The neuroprotective effect of lithium chloride on cognitive impairment through glycogen synthase kinase-3β inhibition in intracerebral hemorrhage rats
The neuroprotective effect of lithium chloride on cognitive impairment through glycogen synthase kinase-3β inhibition in intracerebral hemorrhage rats
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DOI：
10.1016/j.ejphar.2018.10.019
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发表时间：
2018-12-05
影响因子：
5
通讯作者：
Tang, Xiaobo
中科院分区：
文献类型：
--
作者：
Liu, Zhen;Li, Rui;Tang, Xiaobo
对脑出血后认知功能障碍的临床表现，目前尚缺乏全面的神经心理学评估和有效的干预措施。氯化锂是双相情感障碍的经典治疗药物，在包括中风在内的多种中枢神经系统疾病中，通过抑制糖原合成酶激酶-3 β显示出神经保护作用。由于含有谷氨酸的神经元在学习和记忆等心理功能中起着至关重要的作用，因此谷氨酸介导的兴奋性毒性和随后的海马神经元死亡和认知障碍可能共同决定脑出血的临床过程。然而，在脑出血的分子机制方面的研究还很少。本研究采用氯化锂对雄性SD大鼠进行纹状体内输血治疗，并进行神经行为学测试以确定损伤程度和神经功能缺损，Morris水迷宫测试以确定认知障碍，高效液相色谱分析以确定兴奋毒性指数，免疫组织化学分析以确定神经元凋亡，和糖原合成酶激酶-3 β活性的蛋白质印迹分析。我们的研究结果表明，氯化锂抑制糖原合成酶激酶-3 β的激活，一方面抑制下游CRMP-2/NR 2 B，从而降低兴奋毒性指数水平;另一方面，稳定β-连环蛋白，从而调节其下游凋亡相关因子，如NF-κ B，Bcl-2和Bax。同时，糖原合成酶激酶-3 β的失活可通过减少脑出血动物的神经元死亡、改善神经功能缺损和改善认知缺陷而得以消除。这些研究结果表明，氯化锂改善脑出血后谷氨酸介导的兴奋性毒性诱导的认知功能障碍，氯化锂可能是一种潜在的治疗剂脑出血引起的脑损伤。
To the clinical cognitive impairment following intracerebral hemorrhage, comprehensive neuropsychological assessments and efficacious interventions have rarely been conducted. Lithium chloride, a classical treatment for bipolar disorder, has shown neuroprotective effects through glycogen synthase kinase-3 beta inhibition in a variety of central nervous system diseases, including stroke. Since neurons that contain glutamate play crucial roles in psychological functions, such as learning and memory, the glutamate-mediated excitotoxicity and consequent neuronal death and cognitive impairment in hippocampus may co-determine the clinical course of intracerebral hemorrhage. However, the potential molecular mechanisms have rarely been demonstrated in intracerebral hemorrhage researches. In this study, Male Sprague-Dawley rats, subjected to intrastriatal blood infusion, were treated with lithium chloride and underwent neurobehavioral test for equivalent injury severity and neurological functional deficits, Morris water maze test for cognitive impairment, high performance liquid chromatography analysis for excitotoxic index determination, immunohistochemistry analysis for neuronal apoptosis, and Western blot analysis for glycogen synthase kinase-3 beta activity. Our results showed lithium chloride inhibited glycogen synthase kinase-3 beta activation, which on one hand, suppressed downstream CRMP-2/NR2B, thus diminishing the excitotoxic index level; and on the other, stabilized beta-catenin, thus modulating its downstream apoptosis-related factors such as NF-kappa B, Bcl-2 and Bax. Meanwhile, glycogen synthase kinase-3 beta inactivation was paralleled by decreased neuronal death, improved neurological functional deficits and ameliorated cognitive deficits in intracerebral hemorrhage animals. These findings indicate that lithium chloride improves glutamate-mediated excitotoxicity-induced cognitive deficits after intracerebral hemorrhage and that lithium chloride might be a potential therapeutic agent for brain damages caused by intracerebral hemorrhage.