| First Author | Puligheddu M | Year | 2017 |
| Journal | Epilepsia | Volume | 58 |
| Issue | 10 | Pages | 1762-1770 |
| PubMed ID | 28766701 | Mgi Jnum | J:352823 |
| Mgi Id | MGI:7705257 | Doi | 10.1111/epi.13863 |
| Citation | Puligheddu M, et al. (2017) Rationale for an adjunctive therapy with fenofibrate in pharmacoresistant nocturnal frontal lobe epilepsy. Epilepsia 58(10):1762-1770 |
| abstractText | 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 alpha4 or beta2 subunits. Fenofibrate, a common lipid-regulating drug, is an agonist at peroxisome proliferator-activated receptor alpha (PPARalpha) that is a ligand-activated transcription factor, which negatively modulates the function of beta2-containing nAChR. To test clinical efficacy of adjunctive therapy with fenofibrate in pharmacoresistant ADNFLENFLE 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 alpha4-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 PPARalpha as a novel disease-modifying target for antiepileptic drugs due to its ability to regulate dysfunctional nAChRs. |
