB和BDNF的表达。结果:随着饮酒天数及戒断次数的增加,小鼠表现出明显嗜酒现象,饮酒量增加(P0.01),FST和TST测试中的不动时间增加(P0.01)。小鼠给药咯利普兰(0.5和1 mg/kg)28 d后,FST和TST不动时间与模型组相比明显减少(P0.05),且能改善小鼠的嗜酒现象,小鼠饮酒量与模型组相比明显减少(P0.01);相比于正常组,模型组小鼠海马和前额叶皮质cAMP含量明显降低(P0.01),并且海马和额叶皮质PKA、p-CREB和BDNF也明显低于正常水平(P0.01)。咯利普兰(0.5和1 mg/kg)给药28 d后,海马与前额叶皮质cAMP含量明显增加(P0.01),酒精抑制的海马脑区PKA、p-CREB和BDNF表达被逆转(P0.05),且酒精抑制的前额叶皮质PKA和p-CREB表达被逆转(P0.05)。结论:磷酸二酯酶4抑制剂咯利普兰能明显改善酒精中毒及戒断引起的抑郁样症状,且能减轻嗜酒症状,机制可能涉及第二信使cAMP通路。咯利普兰通过抑制PDE4,增加海马与前额叶皮质cAMP水平,进而激活PKA-CREB-BDNF通路,从而产生抗抑郁作用。
[Abstract]:Aim: to study the effects of phosphodiesterase 4 (PDE4) inhibitor Rolipram on depressive behavior induced by abstinence from alcoholism and its effects on camp, protein kinase A (PKA) and camp response element binding protein (CREB) in hippocampus and prefrontal cortex of mice. Effects of phosphorylated CREB (p-CREB) and brain-derived neurotrophic factor (BDNF). Methods: sixty male ICR mice were randomly divided into three groups: blank control group, chronic alcohol model group and clolipram treatment group (0.1 and 1 mg/kg). Alcohol withdrawal was given weekly for 28 days. After chronic alcohol treatment, forced swimming test (FST) and tail suspension test (TST) were used to detect camp content in hippocampus and prefrontal cortex of mice by Elisa. Results: with the increase of drinking days and abstinence times, mice showed obvious alcoholism, and the immobility time in FST and TST test increased (P0.01). The immobility time of FST and TST in mice was significantly decreased compared with the model group (P0.05) after administration of Rolipram (0. 5 and 1 mg/kg) for 28 days (P0.05), and the alcohol consumption in mice was significantly decreased compared with that in the model group (P0. 01), and compared with that in the normal group (P0. 01). The camp contents in hippocampus and prefrontal cortex were significantly decreased in model group (P0.01), and PKAP-CREB and BDNF in hippocampus and frontal cortex were also significantly lower than those in normal group (P0.01). The camp content in hippocampus and prefrontal cortex was significantly increased (P0.01), the expression of PKAP-CREB and BDNF was reversed (P0.05), and the expression of PKA and p-CREB was reversed in alcohol-inhibited prefrontal cortex (P0.05) after administration of Rolipram (0. 5 and 1 mg/kg) for 28 days. Conclusion: ralopram, an inhibitor of phosphodiesterase 4, can significantly improve depression-like symptoms caused by alcoholism and abstinence, and alleviate alcoholism. The mechanism may be involved in the second messenger camp pathway. By inhibiting PDE4, Rolipram increased camp level in hippocampus and prefrontal cortex, and then activated PKA-CREB-BDNF pathway, which resulted in antidepressant effect.
【作者单位】：浙江大学明州医院;浙江医药高等专科学校;温州医科大学;
【基金】：国家自然科学基金资助项目(No.81360195) 宁波市自然科学基金资助项目(No.2016A610239) 浙江医药高等专科学校科研项目(No.ZPCSR2016003)
【分类号】：R749.62

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