Abstracts

Rationale: Objective: Effect of pharmacologic Toll-like receptor inhibition in the development of epilepsy.Epilepsy is one of the most prevalent neurological disorders affecting around 60 million people worldwide. Despite the development of antiepileptic drugs, 35% of patients cannot be controlled with current pharmacologic therapeutic options. Toll-like receptors (TLRs) are a family of innate immune receptors that mediate neuroinflammatory processes in the brain. In?ammation plays a prominent role in the etiology of symptomatic epilepsies that result from traumatic brain injuries, stroke, encephalitis, and status epilepticus (SE). Here we investigated the involvement of TLR3 by pharmacologic inhibition in the onset, development (epileptogenesis), and severity of epilepsy using mice deficient in TLR3 in the pilocarpine model of epilepsy. Methods: Immediately after the induction of status epilepticus (SE) using the anti-cholinergic compound pilocarpine we injected different pharmacologic blockers of TLR3. Each group was separated in one with only immediate treatment (three injections each 24h apart) and one with chronic anti-TLR3 treatment (14 injections each 24h apart). To influence TLR3 receptors we used either 1,2-benzenediamine derivative FC-99 (FC-99; 100 mg/kg) or resveratrol (20 mg/kg). Subsequently, mice were implanted for EEG monitoring with wireless bipolar EEG-electrodes. The electrographic features of SE and chronic seizures are analyzed using a telemetric EEG/video monitoring system. In addition, all animals were sacrificed for stereological assessment of neuroinflammation in the hippocampus using quantification and morphology assessment of astrocytes (GFAP) and gliosis by analyzing the morphology of microglial cells (IBA-1). Furthermore, hippocampal volumetry and quantification of neuronal cell death (NeuN) is performed. Results: We here present the results of the influence of pharmacologic TLR-R inhibitors on chronic seizure frequency in the pilocarpine induced SE epilepsy model in mice. Conclusions: These preliminary results -in a still ongoing study- indicate a central involvement of seizure induction (epileptogenesis) by TLR3 in accordance to our previous results using TLR3 knockout animals. Our current research provide a great basis for future research and possibly drug development to finally change the treatment paradigm of epilepsy from symptomatic seizure control to curable prevention of seizure development. Funding: This research was supported by THE ISRAEL SCIENCE FOUNDATION (grant No. 1010/16).