Razionale sull'impiego del fenofibrato come terapia aggiuntiva nell'epilessia frontale notturna (NFLE) farmacoresistente

Puligheddu, Monica Maria Francesca (2015) Razionale sull'impiego del fenofibrato come terapia aggiuntiva nell'epilessia frontale notturna (NFLE) farmacoresistente, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Scienze mediche specialistiche, 27 Ciclo. DOI 10.6092/unibo/amsdottorato/7057.
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Nocturnal Frontal Lobe Epilepsy (NFLE) is characterized by onset during infancy or childhood with persistence in adulthood, family history of similar nocturnal episodes simulating non-REM parasomnias (sleep terrors or sleepwalking), general absence of morphological substrates, often by normal interictal electroencephalographical recordings (EEGs) during wakefulness. A family history of epilepsy may be present with Mendelian autosomal dominant inheritance has been described in some families. Recent studies indicate the involvement of neuronal nicotinic acetylcholine receptors (nAChRs) in the molecular mechanisms of NFLE. Mutations in the genes encoding for the α4 (CHRNA4) and ß2 (CHRNB2) subunits of the nAChR induce changes in the biophysical properties of nAChR, resulting generally in a “gain of function”. Preclinical studies report that activation of a nuclear receptor called type peroxisome proliferator-activated receptor (PPAR-α) by endogenous molecules or by medications (e.g. fenofibrate) reduces the activity of the nAChR and, therefore, may decrease the frequency of seizures. Thus, we hypothesize that negative modulation of nAChRs might represent a therapeutic strategy to be explored for pharmacological treatment of this form of epilepsy, which only partially responds to conventional antiepileptic drugs. In fact, carbamazepine, the current medication for NFLE, abolishes the seizures only in one third of the patients. The aim of the project is: 1)_to verify the clinical efficacy of adjunctive therapy with fenofibrate in pharmacoresistant NFLE and ADNFLE patients; focousing on the analysis of the polysomnographic action of the PPAR- agonist (fenofibrate). 2)_to demonstrate the subtended mechanism of efficacy by means of electrophysiological and behavioral experiments in an animal model of the disease: particularly, transgenic mice carrying the mutation in the nAChR 4 subunit (Chrna4S252F) homologous to that found in the humans. Given that a PPAR-α agonist, FENOFIBRATE, already clinically utilized for lipid metabolism disorders, provides a promising therapeutic avenue in the treatment of NFLE\ADNFLE.

Tipologia del documento
Tesi di dottorato
Puligheddu, Monica Maria Francesca
Dottorato di ricerca
Scuola di dottorato
Scienze mediche e chirurgiche
Settore disciplinare
Settore concorsuale
Parole chiave
Nocturnal Frontal Lobe Epilepsy (NFLE), nicotinic acetylcholine receptors (nAChRs),gain of function,peroxisome proliferator-activated receptor (PPAR-α)
Data di discussione
17 Aprile 2015

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