{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T15:22:39Z","timestamp":1787844159061,"version":"build-2784847793"},"reference-count":40,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2017,8,2]],"date-time":"2017-08-02T00:00:00Z","timestamp":1501632000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Italian Ministry of University","award":["PRIN 2009: 2009HST9YF; F.M., A.L.M., L.P."],"award-info":[{"award-number":["PRIN 2009: 2009HST9YF; F.M., A.L.M., L.P."]}]},{"DOI":"10.13039\/100007359","name":"Bank of Sardinia Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007359","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Italian Foundation for Research on Epilepsy (FIRE)-Italian Association against Epilepsy (AICE) (M.Pi.)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2017,10]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Nocturnal frontal lobe epilepsy (<jats:styled-content style=\"fixed-case\">NFLE<\/jats:styled-content>) is an idiopathic partial epilepsy with a family history in about 25% of cases, with autosomal dominant inheritance (autosomal dominant NFLE [<jats:styled-content style=\"fixed-case\">ADNFLE<\/jats:styled-content>]). Traditional antiepileptic drugs are effective in about 55% of patients, whereas the rest remains refractory. One of the key pathogenetic mechanisms is a gain of function of neuronal nicotinic acetylcholine receptors (nAChRs) containing the mutated \u03b14 or \u03b22 subunits. Fenofibrate, a common lipid\u2010regulating drug, is an agonist at peroxisome proliferator\u2010activated receptor alpha (<jats:styled-content style=\"fixed-case\">PPAR<\/jats:styled-content>\u03b1) that is a ligand\u2010activated transcription factor, which negatively modulates the function of \u03b22\u2010containing <jats:styled-content style=\"fixed-case\">nAC<\/jats:styled-content>hR. To test clinical efficacy of adjunctive therapy with fenofibrate in pharmacoresistant <jats:styled-content style=\"fixed-case\">ADNFLE<\/jats:styled-content>\\<jats:styled-content style=\"fixed-case\">NFLE<\/jats:styled-content> patients, we first demonstrated the effectiveness of fenofibrate in a mutated mouse model displaying both disease genotype and phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We first tested the efficacy of fenofibrate in transgenic mice carrying the mutation in the \u03b14\u2010<jats:styled-content style=\"fixed-case\">nAChR<\/jats:styled-content> subunit (Chrna4S252F) homologous to that found in humans. Subsequently, an add\u2010on protocol was implemented in a clinical setting and fenofibrate was administered to pharmacoresistant <jats:styled-content style=\"fixed-case\">NFLE<\/jats:styled-content> patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Here, we show that a chronic fenofibrate diet markedly reduced the frequency of large inhibitory postsynaptic currents (<jats:styled-content style=\"fixed-case\">IPSC<\/jats:styled-content>s) recorded from cortical pyramidal neurons in Chrna4S252F mice, and prevented nicotine\u2010induced increase of <jats:styled-content style=\"fixed-case\">IPSC<\/jats:styled-content> frequency. Moreover, fenofibrate abolished differences between genotypes in the frequency of sleep\u2010related movements observed under basal conditions. Patients affected by <jats:styled-content style=\"fixed-case\">NFLE<\/jats:styled-content>, nonresponders to traditional therapy, by means of adjunctive therapy with fenofibrate displayed a reduction of seizure frequency. Furthermore, digital video\u2010polysomnographic recordings acquired in <jats:styled-content style=\"fixed-case\">NFLE<\/jats:styled-content> subjects after 6\u00a0months of adjunctive fenofibrate substantiated the significant effects on control of motor\u2013behavioral seizures.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Our preclinical and clinical studies suggest <jats:styled-content style=\"fixed-case\">PPAR<\/jats:styled-content>\u03b1 as a novel disease\u2010modifying target for antiepileptic drugs due to its ability to regulate dysfunctional <jats:styled-content style=\"fixed-case\">nAChR<\/jats:styled-content>s.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.13863","type":"journal-article","created":{"date-parts":[[2017,8,2]],"date-time":"2017-08-02T11:22:42Z","timestamp":1501672962000},"page":"1762-1770","source":"Crossref","is-referenced-by-count":41,"title":["Rationale for an adjunctive therapy with fenofibrate in pharmacoresistant nocturnal 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