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Rapamycin Effectively Impedes Melamine-Induced Impairments of Cognition and Synaptic Plasticity in Wistar Rats

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Abstract

Our previous investigation demonstrated that autophagy significantly reduced melamine-induced cell death in PC12 cells via inhibiting the excessive generation of ROS. In the present study, we further examine if rapamycin, used as an autophagy activator, can play a significant role in protecting neurons and alleviating the impairment of spatial cognition and hippocampal synaptic plasticity in melamine-treated rats. Male Wistar rats were divided into three groups: control, melamine-treated, and melamine-treated + rapamycin. The animal model was established by administering melamine at a dose of 300 mg/kg/day for 4 weeks. Rapamycin was intraperitoneally given at a dose of 1 mg/kg/day for 28 consecutive days. The Morris water maze test showed that spatial learning and reversal learning in melamine-treated rats were considerably damaged, whereas rapamycin significantly impeded the cognitive function impairment. Rapamycin efficiently alleviated the melamine-induced impairments of both long-term potentiation (LTP) and depotentiation, which were damaged in melamine rats. Rapamycin further increased the expression level of autophagy markers, which were significantly enhanced in melamine rats. Moreover, rapamycin noticeably decreased the reactive oxygen species level, while the superoxide dismutase activity was remarkably increased by rapamycin in melamine rats. Malondialdehyde assay exhibited that rapamycin prominently reduced the malondialdehyde (MDA) level of hippocampal neurons in melamine-treated rats. In addition, rapamycin significantly decreased the caspase-3 activity, which was elevated by melamine. Consequently, our results suggest that regulating autophagy may become a new targeted therapy to relieve the damage induced by melamine.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (11232005, 31171053), and 111 Project (B08011).

Authors’ Contributions

JF, HW, and TZ conceived and designed the experiment, JF, HW, JG, MY, RW, and ZY performed the experiments and analyzed the data; and JF and TZ wrote the manuscript.

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    Authors and Affiliations

    1. College of Life Sciences and Key Laboratory of Bioactive Materials Ministry of Education, Nankai University, 300071, Tianjin, People’s Republic of China

      Jingxuan Fu, Hui Wang, Mei Yu & Tao Zhang

    2. School of Medicine, Nankai University, 300071, Tianjin, People’s Republic of China

      Jing Gao & Zhuo Yang

    3. Institute for Cognitive Neurodynamics, East China University of Science and Technology, Shanghai, 200237, China

      Rubin Wang

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    1. Jingxuan Fu
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    Jingxuan Fu and Hui Wang contributed equally to this work.

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    Fu, J., Wang, H., Gao, J. et al. Rapamycin Effectively Impedes Melamine-Induced Impairments of Cognition and Synaptic Plasticity in Wistar Rats. Mol Neurobiol 54, 819–832 (2017). https://doi.org/10.1007/s12035-016-9687-7

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