Minozac Treatment Prevents Increased Seizure Susceptibility in a Mouse "Two-Hit" Model of Closed Skull Traumatic Brain Injury and Electroconvulsive Shock-Induced Seizures Journal of Neurotrauma. July 2010, 27(7): 1283-1295. The mechanisms linking traumatic brain injury (TBI) to post-traumatic epilepsy (PTE) are not known and no therapy for prevention of PTE is available. We used a mouse closed-skull midline impact model to test the hypotheses that TBI increases susceptibility to seizures in a "two-hit" injury model, and that suppression of cytokine upregulation after the first hit will attenuate the increased susceptibility to the second neurological insult. Adult male CD-1 mice underwent midline closed skull pneumatic impact. At 3 and 6 h after impact or sham procedure, the mice were injected IP with either Minozac (Mzc), a suppressor of proinflammatory cytokine upregulation, or vehicle (saline). On day 7 after sham operation or TBI, seizures were induced using electroconvulsive shock (ECS), and susceptibility to seizures was measured by the current required for seizure induction. Activation of glia, neuronal injury, and metallothionein-immunoreactive cells were quantified in the hippocampus by immunohistochemical methods. Neurobehavioral function over 14-day recovery was quantified using the Barnes maze. Following TBI there was a significant increase in susceptibility to seizures induced by ECS, and this susceptibility was prevented by suppression of cytokine upregulation with Mzc. Astrocyte activation, metallothionein expression, and neurobehavioral impairment were also increased in the two-hit group subjected to combined TBI and ECS. These enhanced responses in the two-hit group were also prevented by suppression of proinflammatory cytokine upregulation with Mzc. These data implicate glial activation in the mechanisms of epileptogenesis after TBI, and identify a potential therapeutic approach to attenuate the delayed neurological sequelae of TBI.
广州生物院利用iPS建立遗传特异毒理学模型 时间:2015年02月12日 广州生物院新年科研又得新斩获 科技日报讯 （刘笑楠黄博纯）新年刚过，中科院广州生物医药与健康院就喜事不断。1月20日，国际著名学术期刊《肝脏》（Hepatology）在线发表了中科院广州生物医药与健康研究院刘兴国研究员领导的研究团队的最新研究成果，该成果利用病人来源的诱导多能干细胞（iPSCs）及分化获得的肝样细胞为模型，阐明了丙戊酸（Valproic Acid, VPA）诱发Alpers-Huttenlocher 综合征（AHS）肝毒性的机理，并基于此发展出相应的候选药物筛选策略。这是首次利用iPS技术建立遗传特异的毒理学模型。据了解，线粒体相关肝病分为遗传原发性和后天继发性两类，是急性肝功能衰竭的最重要原因，至今没有有效的治疗方法。其中，Alpers-Huttenlocher 综合征是线粒体特异性DNA聚合酶POLG突变导致的一种严重的遗传性神经代谢疾病，临床常有难治性癫痫等神经疾病症状。丙戊酸是一种广谱抗癫痫的药物，它对治疗癫痫具有良好的效果，但是使用丙戊酸对Alpers-Huttenlocher综合征病人进行治疗时经常会导致病人急性肝衰竭，但造成这一临床现象的机制一直未阐明。刘兴国团队将iPS技术应用到Alpers-Huttenlocher 综合征中，首次实现了该病成纤维细胞的重编程，获得了诱导多能干细胞，并进一步分化为肝样细胞。通过分析肝样细胞的表型和线粒体形态以及功能的变化，发现病人特异来源的肝细胞线粒体存在形态、能量合成、线粒体DNA含量的缺陷，并且与正常人来源的肝样细胞相比，在用丙戊酸处理以后，更易发生凋亡。进一步研究发现，这种凋亡的敏感性是与线粒体通透性孔道mPTP相关，并且使用mPTP特异性抑制剂可以减少丙戊酸导致的病人细胞的凋亡。该研究不仅在细胞水平阐明了丙戊酸诱发Alpers综合征肝毒性的机理，也为这一临床难题提供了靶点和候选药物筛选策略。更为重要的是，该研究首次将iPS技术应用到遗传特异的临床药物毒性中，是这类临床问题的成功范例。在该院胡文辉课题组的抗老年痴呆症候选药物GIBH130的研究方面也取得了重要进展。该研究先后在江苏正大天晴药业股份有限公司、广州生物院药物研发体系的支持与资助下，与华南新药创制中心合作完成了规范化的临床前研究，已正式向国家食品药品监督管理局申请临床试验。胡文辉课题组在第一代神经炎症抑制剂Minozac的基础上，通过小分子化合物库的构建，综合运用表型筛选、疾病动物模型的药效评价和药代毒理评价，确立了GIBH130为候选药物。GIBH130能够在体外选择性抑制神经免疫细胞释放促炎症细胞因子IL-1β，并在疾病模型动物脑部抑制小胶质细胞激活和促炎症细胞因子的表达，进而阻断AD脑部的炎症恶性循环，保护神经元。GIBH130在注射动物模型和轻/重度老年痴呆转基因小鼠模型中，药物能够有效的透过血脑屏障，到达脑部发挥作用，不同剂量不同程度地改善模型动物的记忆和认知能力，从而有效缓解痴呆症状。
广州生医健康研究院
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