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- Title
Rationale for an adjunctive therapy with fenofibrate in pharmacoresistant nocturnal frontal lobe epilepsy.
- Authors
Puligheddu, Monica; Melis, Miriam; Pillolla, Giuliano; Milioli, Giulia; Parrino, Liborio; Terzano, Giovanni Mario; Aroni, Sonia; Sagheddu, Claudia; Marrosu, Francesco; Pistis, Marco; Muntoni, Anna Lisa
- Abstract
Objective Nocturnal frontal lobe epilepsy ( NFLE) is an idiopathic partial epilepsy with a family history in about 25% of cases, with autosomal dominant inheritance (autosomal dominant NFLE [ ADNFLE]). 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 α4 or β2 subunits. Fenofibrate, a common lipid-regulating drug, is an agonist at peroxisome proliferator-activated receptor alpha ( PPARα) that is a ligand-activated transcription factor, which negatively modulates the function of β2-containing nAChR. To test clinical efficacy of adjunctive therapy with fenofibrate in pharmacoresistant ADNFLE\ NFLE patients, we first demonstrated the effectiveness of fenofibrate in a mutated mouse model displaying both disease genotype and phenotype. Methods We first tested the efficacy of fenofibrate in transgenic mice carrying the mutation in the α4- nAChR subunit (Chrna4S252F) homologous to that found in humans. Subsequently, an add-on protocol was implemented in a clinical setting and fenofibrate was administered to pharmacoresistant NFLE patients. Results Here, we show that a chronic fenofibrate diet markedly reduced the frequency of large inhibitory postsynaptic currents ( IPSCs) recorded from cortical pyramidal neurons in Chrna4S252F mice, and prevented nicotine-induced increase of IPSC frequency. Moreover, fenofibrate abolished differences between genotypes in the frequency of sleep-related movements observed under basal conditions. Patients affected by NFLE, nonresponders to traditional therapy, by means of adjunctive therapy with fenofibrate displayed a reduction of seizure frequency. Furthermore, digital video-polysomnographic recordings acquired in NFLE subjects after 6 months of adjunctive fenofibrate substantiated the significant effects on control of motor-behavioral seizures. Significance Our preclinical and clinical studies suggest PPARα as a novel disease-modifying target for antiepileptic drugs due to its ability to regulate dysfunctional nAChRs.
- Subjects
FRONTAL lobe epilepsy; POLYCYSTIC kidney disease; NICOTINIC acetylcholine receptors; PEROXISOME proliferator-activated receptors; POSTSYNAPTIC potential
- Publication
Epilepsia (Series 4), 2017, Vol 58, Issue 10, p1762
- ISSN
0013-9580
- Publication type
Article
- DOI
10.1111/epi.13863