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

Abstract

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 nor delay onset of acute symptomatic seizures. However, VPA-treated mice were no different from 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.

Indoleamine 2,3‐dioxygenase 1 deletion promotes Theiler's virus–induced seizures in C57BL/6J mice

“…However, 41% of TMEV‐infected C57BL/6J mice exhibited seizures within 6 days versus 74% of infected Ido1‐KO mice (Figure A). Examination of cumulative seizure burden has been efficacious in evaluating seizure severity and number over time . We found that cumulative seizure burden was greater in Ido1‐KO mice compared to C57BL/6J mice at day 6 p.i.…”

“…Seizure incidence was calculated by dividing the number of mice with seizures, ≥3 at any time during the study, by the number of mice infected in that genotype . Cumulative seizure burden for a particular day was calculated by adding the Racine score of that day to the sum of all preceding scores; any day without an observed seizure (Racine = 0) maintained the previous day's cumulative burden score …”

Lamotrigine‐resistant corneal‐kindled mice: A model of pharmacoresistant partial epilepsy for moderate‐throughput drug discovery

“…MIN possess acute anticonvulsant efficacy in the mouse 6 Hz model (median effective dose of 170 mg/kg, ip) . We chose to forgo any dose‐response with MIN because kindled rodents are more sensitive than naïve rodents to adverse drug effects and we have also previously reported mortality associated with MIN in mice with a history of seizures . Pilot studies with LTG‐resistant CKM resulted in mortality with MIN doses >100 mg/kg (data not shown), a dose well below that which is motor‐impairing in naive mice (250 mg/kg).…”

“…A cohort of CKM from both treatment groups (n = 20/group), and sham‐kindled mice (n = 5), underwent behavioral assessment of general hyperexcitability during the kindling acquisition process and immediately after achieving kindling criterion based on a hyperexcitability test adapted from a rat post‐pilocarpine model . The mice were also tested shortly after the final kindling stimulation (day 21) in an automated open‐field (OF) test of anxiety‐like behavior …”

Neuroinflammation in epileptogenesis: Insights and translational perspectives from new models of epilepsy

“…In recent years, the Theiler's murine encephalomyelitis virus (TMEV) mouse model has emerged as a novel “hit and run” model that begins to address this matter . C57BL/6 mice, but not SJL mice, exposed to TMEV intracerebrally display many of the characteristics of encephalitis‐induced human temporal lobe epilepsy (TLE), including neuroinflammation, neurodegeneration, and behavioral comorbidities such as anxiety‐like behavior and cognitive deficit . Moreover, mice infected with TMEV that present with acute symptomatic seizures display reduced seizure threshold and an increased liability for the development of abnormal EEG activity and SRS for weeks to months following intracerebral inoculation with TMEV .…”