{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T01:40:46Z","timestamp":1782351646284,"version":"3.54.5"},"reference-count":35,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T00:00:00Z","timestamp":1751932800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T00:00:00Z","timestamp":1751932800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2026,2]]},"abstract":"\n Abstract<\/jats:title>\n \n Temporal lobe epilepsy (TLE) is the most common and severe form of adult focal epilepsy and is frequently associated with hippocampal sclerosis (HS). Accumulating evidence suggests that brain inflammation plays an important pathophysiological role in TLE. A key pro\u2010inflammatory mediator is tumour necrosis factor \u03b1 (TNF\u03b1), which can trigger necroptosis pathways regulated by RIPK1, RIPK3 and MLKL through binding to the TNF receptor 1 (TNFR1). Previously, we detected activation of RIPK1, RIPK3 and MLKL in hippocampal CA1 astrocytes, along with a reduction in astrocyte density, during the early stages of experimentally induced TLE\u2010HS, providing strong evidence for necroptotic astrocytic cell death. Using immunohistochemistry, pharmacology and long\u2010term EEG recording, here we unravel the mechanisms underlying necroptosis induction in astrocytes and its role in epileptogenesis. The results show that pharmacological inhibition of necroptosis using Nec\u20101s, a specific inhibitor of RIPK1, or selective inhibition of soluble TNF\u03b1 by XPro1595, as well as genetic knockout of TNFR1, effectively rescued CA1 astrocyte loss caused by kainate\u2010induced status epilepticus. Furthermore, targeting necroptosis by Nec\u20101s administration attenuated CA1 astrogliosis, degeneration of pyramidal neurons, granular cell dispersion and shrinkage of the CA1 subfield. In contrast, Nec\u20101s did not affect acute and chronic epileptic activity in the TLE\u2010HS model. Our findings demonstrate that TNF\u03b1\u2010induced necroptotic astrocyte death is involved in the pathogenesis of TLE.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n In the early stage of experimental temporal lobe epilepsy with hippocampal sclerosis (TLE\u2010HS), we observed activation of RIPK1, RIPK3 and MLKL in CA1 astrocytes, along with a reduction in astrocyte density, providing evidence for necroptotic cell death.<\/jats:p>\n <\/jats:list-item>\n \n Pharmacological inhibition of necroptosis (Nec\u20101s), blockade of soluble tumour necrosis factor \u03b1 (XPro1595) or genetic knockout of TNFR1 prevented astrocyte loss after status epilepticus.<\/jats:p>\n <\/jats:list-item>\n \n Continuous telemetric EEG recordings showed that Nec\u20101s has no effect on acute or chronic epileptic activity in the TLE\u2010HS model.<\/jats:p>\n <\/jats:list-item>\n \n Immunohistochemical analysis revealed that Nec\u20101s treatment reduced the extent of hippocampal sclerosis in experimental TLE\u2010HS.<\/jats:p>\n <\/jats:list-item>\n \n Our results provide further insights into the molecular mechanisms underlying the development and progression of TLE.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp287565","type":"journal-article","created":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T12:44:14Z","timestamp":1752065054000},"page":"1695-1707","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Targeting necroptosis protects against astrocyte death and hippocampal sclerosis in experimental temporal lobe epilepsy"],"prefix":"10.1113","volume":"604","author":[{"given":"Zhou","family":"Wu","sequence":"first","affiliation":[{"name":"Institute of Cellular Neurosciences I, Medical Faculty University of Bonn Bonn 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