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Epigenetic Suppression of GADs Expression is Involved in Temporal Lobe Epilepsy and Pilocarpine-Induced Mice Epilepsy

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Abstract

Recent studies have shown that histone acetylation is involved with the regulation of enzyme glutamate decarboxylases (GADs), including GAD67 and GAD65. Here, we investigated the histone acetylation modifications of GADs in the pathogenesis of epilepsy and explored the therapeutic effect of a novel second-generation histone deacetylase inhibitor (HDACi) JNJ-26481585 in epilepsy animals. We revealed the suppression of GADs protein and mRNA level, and histone hypoacetylation in patients with temporal lobe epilepsy and pilocarpine-induced epilepsy mice model. Double-immunofluorescence also indicated that the hypoacetyl-H3 was located in hippocampal GAD67/GAD65 positive neurons in epilepsy mice. JNJ-26481585 significantly reversed the decrease of the GAD67/GAD65 both protein and mRNA levels, and the histone hypoacetylation of GABAergic neurons in epilepsy mice. Meanwhile, single-cell real-time PCR performed in GFP-GAD67/GAD65 transgenic mice demonstrated that JNJ-26481585 induced increase of GAD67/GAD65 mRNA level in GABAergic neurons. Furthermore, JNJ-26481585 significantly alleviated the epileptic seizures in mice model. Together, our findings demonstrate inhibition of GADs gene via histone acetylation plays an important role in the pathgenesis of epilepsy, and suggest JNJ-26481585 as a promising therapeutic strategy for epilepsy.

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Acknowledgments

This study was supported by Grants of the National Natural Science Foundation of China (Nos. 81201005, 81501115).

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    Authors and Affiliations

    1. Department of Neurosurgery, The 463rd Hospital of PLA, Shenyang, Liaoning, 110042, People’s Republic of China

      Jin-Gang Wang & Jun Zheng

    2. Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi’an, 710032, People’s Republic of China

      Qing Cai, Chao Wang & Ju-Lei Wang

    3. Department of Neurosurgery, General Hospital of Shenyang Military Command Area, Shenyang, Liaoning, 110016, People’s Republic of China

      Yu-Shu Dong, Jin-Jiang Li, Jing-Chen Li & Guang-Zhi Hao

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    1. Jin-Gang Wang
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    Correspondence to Chao Wang or Ju-Lei Wang.

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    Jin-Gang Wang, Qing Cai and Jun Zheng have contributed equally to this work.

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    Wang, JG., Cai, Q., Zheng, J. et al. Epigenetic Suppression of GADs Expression is Involved in Temporal Lobe Epilepsy and Pilocarpine-Induced Mice Epilepsy. Neurochem Res 41, 1751–1760 (2016). https://doi.org/10.1007/s11064-016-1891-3

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