A novel anti-epileptogenesis strategy of temporal lobe epilepsy based on nitric oxide donor
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...
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Springer Nature
2024-12-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.1038/s44321-024-00168-1 |
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| author | Xian-Hui Zhu Ya-Ping Zhou Qiao Zhang Ming-Yi Zhu Xiao-Wei Song Jun Li Jiang Chen Yun Shi Kang-Jian Sun Yong-Jie Zhang Jing Zhang Tian Xia Bao-Sheng Huang Fan Meng Qi-Gang Zhou |
| author_facet | Xian-Hui Zhu Ya-Ping Zhou Qiao Zhang Ming-Yi Zhu Xiao-Wei Song Jun Li Jiang Chen Yun Shi Kang-Jian Sun Yong-Jie Zhang Jing Zhang Tian Xia Bao-Sheng Huang Fan Meng Qi-Gang Zhou |
| author_sort | Xian-Hui Zhu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-473af385a426441981cbbf294a61d04f |
| institution | Kabale University |
| issn | 1757-4684 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-473af385a426441981cbbf294a61d04f2025-01-19T12:34:40ZengSpringer NatureEMBO Molecular Medicine1757-46842024-12-011718511110.1038/s44321-024-00168-1A novel anti-epileptogenesis strategy of temporal lobe epilepsy based on nitric oxide donorXian-Hui Zhu0Ya-Ping Zhou1Qiao Zhang2Ming-Yi Zhu3Xiao-Wei Song4Jun Li5Jiang Chen6Yun Shi7Kang-Jian Sun8Yong-Jie Zhang9Jing Zhang10Tian Xia11Bao-Sheng Huang12Fan Meng13Qi-Gang Zhou14Department of Clinical Pharmacology, School of Pharmacy, Nanjing Medical UniversityDepartment of Clinical Pharmacology, School of Pharmacy, Nanjing Medical UniversityDepartment of Clinical Pharmacology, School of Pharmacy, Nanjing Medical UniversityDepartment of Clinical Pharmacology, School of Pharmacy, Nanjing Medical UniversitySir Run Run Hospital, Nanjing Medical UniversityDepartment of Pharmacy, Nanjing First Hospital, Nanjing Medical UniversityDepartment of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing UniversityDepartment of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing UniversityDepartment of Neurosurgery, Nanjing Jinling UniversityDepartment 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 UniversityDepartment of Clinical Pharmacology, School of Pharmacy, Nanjing Medical UniversityDepartment of Clinical Pharmacology, School of Pharmacy, Nanjing Medical UniversitySir Run Run Hospital, Nanjing Medical UniversityDepartment of Clinical Pharmacology, School of Pharmacy, Nanjing Medical UniversityDepartment of Clinical Pharmacology, School of Pharmacy, Nanjing Medical UniversityAbstract 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.https://doi.org/10.1038/s44321-024-00168-1EpileptogenesisNeuronal Nitric Oxide SynthaseHilar InterneuronsDentate Granule CellsPilocarpine |
| spellingShingle | Xian-Hui Zhu Ya-Ping Zhou Qiao Zhang Ming-Yi Zhu Xiao-Wei Song Jun Li Jiang Chen Yun Shi Kang-Jian Sun Yong-Jie Zhang Jing Zhang Tian Xia Bao-Sheng Huang Fan Meng Qi-Gang Zhou A novel anti-epileptogenesis strategy of temporal lobe epilepsy based on nitric oxide donor EMBO Molecular Medicine Epileptogenesis Neuronal Nitric Oxide Synthase Hilar Interneurons Dentate Granule Cells Pilocarpine |
| title | A novel anti-epileptogenesis strategy of temporal lobe epilepsy based on nitric oxide donor |
| title_full | A novel anti-epileptogenesis strategy of temporal lobe epilepsy based on nitric oxide donor |
| title_fullStr | A novel anti-epileptogenesis strategy of temporal lobe epilepsy based on nitric oxide donor |
| title_full_unstemmed | A novel anti-epileptogenesis strategy of temporal lobe epilepsy based on nitric oxide donor |
| title_short | A novel anti-epileptogenesis strategy of temporal lobe epilepsy based on nitric oxide donor |
| title_sort | novel anti epileptogenesis strategy of temporal lobe epilepsy based on nitric oxide donor |
| topic | Epileptogenesis Neuronal Nitric Oxide Synthase Hilar Interneurons Dentate Granule Cells Pilocarpine |
| url | https://doi.org/10.1038/s44321-024-00168-1 |
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