Evaluating the Effectiveness of GTM-1, Rapamycin, and Carbamazepine on Autophagy and Alzheimer Disease
Lijuan Zhang, Lina Wang, Run Wang, Yuan Gao, Haoyue Che, Yonghua Pan, Peng Fu
Department of Pharmacy, Changhai Hospital, Second Military Medical University, Shanghai, China (mainland)
Med Sci Monit 2017; 23:801-808
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 AND 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.
Keywords: Animals, Alzheimer Disease - pathology, Autophagy - drug effects, Carbamazepine - pharmacology, Disease Models, Animal, Hippocampus - pathology, Male, Maze Learning - drug effects, Mice, Neurons - pathology, Neuroprotective Agents - pharmacology, Plaque, Amyloid - pathology, Quinazolines - pharmacology, Random Allocation, Sirolimus - pharmacology, Spatial Memory - drug effects