Evaluating the Effectiveness of GTM-1, Rapamycin, and Carbamazepine on Autophagy and Alzheimer Disease.
Evaluating the Effectiveness of GTM-1, Rapamycin, and Carbamazepine on Autophagy and Alzheimer Disease.
复制标题
评估 GTM-1、雷帕霉素和卡马西平对自噬和阿尔茨海默病的有效性
DOI：
10.12659/msm.898679
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发表时间：
2017-02-14
期刊：
影响因子：
--
通讯作者：
Fu P
中科院分区：
文献类型：
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作者：
Zhang L;Wang L;Wang R;Gao Y;Che H;Pan Y;Fu P
本研究旨在比较GTM-1、雷帕霉素（Rapamycin，Rap）和卡马西平（Carbamazepine，CBZ）治疗阿尔茨海默病（Alzheimer disease，AD）的疗效和安全性。本研究还探讨了上述治疗药物对自噬的影响。材料/方法将3只Tg × AD小鼠随机分为4组，每组10只，分别给予二甲亚砜（DMSO）、GTM-1（6 mg/kg）、Rap（1 mg/kg）和CBZ（100 mg/kg）治疗。采用Morris水迷宫测试小鼠的空间记忆和学习能力。进行血常规检查以评估这些药物的毒性。采用ELISA法和免疫组化法检测β淀粉样蛋白（Aβ42）含量。Western blot检测自噬相关蛋白。结果GTM-1、Rap和CBZ均能显著提高3×Tg AD小鼠的空间记忆能力（P均<0.05）。此外，本研究显示CBZ剂量与小鼠毒性相关。上述药物均能显著增加3×Tg AD小鼠海马LC 3-II表达，降低Aβ42水平（P均<0.05）。另一方面，GTM-1和CBZ对mTOR通路上的蛋白质表达都没有显著影响。结论GTM-1可通过依赖mTOR通路激活自噬来缓解AD综合征，可作为Rap的替代药物。
Background This study was proposed to compare the efficacy and safety of GTM-1, Rapamycin (Rap), and Carbamazepine (CBZ) in managing Alzheimer disease (AD). The impact of the above mentioned therapeutic drugs on autophagy was also investigated in our study. Material/Methods Firstly, 3×Tg AD mice were randomly allocated into 4 groups (each group with 10 mice), in which AD mice were separately treated with dimethylsulfoxide (DMSO, vehicle group), GTM-1 (6 mg/kg), Rap (1 mg/kg), and CBZ (100 mg/kg). Then spatial memory and learning ability of mice was tested using the Morris water maze. Routine blood tests were performed to evaluate the toxicity of these drugs. Amyloid-β42 (Aβ42) concentration was detected by ELISA and immunohistochemistry. Proteins related to autophagy were detected by Western blot. Results GTM-1, Rap, and CBZ significantly improved the spatial memory of 3×Tg AD mice compared to that in the vehicle group (all P<0.05). Moreover, this study revealed that CBZ dosage was related to toxicity in mice. All of the above drugs significantly increased the expression of LC3-II and reduced Aβ42 levels in hippocampi of 3×Tg AD mice (all P<0.05). On the other hand, neither GTM-1 nor CBZ had significant influence on the expression of proteins on the mTOR pathway. Conclusions GTM-1 can alleviate the AD syndrome by activating autophagy in a manner that is dependent on the mTOR pathway and it therefore can be considered as an alternative to Rap.