Zierath, D. | bioRxiv Science

bioRxiv2025

Acute Dose-Related Effect of Antiseizure Medicines on Open Field Exploration of Male Rats with Established Epilepsy

Antiseizure medicines (ASMs) cause both acute and chronic behavioral side effects in individuals with epilepsy. While clinical and preclinical studies often focus on chronic effects, the acute dose-related impact of ASMs on behavior is underreported, especially in rodent temporal lobe epilepsy (TLE) models. Investigating the acute effects of both therapeutic and behaviorally impairing doses may inform clinically relevant adverse effects, such as sedation, hyperactivity, and impaired coordination, which are essential for evaluating drug safety and tolerability. This study investigated the acute effects of anticonvulsant doses of carbamazepine (CBZ), valproic acid (VPA), levetiracetam (LEV), and cenobamate (CNB) on locomotor activity and exploratory behavior in rats 8-13 weeks after kainic acid-induced status epilepticus to elicit confirmed spontaneous recurrent seizures consistent (SRS) with TLE. Behavioral outcomes were quantified using an automated open field task (OFT) in both epileptic and non-epileptic (naive) rats. Our findings revealed that anticonvulsant doses of CNB affected locomotor behavior while other ASMs did not alter exploratory behavior. However, the motor impairing doses of CBZ and CNB equally suppressed exploratory behavior, likely due to sedative effects, in both epileptic and non-epileptic rats. LEV was unique, showing no sedative effects even at high doses, while VPA exhibited an anxiolytic effect in SRS rats and a sedative effect in naive rats at high dose. This study provides essential insight into the efficacy and tolerability profiles of a diversity of FDA-approved ASMs in a clinically relevant TLE model. Thus, SRS may influence ASM tolerability in preclinical TLE models that may inform clinical translation.

animal behavior and cognition↗

bioRxiv2023

Diet composition and sterilization modifies intestinal microbiome diversity and burden of Theiler's virus infection-induced acute seizures

ObjectiveCentral nervous system infection with Theilers murine encephalomyelitis virus (TMEV) in C57BL/6J mice can model acquired epileptogenesis. Diet alters the acute seizure incidence in TMEV-infected mice; yet it is unclear whether intestinal dysbiosis may also impact acute or chronic behavioral comorbidities. This study thus assessed the impact of diet sterilization in a specific pathogen-free vivarium on acute seizure presentation, the composition of the gut microbiome, and chronic behavioral comorbidities of epilepsy. MethodsBaseline fecal samples were collected from male C57BL/6J mice (4-5 weeks-old; Jackson Labs) upon arrival. Mice were randomized to either autoclaved (AC) or irradiated (IR) diet (Prolab RMH 3000 - UU diets) or IR (Picolab 5053 - UW IR diet). Mice then underwent intracerebral TMEV or PBS injection three days later. Fecal samples were collected from a subset of mice at infection (Day 0) and Day 7 post-infection. Epilepsy-related working memory deficits and seizure threshold were assessed 6 weeks post-infection. Gut microbiome diversity was determined by 16S rRNA amplicon sequencing of fecal samples. ResultsTMEV-infected mice displayed acute handling-induced seizures, regardless of diet: 28/57 UW IR (49.1%), 30/41 UU IR (73.2%), and 47/77 UU AC (61%) mice displayed seizures. The number of observed seizures significantly differed: UW IR mice had 2.2{+/-}2.8 seizures (mean{+/-}standard deviation), UU IR mice had 3.5{+/-}2.9 seizures, and UU AC mice had 4.4{+/-}3.8 seizures during the 7-day monitoring period. The composition of the gut microbiome significantly differed in TMEV-infected mice fed the UU AC diet, with most measured differences occurring in Gram-positive bacteria. TMEV-infected mice fed the UU AC diet displayed worsened chronic working memory. SignificanceIntestinal dysbiosis evokes stark differences in acute seizure presentation in the TMEV model and vastly influences the trajectory of post-TMEV infection-induced behavioral comorbidities of epilepsy. Our study reveals a novel disease-modifying contribution of intestinal bacterial species after TMEV-induced acute seizures.

neuroscience↗