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Therapeutic treatment of acute behavioral seizures in the Theiler’s murine

encephalomyelitis virus model of acquired epilepsy improves long-term behavioral outcome

<h3>Melissa L. Barker-Haliski, E. Jill Dahle, Timothy H. Pruess, Taylor D. Heck, Fabiola Vanegas,</h3>

Karen S. Wilcox, and H. Steve White

Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology,

University of Utah, Salt Lake City, UT 84108

Inflammation represents a significant risk factor for seizure induction and maintenance, with proinflammatory cytokines being highly expressed in various animal seizure models and human

patients with epilepsy. Infections of the CNS can contribute to the development of chronic epilepsy due to an increased risk of seizures and status epilepticus. Theiler’s murine encephalomyelitis virus (TMEV), when injected into brains of C57/Bl6 mice, provides a novel model of infection-induced epilepsy. Approximately 50-65% of infected mice develop acute, handling-induced seizures during the infection and subsequently develop spontaneous, recurrent seizures and behavioral impairment weeks later. It is unknown whether treatment

during the acute infection can attenuate handling-induced seizures, as well as ameliorate longterm behavioral comorbidities associated with epilepsy. This study investigated the efficacy of the antiseizure drugs (ASDs) valproic acid (VPA) and carbamazepine (CBZ), and the antiinflammatory antibiotic, minocycline (MIN) on TMEV-induced seizures and behavioral comorbidity. On Day 0, male C57/Bl6 mice were infected with TMEV, then treated daily (Day 0-8) with CBZ (n = 28; 20 mg/kg b.i.d., i.p.), VPA (n = 28; 100 mg/kg q.d., i.p.), MIN (n = 28; 50

mg/kg q.d., i.p.), or vehicle control (n = 28). Mice were assessed twice daily for 7 days for

handling-induced seizures by an experimenter blinded to treatment. Relative to controls,

significantly more CBZ-treated mice presented with seizures; VPA reduced the proportion with

seizures, and MIN conferred no change. In animals with seizures, VPA, but not CBZ or MIN, increased the latency to the first observed seizure; only MIN-treated mice demonstrated improved open-field exploratory behavior, a measure of anxiety-like behavior. Furthermore, only MIN significantly reduced the proportion of mice displaying tonic-extension seizures or mortality with PTZ. These data suggest that while treatment with prototype ASDs may alter acute seizure

expression in the TMEV model, treatment with anti-inflammatory agents during the acute

infection period may mitigate long-term behavioral comorbidities and seizure threshold changes.

Such information supports a growing body of evidence suggesting a role for inflammation in seizure disorders and associated comorbidities.

Supported by NIH HHSN 271201100029C (HSW) and 1-R01-NS065434 (KSW and HSW).