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.Electronic supplementary materialThe online version of this article (10.1007/s13311-018-0607-6) contains supplementary material, which is available to authorized users.

In Parkinson’s disease (PD), dopaminergic therapies are often associated with the development of motor complications. Attention has therefore been focused on the use of non-dopaminergic drugs. This study developed a new behavioural method capable of demonstrating the added value of combining adenosinergic and glutamatergic receptor antagonists in unilateral 6-OHDA lesioned rats. Rats were dosed orally with Tozadenant, a selective A2A receptor antagonist, and three different doses of Radiprodil, an NR2B-selective NMDA receptor antagonist. The drugs were given alone or in combination and rats were placed in an open-field for behavioural monitoring. Video recordings were automatically analysed. Five different behaviours were scored: distance traveled, ipsi- and contraversive turns, body position, and space occupancy. The results show that A2A or NR2B receptor antagonists given alone or in combination did not produce enhanced turning as observed with an active dose of L-Dopa/benserazide. Instead the treated rats maintained a straight body position, were able to shift from one direction to the other and occupied a significantly larger space in the arena. The highest “Tozadenant/Radiprodil” dose combination significantly increased all five behavioural parameters recorded compared to rats treated with vehicle or the same doses of the drugs alone. Our data suggest that the A2A/NR2B antagonist combination may be able to stimulate motor activity to a similar level as that achieved by L-Dopa but in the absence of the side-effects that are associated with dopaminergic hyperstimulation. If these results translate into the clinic, this combination could represent an alternative symptomatic treatment option for PD.

Our works shows the ability of machine learning to discriminate pharmacologically relevant animal groups based on their walking behavior in a multivariate manner. Further interesting aspects of the approach include the ability to learn from past experiments, improve with more data arriving and to make predictions for single animals in future studies.