title: Standard dose valproic acid does not cause additional cognitive impact in a rodent model of intractable epilepsy.
abstract: Children with epilepsy face significant cognitive and behavioral impairments. These impairments are due to a poorly characterized interaction between the underlying etiology, the effect of seizures and the effect of medication. The large variation in these factors make understanding the main drivers of cognitive impairment in humans extremely difficult. Therefore, we investigated the cognitive effect of seizures and the antiepileptic drug valproic acid in a rodent model of cortical dysplasia. Rats were divided into seizure-receiving and non-receiving groups. Rats experienced frequent early life seizures using the flurothyl inhalation method: 50 seizures between postnatal day 5 and 15 and then one seizure a day following that. Rats were further divided into drug-treated and vehicle treated groups. Valproic acid treated animals were treated from 5 days preceding behavioral testing in the Morris water maze at a clinically relevant concentration. We show here that the main driver of cognitive impairments are the brain malformations, and that persistent seizures in animals with brain malformations and valproic acid caused no additional impact. These findings suggest that neither an appropriate dose of a standard antiepileptic drug or intractable seizures worsen cognition associated with a malformation of cortical development and that alternative treatment strategies to improve cognition are required.
authors.affiliation: Department of Neurology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA; University of Bath, Biology and Biochemistry, Bath BA2 7AY, UK.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Jellett
authors.affiliation: Department of Neurology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Jenks
authors.affiliation: Department of Neurology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
authors.forename: Marcella
authors.initials: M
authors.lastname: Lucas
authors.affiliation: University College London, Institute of Child Health, London WC1N 1EH, UK; Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, VT 05405, USA. Electronic address: rodney.scott@med.uvm.edu.
authors.forename: Rod C
authors.initials: RC
authors.lastname: Scott
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000009:adverse effects / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D003072:Cognition Disorders / Q000209:etiology; D004195:Disease Models, Animal; D004827:Epilepsy / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology / Q000523:psychology*; D005260:Female; D005481:Flurothyl; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D054220:Malformations of Cortical Development / Q000150:complications / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008746:Methylazoxymethanol Acetate; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D016019:Survival Analysis; D014635:Valproic Acid / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D008746:Methylazoxymethanol Acetate; D014635:Valproic Acid; D005481:Flurothyl
keywords: Hippocampus; Methylazoxymethanol acetate; Pediatric epilepsy; Valproic acid