Reduction of epileptiform activity through local valproate-implants in a rat neocortical epilepsy model

Pharmacotherapy of epilepsies is limited due to low concentrations at epileptogenic foci, side effects of high systemic doses and that some potentially efficient substances do not pass the blood-brain barrier. To overcome these limitations, we tested the efficacy of local valproate (VPA)-containing polymer implants in a model of necocortical injected tetanus toxin (TeT) in the rat.

Tetanus toxin was injected intracortically and cobalt (II) chloride (CoCl2) was applied on the cortical surface. Video-electrocorticography recordings with intracortical electrodes were performed. VPA-containing polymers were implanted above the cortical focus. Antiepileptic effects were evaluated as reductions of epileptiform potentials (EPs) per hour in comparison to saline (NaCl)-containing polymer implants.

Triple 50ng TeT injections plus CoCl2 application (20/10mg) showed consistent EPs. NaCl-implanted animals (n=6) showed a mean of 10.5EPs/h after the first week, the EP frequency increased to 53.5EPs/h after the second week. VPA-implant animals (n=5) showed a reduction in EP frequency from 71.6 to 4.8EPs/h after the second week. The EP frequency after the second week was higher in the NaCl-implanted animals than in the VPA-implanted (p=0.0303). The mean EPs/h increase in NaCl-implanted rats (+42.9EPs/h) was different (p=0.0087) from the mean EPs/h decrease in VPA-implanted rats (-66.8EPs/h).

Despite former publications no clear seizures could be reproduced but it was possible to establish focal EPs, which proved to be a reliable marker for epileptic activity. Local antiepileptic therapy with VPA has shown efficacy in decreasing EP frequency.