{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T18:34:33Z","timestamp":1772994873442,"version":"3.50.1"},"reference-count":62,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T00:00:00Z","timestamp":1751500800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T00:00:00Z","timestamp":1751500800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["GGP14198"],"award-info":[{"award-number":["GGP14198"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009647","name":"Ministry of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009647","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Developmental and epileptic encephalopathy type 1 (DEE1) is a rare drug\u2010resistant pediatric epilepsy caused by trinucleotide repeat expansions in the X\u2010linked\n                      <jats:italic>ARX<\/jats:italic>\n                      gene, leading to elongation of the first polyalanine tract. It presents with early onset tonic seizures or spasms, developmental and cognition delay, and high risk of premature mortality. We evaluated the therapeutic potential of highly purified cannabidiol (CBD) in\n                      <jats:italic>Arx<\/jats:italic>\n                      <jats:sup>(GCG)7\/Y<\/jats:sup>\n                      mice, a genetic DEE1 model that replicates key features of the human condition.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Arx<\/jats:italic>\n                      <jats:sup>(GCG)7\/Y<\/jats:sup>\n                      mice received daily intraperitoneal CBD (100\u2009mg\/kg) for 7\u2009days. The epileptic phenotype was evaluated via video monitoring and a scoring matrix. In\n                      <jats:italic>Arx<\/jats:italic>\n                      \u2010DEE1 male cortex, real\u2010time polymerase chain reaction and Western blotting assessed CBD effects on proinflammatory and neuronal markers. Microglial morphology was analyzed by Iba1 immunostaining and Sholl analysis. In\u00a0vitro patch\u2010clamp recordings tested CBD activity on\n                      <jats:italic>Arx<\/jats:italic>\n                      <jats:sup>(GCG)7\/Y<\/jats:sup>\n                      cortical neurons.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CBD reduced the severity and frequency of spontaneous recurrent seizures and significantly extended the lifespan of epileptic mice. In mutant symptomatic mice, CBD activated peroxisome\n                      <jats:italic>Pparg<\/jats:italic>\n                      expression and the concurrent desensitization\/inactivation of TRPV1 channels. Additionally, CBD counteracted the dysregulated expression of the proinflammatory genes\n                      <jats:italic>Ptgs2, Mmp9, Il12, Cd68, Ccl2,<\/jats:italic>\n                      and\n                      <jats:italic>Irf3,<\/jats:italic>\n                      while also restoring normal microglial morphology. Further molecular analysis demonstrated that CBD effectively offsets normal alternative splicing for the presynaptic receptor genes\n                      <jats:italic>Nrnx1<\/jats:italic>\n                      and\n                      <jats:italic>Nrnx3<\/jats:italic>\n                      . Consistent with this, CBD rescued proper\n                      <jats:italic>Nrnx1<\/jats:italic>\n                      splicing in mutant cortical neurons after K\n                      <jats:sup>+<\/jats:sup>\n                      \u2010induced depolarization. Finally, we found that CBD reduced neuronal excitability by inducing hyperpolarization, raising the action potential threshold, and reducing the frequency and mean charge of inhibitory postsynaptic currents and the mean charge of excitatory postsynaptic currents.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>These findings represent the first preclinical evidence of CBD efficacy in a murine model of genetic DEE1, identifying CBD\u2010sensitive downstream targets and paving the way to further exploration of CBD effects in this disease for future clinical consideration.<\/jats:p>\n                  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