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3BDO Alleviates Seizures and Improves Cognitive Function by Regulating Autophagy in Pentylenetetrazol (PTZ)-Kindled Epileptic Mice Model

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Abstract

3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3 H)-one (3BDO) is a mTOR agonist that inhibits autophagy. The main purpose of this study is to investigate the effects of 3BDO on seizure and cognitive function by autophagy regulation in pentylenetetrazol (PTZ)-kindled epileptic mice model. The PTZ-kindled epileptic mice model was used in study. The behavioral changes and electroencephalogram (EEG) of the mice in each group were observed. The cognitive functions were tested by Morris water maze test. The loss of hippocampal neurons was detected by hematoxylin-eosin (HE) staining and immunofluorescence analysis. Immunohistochemistry, western blot and q-PCR were employed to detect the expression of autophagy-related proteins and mTOR in the hippocampus and cortex. Less seizures, increased hippocampal neurons and reduced astrocytes of hippocampus were observed in the 3BDO-treated epileptic mice than in the PTZ-kindled epileptic mice. Morris water maze test results showed that 3BDO significantly improved the cognitive function of the PTZ-kindled epileptic mice. Western blot analyses and q-PCR revealed that 3BDO inhibited the expression of LC3, Beclin-1, Atg5, Atg7 and p-ULK1/ULK1, but increased that of p-mTOR/mTOR, p-P70S6K/P70S6K in the hippocampus and temporal lobe cortex of epileptic mice. Immunohistochemistry and immunofluorescence also showed 3BDO inhibited the LC3 expression and increased the mTOR expression in the hippocampus of epileptic mice. In addition, the autophagy activator EN6 reversed the decrease in the 3BDO-induced autophagy and aggravated the seizures and cognitive dysfunction in the epileptic mice. 3BDO regulates autophagy by activating the mTOR signaling pathway in PTZ-kindled epileptic mice model, thereby alleviating hippocampus neuronal loss and astrocytes proliferation, reducing seizures and effectively improving cognitive function. Therefore, 3BDO may have potential value in the treatment of epilepsy.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This study was supported by grants from the Natural Science Foundation of Hainan Province (819QN370 and 819QN367), the National Natural Science Foundation of China (81760244, 81960249 and 82260270), Hainan Provincial Key Research and Development Plan of China (ZDYF2019124 and ZDYF2022SHFZ109), Epilepsy Research Science Innovation Group of Hainan Medical University (2022), Hainan Province Clinical Medical Center (2021) and the Excellent Talent Team of Hainan Province (No. QRCBT202121).

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Author notes

  1. Meiwen Guo and Shuang Chen have equally contributed to this work.

Authors and Affiliations

  1. Department of Neurology, the First Affiliated Hospital of Hainan Medical University, Haikou, China

    Meiwen Guo, Shuang Chen, Jitong Lao, Jiantang Liang, Hao Chen, Jingyi Tong, Dandan Jia & Qifu Li

  2. Key Laboratory of Brain Science Research & Transformation in Tropical Environment of Hainan Province, Hainan Medical University, Haikou, China

    Meiwen Guo, Jiantang Liang, Hao Chen, Jingyi Tong, Dandan Jia & Qifu Li

  3. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Shuang Chen

  4. The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China

    Jitong Lao

  5. Hainan Medical University, Haikou, China

    Yonghao Huang

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  1. Meiwen Guo
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Contributions

MG conceived the experimental design, performed the project research, and participated in the experimental process. MG and SC searched the available literature, sorted the references, and wrote this manuscript. JL and HC were involved in the literature search. QL and DJ coordinated and supervised the study, provided research direction, designed the research strategy, and modified the final draft. All authors have carefully read and confirmed the final version of the manuscript.

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Correspondence to Dandan Jia or Qifu Li.

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Guo, M., Chen, S., Lao, J. et al. 3BDO Alleviates Seizures and Improves Cognitive Function by Regulating Autophagy in Pentylenetetrazol (PTZ)-Kindled Epileptic Mice Model. Neurochem Res 47, 3777–3791 (2022). https://doi.org/10.1007/s11064-022-03778-8

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