Abstracts

Rationale: Nocturnal frontal lobe epilepsy (NFLE) is an idiopathic partial epilepsy with a family history in about 25% of cases with autosomal dominant inheritance (ADNFLE). 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 (PPAR-α) that is a ligand-activated transcription factor, which negatively modulates β2*nAChR function. In this study, we intend to test the clinical efficacy of adjunctive therapy with fenofibrate in pharmaco-resistant ADNFLENFLE patients. To this aim, we first demonstrated the effectiveness of fenofibrate in a mutated (Chrna4S252F) mouse model displaying the disease genotype and phenotype in both in vitro and in vivo experiments. An add-on clinical protocol was subsequently implemented in a clinical setting.Methods: Animal studies: for all the experiments we used male wild type and heterozygous mice model of NFLE (Chrna4S252F). We performed in vitro electrophysiology and electroencephalographic recordings coupled with behavioural observations. Mice were chronically administered with fenofibrate in the diet (0.2%) for 14 days. Control mice received normal food pellets. Clinical study (EC N.257): twelve subjects affected by drug-resistant ADNFLE and NFLE (enrolled from outpatients attending the Epilepsy Diagnostic and Sleep Disorders Centres of Cagliari and Parma) underwent adjunctive therapy with fenofibrate, orally administered off label at 600 mg per day, 3 times a day for 6 months. After 6 months of add-on therapy (T1-FEN), quality of life was assessed and daily seizures diaries were collected. Concomitant videopolysomnography (VPSG) was performed a T0 and T1-FEN time points in order to evaluate major and minor motor events.Results: Chronic fenofibrate markedly reduced the frequency of large inhibitory post synaptic currents (IPSCs) recorded from cortical pyramidal neurons in Chrna4S252F mice and prevented nicotine-induced increase of IPSC frequency. Moreover, fenofibrate diet eliminated the differences observed between genotypes in the frequency of sleep-related movements under basal conditions. Accordingly, fenofibrate-treated NFLE patients displayed a significant reduction in seizure frequency (p =0.001***). Furthermore, digital VPSG recordings acquired after the 6-month therapy showed significant effects on motor-behavioural seizures control (p=0.0038**).Conclusions: The major finding of the present study is the clinical efficacy of the add-on therapy with fenofibrate in NFLE patients, which exhibited a remarkable seizure reduction with a good control of the disease. We also confirmed our previous studies showing PPAR-alpha as a key regulator of neuronal activity through the modulation of nAChR. Our results support also the notion that nAChRs play a major role in diverse idiopathic and/or genetically determined forms of epilepsy and provide a new perspective of epileptic treatment.