{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T10:19:31Z","timestamp":1787998771406,"version":"build-2784847793"},"reference-count":47,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["DFG PO 681\/12\u20101"],"award-info":[{"award-number":["DFG PO 681\/12\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000921","name":"European Cooperation in Science and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000921","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Sigma\u20101 is a chaperone protein that serves as a key homeostatic regulator, implicated in neuronal excitability and seizure control. Positive allosteric modulators offer a use\u2010dependent means to enhance Sigma\u20101 activity, potentially with favorable tolerability compared to direct agonists. This study examined the role of sigma\u20101 in ictogenesis, seizure spread, and termination, and evaluated whether sigma\u20101 targeting could modify progression in the amygdala kindling model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using the mouse amygdala kindling paradigm, we assessed the effects of subchronic administration of the sigma\u20101 positive allosteric modulator E1R and of the antiseizure medication fenfluramine on seizure thresholds, severity, duration, and progression of kindling. Tolerability, behavioral outcomes, and potential disease\u2010modifying effects were evaluated. Additional experiments investigated the influence of sigma\u20101 antagonism (NE\u2010100) and genetic sigma\u20101 deficiency on E1R efficacy and seizure development.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>E1R delayed kindling acquisition, increased seizure thresholds in both na\u00efve and kindled animals, and reduced seizure duration without evidence of tolerance or significant adverse effects. Subchronic E1R exposure slowed or prevented progression to generalized seizures, although effects did not persist after drug withdrawal. Sigma\u20101 deficiency prolonged seizure duration, supporting a role in the termination of endogenous seizures. High\u2010dose NE\u2010100 partially antagonized E1R effects, whereas genetic deficiency did not, possibly due to compensatory mechanisms. Fenfluramine did not affect kindling progression in this model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>Positive allosteric modulation of sigma\u20101 attenuates ictogenesis and seizure severity and appears to contribute to endogenous seizure\u2010termination mechanisms. Although E1R influences seizure generation in response to repeated stimulation, it does not produce sustained disease\u2010modifying effects after discontinuation. These findings support a functional role of sigma\u20101 positive allosteric modulators as promising candidates for seizure management in the model used. The absence of persistent effects after withdrawal argues against disease modification under the current conditions and warrants further investigation in chronic epilepsy models evaluating long\u2010term therapeutic, disease\u2010modifying, or preventive potential.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/epi.70270","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T16:41:07Z","timestamp":1777480867000},"page":"4292-4304","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Effects of fenfluramine and sigma\u20101\u2010dependent pharmacological and genetic modulation in a mouse kindling model"],"prefix":"10.1002","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6864-5081","authenticated-orcid":false,"given":"Eva\u2010Lotta","family":"von R\u00fcden","sequence":"first","affiliation":[{"name":"Institute of Pharmacology, Toxicology, and Pharmacy Ludwig\u2010Maximilians\u2010Universit\u00e4t  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2705-4565","authenticated-orcid":false,"given":"Verena","family":"Buchecker","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, Toxicology, and Pharmacy Ludwig\u2010Maximilians\u2010Universit\u00e4t  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4107-3678","authenticated-orcid":false,"given":"Amelie","family":"Wagner","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, Toxicology, and Pharmacy Ludwig\u2010Maximilians\u2010Universit\u00e4t  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8605-1747","authenticated-orcid":false,"given":"Victoria M.","family":"Stocker","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, Toxicology, and 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