Understanding the mechanisms of epileptogenesis is essential to develop novel drugs that could prevent or modify the disease.
Neuroinflammation has been proposed as a promising target for therapeutic interventions to inhibit the epileptogenic process that evolves from
traumatic brain injury. However, it remains unclear whether
cytokine-related pathways, particularly TNFα signaling, have a critical role in the development of
epilepsy. In this study, we investigated the role of innate
inflammation in an in vitro model of post-traumatic epileptogenesis. We combined organotypic hippocampal slice cultures, representing an in vitro model of
post-traumatic epilepsy, with multi-
electrode array recordings to directly monitor the development of epileptiform activity and to examine the concomitant changes in
cytokine release, cell death, and glial cell activation. We report that synchronized ictal- and interictal-like activities spontaneously evolve in this culture. Dynamic changes in the release of the pro-inflammatory
cytokines IL-1β, TNFα, and
IL-6 were observed throughout the culture period (3 to 21 days in vitro) with persistent activation of microglia and astrocytes. We found that neutralizing TNFα with a polyclonal antibody significantly reduced ictal discharges, and this effect lasted for 1 week after antibody washout. Neither
phenytoin nor an anti-IL-6 polyclonal antibody was efficacious in inhibiting the development of epileptiform activity. Our data show a sustained effect of the anti-TNFα antibody on the ictal progression in organotypic hippocampal slice cultures supporting the critical role of inflammatory mediators in
epilepsy and establishing a proof-of-principle evidence for the utility of this preparation to test the
therapeutic effects of anti-inflammatory treatments.