title: Evaluating an etiologically relevant platform for therapy development for temporal lobe epilepsy: effects of carbamazepine and valproic acid on acute seizures and chronic behavioral comorbidities in the Theiler's murine encephalomyelitis virus mouse model.
abstract: Central nervous system infections can underlie the development of epilepsy, and Theiler's murine encephalomyelitis virus (TMEV) infection in C57BL/6J mice provides a novel model of infection-induced epilepsy. Approximately 50-65% of infected mice develop acute, handling-induced seizures during the infection. Brains display acute neuropathology, and a high number of mice develop spontaneous, recurrent seizures and behavioral comorbidities weeks later. This study characterized the utility of this model for drug testing by assessing whether antiseizure drug treatment during the acute infection period attenuates handling-induced seizures, and whether such treatment modifies associated comorbidities. Male C57BL/6J mice infected with TMEV received twice-daily valproic acid (VPA; 200 mg/kg), carbamazepine (CBZ; 20 mg/kg), or vehicle during the infection (days 0-7). Mice were assessed twice daily during the infection period for handling-induced seizures. Relative to vehicle-treated mice, more CBZ-treated mice presented with acute seizures; VPA conferred no change. In mice displaying seizures, VPA, but not CBZ, reduced seizure burden. Animals were then randomly assigned to acute and long-term follow-up. VPA was associated with significant elevations in acute (day 8) glial fibrillary acidic protein (astrocytes) immunoreactivity, but did not affect NeuN (neurons) immunoreactivity. Additionally, VPA-treated mice showed improved motor performance 15 days postinfection (DPI). At 36 DPI, CBZ-treated mice traveled significantly less distance through the center of an open field, indicative of anxiety-like behavior. CBZ-treated mice also presented with significant astrogliosis 36 DPI. Neither CBZ nor VPA prevented long-term reductions in NeuN immunoreactivity. The TMEV model thus provides an etiologically relevant platform to evaluate potential treatments for acute seizures and disease modification.
authors.affiliation: Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah melissa.barker@utah.edu.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Barker-Haliski
authors.affiliation: Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah.
authors.forename: E Jill
authors.initials: EJ
authors.lastname: Dahle
authors.affiliation: Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah.
authors.forename: Taylor D
authors.initials: TD
authors.lastname: Heck
authors.affiliation: Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah.
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Pruess
authors.affiliation: Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Vanegas
authors.affiliation: Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Wilcox
authors.affiliation: Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah.
authors.forename: H Steve
authors.initials: HS
authors.lastname: White
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D001007:Anxiety / Q000139:chemically induced; D001522:Behavior, Animal / Q000187:drug effects*; D002220:Carbamazepine / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D018188:Cardiovirus Infections / Q000150:complications; D015897:Comorbidity; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000150:complications / Q000188:drug therapy* / Q000209:etiology* / Q000821:virology; D005904:Glial Fibrillary Acidic Protein; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D045442:Rotarod Performance Test; D017945:Theilovirus / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014635:Valproic Acid / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D009687:Nuclear Proteins; C528900:glial fibrillary astrocytic protein, mouse; D002220:Carbamazepine; D014635:Valproic Acid