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  3. A novel anti-epileptogenesis strategy of temporal lobe epilepsy based on nitric oxide donor

A novel anti-epileptogenesis strategy of temporal lobe epilepsy based on nitric oxide donor

  • EMBO Mol Med. 2025 Jan;17(1):85-111. doi: 10.1038/s44321-024-00168-1.
Xian-Hui Zhu # 1 2,  Ya-Ping Zhou # 1 3,  Qiao Zhang # 1 4,  Ming-Yi Zhu # 1 5,  Xiao-Wei Song 2 6,  Jun Li 7,  Jiang Chen 8,  Yun Shi 8,  Kang-Jian Sun 9,  Yong-Jie Zhang 10,  Jing Zhang 1 11,  Tian Xia 12,  Bao-Sheng Huang 13,  Fan Meng 14 15,  Qi-Gang Zhou 16 17 18
Affiliations

Affiliations

  • 1 Department of Clinical Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.
  • 2 Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211166, China.
  • 3 Changzhou Hygiene Vocational Technology College, Changzhou, 213002, China.
  • 4 Suqian First Hospital, Nanjing Medical University, Suqian, 223800, China.
  • 5 Centre of Medicinal Preparations, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, 210042, China.
  • 6 Department of Neurosurgery, The Second Affiliated Hospital of Nantong University, Nantong First People's Hospital, Nantong, 226001, China.
  • 7 Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China.
  • 8 Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing University, Nanjing, 210032, China.
  • 9 Department of Neurosurgery, Nanjing Jinling University, Nanjing, 210002, China.
  • 10 Department of Human Anatomy, Human Brain Tissue Resource Center of Nanjing Medical University, National Health and Disease Human Brain Tissue Resource Center-sub-center of Nanjing Medical University, Nanjing, 211166, China.
  • 11 The Key Center of Gene Technology Drugs of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, China.
  • 12 Department of Clinical Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China. 137012558@qq.com.
  • 13 Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211166, China. bs.huang@njmu.edu.cn.
  • 14 Department of Clinical Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China. mengfan199005@njmu.edu.cn.
  • 15 The Key Center of Gene Technology Drugs of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, China. mengfan199005@njmu.edu.cn.
  • 16 Department of Clinical Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China. qigangzhou@njmu.edu.cn.
  • 17 The Key Center of Gene Technology Drugs of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, China. qigangzhou@njmu.edu.cn.
  • 18 Department of Pharmacy of First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China. qigangzhou@njmu.edu.cn.
  • # Contributed equally.
PMID: 39653809 DOI: 10.1038/s44321-024-00168-1
Abstract

The molecular mechanism underlying the role of hippocampal hilar interneuron degeneration in temporal lobe epilepsy (TLE) remains unclear. Especially, very few studies have focused on the role of neuronal nitric oxide synthase (nNOS, encoded by Nos1) containing hilar interneurons in TLE. In the present study, Nos1 conditional knockout mice were constructed, and we found that selective deletion of Nos1 in hilar interneurons rather than dentate granular cells (DGCs) triggered epileptogenesis. The level of nNOS was downregulated in patients and mice with TLE. Nos1 deletion led to excessive epilepsy-like excitatory input circuit formation and hyperexcitation of DGCs. Replenishment of hilar nNOS protein blocked epileptogenic development and memory impairment in pilocarpine-induced TLE mice. Moreover, chronic treatment with DETA/NONOate, a slowly released exogenous nitric oxide (NO) donor, prevented aberrant neural circuits of DGCs and the consequent epileptogenesis without acute antiseizure effects. Therefore, we concluded that NO donor therapy may be a novel anti-epileptogenesis strategy, different from existing antiseizure medications (ASMs), for curing TLE.

Keywords

Dentate Granule Cells; Epileptogenesis; Hilar Interneurons; Neuronal Nitric Oxide Synthase; Pilocarpine.

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