title: The Role of Sirt1 in Epileptogenesis.
abstract: The mechanisms by which brain insults lead to subsequent epilepsy remain unclear. Insults, including trauma, stroke, tumors, infections, and long seizures [status epilepticus (SE)], create a neuronal state of increased metabolic demand or decreased energy supply. Neurons express molecules that monitor their metabolic state, including sirtuins (Sirts). Sirtuins deacetylate cytoplasmic proteins and nuclear histones, and their epigenetic modulation of the chromatin governs the expression of many genes, influencing neuronal properties. Thus, sirtuins are poised to enduringly modulate neuronal properties following SE, potentially contributing to epileptogenesis, a hypothesis supported by the epilepsy-attenuating effects of blocking a downstream target of Sirt1, Neuron-Restrictive Silencer Factor (NRSF) also know as REST (RE1-Silencing Transcription factor). Here we used an adult male rat model of epileptogenesis provoked by kainic acid-induced SE (KA-SE). We assessed KA-SE-provoked Sirt1 activity, infused a Sirt1 inhibitor (EX-527) after KA-SE, and examined for epileptogenesis using continuous digital video-EEG. Sirt1 activity, measured using chromatin immunoprecipitation for Sirt1 binding at a target gene, increased rapidly after SE.Post hocinfusion of the Sirt1 inhibitor prevented Sirt1-mediated repression of a target gene. Blocking Sirt1 activity transiently after KA-SE did not significantly influence the time- course and all of the parameters of epilepsy development. Specifically, latency to first seizure and seizure number, duration, and severity (using the Racine scale and EEG measures) as well as the frequency and duration of interictal spike series, were all unchanged. KA-SE provoked a robust inflammatory response and modest cell loss, yet neither was altered by blocking Sirt1. In conclusion, blocking Sirt1 activity after KA-SE does not abrogate epilepsy development, suggesting that the mechanisms of such acquired epileptogenesis are independent of Sirt1 function.
authors.affiliation: Department of Pediatrics, University of California, Irvine , Irvine, California 92697.
authors.forename: Alicia M
authors.identifier: 0000-0002-2746-4804
authors.initials: AM
authors.lastname: Hall
authors.affiliation: Department of Pediatrics, University of California, Irvine, Irvine, California 92697; Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, California 92697.
authors.forename: Gary P
authors.initials: GP
authors.lastname: Brennan
authors.affiliation: Department of Pediatrics, University of California, Irvine , Irvine, California 92697.
authors.forename: Tiffany M
authors.initials: TM
authors.lastname: Nguyen
authors.affiliation: Department of Pediatrics, University of California, Irvine , Irvine, California 92697.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Singh-Taylor
authors.affiliation: Department of Pediatrics, University of California, Irvine , Irvine, California 92697.
authors.forename: Hyun-Seung
authors.initials: HS
authors.lastname: Mun
authors.affiliation: Department of Pediatrics, University of California, Irvine , Irvine, California 92697.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Sargious
authors.affiliation: Department of Pediatrics, University of California, Irvine, Irvine, California 92697; Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, California 92697.
authors.forename: Tallie Z
authors.initials: TZ
authors.lastname: Baram
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002227:Carbazoles / Q000494:pharmacology; D002452:Cell Count; D002491:Central Nervous System Agents / Q000494:pharmacology; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D004569:Electroencephalography; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism; D007608:Kainic Acid; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012640:Seizures / Q000378:metabolism* / Q000473:pathology; D012720:Severity of Illness Index; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013226:Status Epilepticus / Q000378:metabolism* / Q000473:pathology; D014741:Video Recording
chemical_list: C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D002227:Carbazoles; D002491:Central Nervous System Agents; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D007608:Kainic Acid
keywords: epigenetics; epilepsy; epileptogenesis; intervention; metabolic stress; sirtuins