PPAR-alpha agonists as novel antiepileptic drugs: preclinical findings.

Nicotinic acetylcholine receptors (nAChRs) are involved in seizure mechanisms. Hence, nocturnal frontal lobe epilepsy was the first idiopathic epilepsy linked with specific mutations in α4 or β2 nAChR subunit genes. These mutations confer gain of function to nAChRs by increasing sensitivity toward a...

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Autores principales:	Monica Puligheddu, Giuliano Pillolla, Miriam Melis, Salvatore Lecca, Francesco Marrosu, Maria Graziella De Montis, Simona Scheggi, Gianfranca Carta, Elisabetta Murru, Sonia Aroni, Anna Lisa Muntoni, Marco Pistis
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1dbc15029d9a4fd188a75a6d01878efa
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spelling	oai:doaj.org-article:1dbc15029d9a4fd188a75a6d01878efa2021-11-18T07:44:14ZPPAR-alpha agonists as novel antiepileptic drugs: preclinical findings.1932-620310.1371/journal.pone.0064541https://doaj.org/article/1dbc15029d9a4fd188a75a6d01878efa2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23724059/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Nicotinic acetylcholine receptors (nAChRs) are involved in seizure mechanisms. Hence, nocturnal frontal lobe epilepsy was the first idiopathic epilepsy linked with specific mutations in α4 or β2 nAChR subunit genes. These mutations confer gain of function to nAChRs by increasing sensitivity toward acetylcholine. Consistently, nicotine elicits seizures through nAChRs and mimics the excessive nAChR activation observed in animal models of the disease. Treatments aimed at reducing nicotinic inputs are sought as therapies for epilepsies where these receptors contribute to neuronal excitation and synchronization. Previous studies demonstrated that peroxisome proliferator-activated receptors-α (PPARα), nuclear receptor transcription factors, suppress nicotine-induced behavioral and electrophysiological effects by modulating nAChRs containing β2 subunits. On these bases, we tested whether PPARα agonists were protective against nicotine-induced seizures. To this aim we utilized behavioral and electroencephalographic (EEG) experiments in C57BL/J6 mice and in vitro patch clamp recordings from mice and rats. Convulsive doses of nicotine evoked severe seizures and bursts of spike-waves discharges in ∼100% of mice. A single dose of the synthetic PPARα agonist WY14643 (WY, 80 mg/kg, i.p.) or chronic administration of fenofibrate, clinically available for lipid metabolism disorders, in the diet (0.2%) for 14 days significantly reduced or abolished behavioral and EEG expressions of nicotine-induced seizures. Acute WY effects were reverted by the PPARα antagonist MK886 (3 mg/kg, i.p.). Since neocortical networks are crucial in the generation of ictal activity and synchrony, we performed patch clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs) from frontal cortex layer II/III pyramidal neurons. We found that both acute and chronic treatment with PPARα agonists abolished nicotine-induced sIPSC increases. PPARα within the CNS are key regulators of neuronal activity through modulation of nAChRs. These effects might be therapeutically exploited for idiopathic or genetically determined forms of epilepsy where nAChRs play a major role.Monica PulighedduGiuliano PillollaMiriam MelisSalvatore LeccaFrancesco MarrosuMaria Graziella De MontisSimona ScheggiGianfranca CartaElisabetta MurruSonia AroniAnna Lisa MuntoniMarco PistisPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 5, p e64541 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Monica Puligheddu Giuliano Pillolla Miriam Melis Salvatore Lecca Francesco Marrosu Maria Graziella De Montis Simona Scheggi Gianfranca Carta Elisabetta Murru Sonia Aroni Anna Lisa Muntoni Marco Pistis PPAR-alpha agonists as novel antiepileptic drugs: preclinical findings.
description	Nicotinic acetylcholine receptors (nAChRs) are involved in seizure mechanisms. Hence, nocturnal frontal lobe epilepsy was the first idiopathic epilepsy linked with specific mutations in α4 or β2 nAChR subunit genes. These mutations confer gain of function to nAChRs by increasing sensitivity toward acetylcholine. Consistently, nicotine elicits seizures through nAChRs and mimics the excessive nAChR activation observed in animal models of the disease. Treatments aimed at reducing nicotinic inputs are sought as therapies for epilepsies where these receptors contribute to neuronal excitation and synchronization. Previous studies demonstrated that peroxisome proliferator-activated receptors-α (PPARα), nuclear receptor transcription factors, suppress nicotine-induced behavioral and electrophysiological effects by modulating nAChRs containing β2 subunits. On these bases, we tested whether PPARα agonists were protective against nicotine-induced seizures. To this aim we utilized behavioral and electroencephalographic (EEG) experiments in C57BL/J6 mice and in vitro patch clamp recordings from mice and rats. Convulsive doses of nicotine evoked severe seizures and bursts of spike-waves discharges in ∼100% of mice. A single dose of the synthetic PPARα agonist WY14643 (WY, 80 mg/kg, i.p.) or chronic administration of fenofibrate, clinically available for lipid metabolism disorders, in the diet (0.2%) for 14 days significantly reduced or abolished behavioral and EEG expressions of nicotine-induced seizures. Acute WY effects were reverted by the PPARα antagonist MK886 (3 mg/kg, i.p.). Since neocortical networks are crucial in the generation of ictal activity and synchrony, we performed patch clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs) from frontal cortex layer II/III pyramidal neurons. We found that both acute and chronic treatment with PPARα agonists abolished nicotine-induced sIPSC increases. PPARα within the CNS are key regulators of neuronal activity through modulation of nAChRs. These effects might be therapeutically exploited for idiopathic or genetically determined forms of epilepsy where nAChRs play a major role.
format	article
author	Monica Puligheddu Giuliano Pillolla Miriam Melis Salvatore Lecca Francesco Marrosu Maria Graziella De Montis Simona Scheggi Gianfranca Carta Elisabetta Murru Sonia Aroni Anna Lisa Muntoni Marco Pistis
author_facet	Monica Puligheddu Giuliano Pillolla Miriam Melis Salvatore Lecca Francesco Marrosu Maria Graziella De Montis Simona Scheggi Gianfranca Carta Elisabetta Murru Sonia Aroni Anna Lisa Muntoni Marco Pistis
author_sort	Monica Puligheddu
title	PPAR-alpha agonists as novel antiepileptic drugs: preclinical findings.
title_short	PPAR-alpha agonists as novel antiepileptic drugs: preclinical findings.
title_full	PPAR-alpha agonists as novel antiepileptic drugs: preclinical findings.
title_fullStr	PPAR-alpha agonists as novel antiepileptic drugs: preclinical findings.
title_full_unstemmed	PPAR-alpha agonists as novel antiepileptic drugs: preclinical findings.
title_sort	ppar-alpha agonists as novel antiepileptic drugs: preclinical findings.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/1dbc15029d9a4fd188a75a6d01878efa
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PPAR-alpha agonists as novel antiepileptic drugs: preclinical findings.

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