title: Acute treatment with minocycline, but not valproic acid, improves long-term behavioral outcomes in the Theiler's virus model of temporal lobe epilepsy.
abstract: Infection with Theiler's murine encephalomyelitis virus (TMEV) in C57Bl/6J mice induces acute seizures and development of spontaneous recurrent seizures and behavioral comorbidities weeks later. The present studies sought to determine whether acute therapeutic intervention with an anti-inflammatory-based approach could prevent or modify development of TMEV-induced long-term behavioral comorbidities. Valproic acid (VPA), in addition to its prototypical anticonvulsant properties, inhibits histone deacetylase (HDAC) activity, which may alter expression of the inflammasome. Minocycline (MIN) has previously demonstrated an antiseizure effect in the TMEV model via direct anti-inflammatory mechanisms, but the long-term effect of MIN treatment on the development of chronic behavioral comorbidities is unknown.
  
  
  
  Mice infected with TMEV were acutely administered MIN (50 mg/kg, b.i.d. and q.d.) or VPA (100 mg/kg, q.d.) during the 7-day viral infection period. Animals were evaluated for acute seizure severity and subsequent development of chronic behavioral comorbidities and seizure threshold.
  
  
  
  Administration of VPA reduced the proportion of mice with seizures, delayed onset of symptomatic seizures, and reduced seizure burden during the acute infection. This was in contrast to the effects of administration of once-daily MIN, which did not affect the proportion of mice with seizures or delay onset of acute symptomatic seizures. However, VPA-treated mice were no different from vehicle (VEH)-treated mice in long-term behavioral outcomes, including open field activity and seizure threshold. Once-daily MIN treatment, despite no effect on the maximum observed Racine stage seizure severity, was associated with improved long-term behavioral outcomes and normalized seizure threshold.
  
  
  
  Acute seizure control alone is insufficient to modify chronic disease comorbidities in the TMEV model. This work further supports the role of an inflammatory response in the development of chronic behavioral comorbidities and further highlights the utility of this platform for the development of mechanistically novel pharmacotherapies for epilepsy.
authors.affiliation: Department of Pharmacology & Toxicology, Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, Utah, U.S.A.|Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, Washington, U.S.A.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Barker-Haliski
authors.affiliation: Department of Pharmacology & Toxicology, Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, Utah, U.S.A.
authors.forename: Taylor D
authors.initials: TD
authors.lastname: Heck
authors.affiliation: Department of Pharmacology & Toxicology, Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, Utah, U.S.A.
authors.forename: E Jill
authors.initials: EJ
authors.lastname: Dahle
authors.affiliation: Department of Pharmacology & Toxicology, Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, Utah, U.S.A.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Vanegas
authors.affiliation: Department of Pharmacology & Toxicology, Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, Utah, U.S.A.
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Pruess
authors.affiliation: Department of Pharmacology & Toxicology, Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, Utah, U.S.A.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Wilcox
authors.affiliation: Department of Pharmacology & Toxicology, Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, Utah, U.S.A.|Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, Washington, U.S.A.
authors.forename: H Steve
authors.initials: HS
authors.lastname: White
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001008:Anxiety Disorders / Q000188:drug therapy / Q000209:etiology; D001522:Behavior, Animal / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D016009:Chi-Square Distribution; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy / Q000209:etiology / Q000821:virology; D005106:Exploratory Behavior / Q000187:drug effects; D051379:Mice; D008911:Minocycline / Q000627:therapeutic use*; D009043:Motor Activity / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D045442:Rotarod Performance Test; D017945:Theilovirus / Q000472:pathogenicity*; D014635:Valproic Acid / Q000627:therapeutic use*
chemical_list: D000927:Anticonvulsants; D014635:Valproic Acid; D008911:Minocycline
keywords: Acquired epilepsy; Anxiety-like behavior; Minocycline; Seizure threshold; Temporal lobe epilepsy; Valproic acid