PPAR-Alpha Agonists as Novel Antiepileptic Drugs: Preclinical Findings
- Publication Date
- May 27, 2013
- Journal
- PLOS ONE
- Authors
- Monica Puligheddu, Giuliano Pillolla, Miriam Melis, Salvatore Lecca, et al
- Volume
- 8
- Issue
- 5
- Pages
- e64541
- DOI
- https://dx.plos.org/10.1371/journal.pone.0064541
- Publisher URL
- http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0064541
- PubMed
- http://www.ncbi.nlm.nih.gov/pubmed/23724059
- PubMed Central
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664607
- Europe PMC
- http://europepmc.org/abstract/MED/23724059
- Web of Science
- 000319738100028
- Scopus
- 84878319533
- Mendeley
- http://www.mendeley.com/research/pparalpha-agonists-novel-antiepileptic-drugs-preclinical-findings
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Mendeley | Further Information
{"title"=>"PPAR-Alpha Agonists as Novel Antiepileptic Drugs: Preclinical Findings", "type"=>"journal", "authors"=>[{"first_name"=>"Monica", "last_name"=>"Puligheddu", "scopus_author_id"=>"6602663838"}, {"first_name"=>"Giuliano", "last_name"=>"Pillolla", "scopus_author_id"=>"13605492200"}, {"first_name"=>"Miriam", "last_name"=>"Melis", "scopus_author_id"=>"7102493419"}, {"first_name"=>"Salvatore", "last_name"=>"Lecca", "scopus_author_id"=>"35233959300"}, {"first_name"=>"Francesco", "last_name"=>"Marrosu", "scopus_author_id"=>"14048747500"}, {"first_name"=>"Maria Graziella", "last_name"=>"De Montis", "scopus_author_id"=>"7004644054"}, {"first_name"=>"Simona", "last_name"=>"Scheggi", "scopus_author_id"=>"6603202432"}, {"first_name"=>"Gianfranca", "last_name"=>"Carta", "scopus_author_id"=>"7101609523"}, {"first_name"=>"Elisabetta", "last_name"=>"Murru", "scopus_author_id"=>"6603655261"}, {"first_name"=>"Sonia", "last_name"=>"Aroni", "scopus_author_id"=>"55750130300"}, {"first_name"=>"Anna Lisa", "last_name"=>"Muntoni", "scopus_author_id"=>"35591621700"}, {"first_name"=>"Marco", "last_name"=>"Pistis", "scopus_author_id"=>"6701636492"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84878319533", "doi"=>"10.1371/journal.pone.0064541", "pui"=>"369013299", "pmid"=>"23724059", "scopus"=>"2-s2.0-84878319533", "issn"=>"19326203", "isbn"=>"1932-6203 (Electronic)\\n1932-6203 (Linking)"}, "id"=>"25d374da-f6dd-300d-8a10-ba7deada1fa8", "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.", "link"=>"http://www.mendeley.com/research/pparalpha-agonists-novel-antiepileptic-drugs-preclinical-findings", "reader_count"=>30, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>4, "Researcher"=>9, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>5, "Other"=>5, "Student > Master"=>3, "Student > Bachelor"=>2}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>4, "Researcher"=>9, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>5, "Other"=>5, "Student > Master"=>3, "Student > Bachelor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>2, "Agricultural and Biological Sciences"=>4, "Medicine and Dentistry"=>9, "Neuroscience"=>4, "Pharmacology, Toxicology and Pharmaceutical Science"=>4, "Psychology"=>1, "Chemistry"=>2, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>9}, "Neuroscience"=>{"Neuroscience"=>4}, "Chemistry"=>{"Chemistry"=>2}, "Psychology"=>{"Psychology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>4}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>3}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>4}}, "reader_count_by_country"=>{"Canada"=>1, "United States"=>1, "France"=>1}, "group_count"=>3}CrossRef
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Scopus | Further Information
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Wikipedia | Further Information
- {"title"=>"Peroxisome proliferator-activated receptor alpha", "url"=>"http://en.wikipedia.org/wiki/Peroxisome_proliferator-activated_receptor_alpha", "timestamp"=>"2019-02-22T03:31:30Z"}
- {"title"=>"Anticonvulsant", "url"=>"http://en.wikipedia.org/wiki/Anticonvulsant", "timestamp"=>"2019-03-23T09:34:57Z"}
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PMC Usage Stats | Further Information
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Relative Metric
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