Department of Biopharmaceutical Sciences (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Heilongjiang, China.
Department of Biopharmaceutical Sciences (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Heilongjiang, China.
Eur J Pharmacol. 2018 Dec 5;840:50-59. doi: 10.1016/j.ejphar.2018.10.019. Epub 2018 Oct 15.
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-3β 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-3β activity. Our results showed lithium chloride inhibited glycogen synthase kinase-3β activation, which on one hand, suppressed downstream CRMP-2/NR2B, thus diminishing the excitotoxic index level; and on the other, stabilized β-catenin, thus modulating its downstream apoptosis-related factors such as NF-κB, Bcl-2 and Bax. Meanwhile, glycogen synthase kinase-3β 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.
针对脑出血后的临床认知障碍，很少进行全面的神经心理学评估和有效的干预。氯化锂作为双相情感障碍的经典治疗药物，通过抑制糖原合酶激酶-3β，在包括中风在内的多种中枢神经系统疾病中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以及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，在脑出血研究中很少证明其潜在的分子机制。在这项研究中，雄性 Sprague-Dawley 大鼠接受纹状体内血液输注后，用氯化锂治疗，并进行神经行为测试以评估等效损伤严重程度和神经功能缺陷、Morris 水迷宫测试以评估认知障碍、高效液相色谱分析以确定兴奋性指数、免疫组织化学分析以评估神经元凋亡、以及 Western blot 分析以评估糖原合酶激酶-3β活性。我们的结果表明，氯化锂抑制糖原合酶激酶-3β的激活，一方面抑制下游的 CRMP-2/NR2B，从而降低兴奋性指数水平；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-κB、Bcl-2 和 Bax。同时，神经元死亡减少、神经功能缺陷改善和认知障碍改善与脑出血动物中糖原合酶激酶-3β失活平行。这些发现表明，氯化锂可改善脑出血后谷氨酸介导的兴奋性毒性引起的认知障碍，并且氯化锂可能是脑出血引起的脑损伤的潜在治疗药物。
