Acute treatment with minocycline, but not valproic acid, improves long‐term behavioral outcomes in the Theiler's virus model of temporal lobe epilepsy

Summary Objective 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. Methods 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. Results 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. Significance 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.