title: PPAR-alpha agonists as novel antiepileptic drugs: preclinical findings.
abstract: 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.
authors.affiliation: Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Puligheddu
authors.forename: Giuliano
authors.initials: G
authors.lastname: Pillolla
authors.forename: Miriam
authors.initials: M
authors.lastname: Melis
authors.forename: Salvatore
authors.initials: S
authors.lastname: Lecca
authors.forename: Francesco
authors.initials: F
authors.lastname: Marrosu
authors.forename: Maria Graziella
authors.initials: MG
authors.lastname: De Montis
authors.forename: Simona
authors.initials: S
authors.lastname: Scheggi
authors.forename: Gianfranca
authors.initials: G
authors.lastname: Carta
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Murru
authors.forename: Sonia
authors.initials: S
authors.lastname: Aroni
authors.forename: Anna Lisa
authors.initials: AL
authors.lastname: Muntoni
authors.forename: Marco
authors.initials: M
authors.lastname: Pistis
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D017034:Epilepsy, Frontal Lobe / Q000175:diagnosis / Q000188:drug therapy; D011345:Fenofibrate / Q000008:administration & dosage / Q000494:pharmacology; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009538:Nicotine / Q000009:adverse effects; D047493:PPAR alpha / Q000819:agonists*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation / Q000187:drug effects; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy
chemical_list: D000927:Anticonvulsants; D011345:Fenofibrate; D009538:Nicotine; D047493:PPAR alpha; D011743:Pyrimidines; D011978:Receptors, Nicotinic; C006253:pirinixic acid