Locally Applied Valproate Enhances Survival in Rats after Neocortical Treatment with Tetanus Toxin and Cobalt Chloride

Abstract

Purpose. In neocortical epilepsies not satisfactorily responsive to systemic antiepileptic drug therapy, local application of antiepileptic agents onto the epileptic focus may enhance treatment efficacy and tolerability. We describe the effects of focally applied valproate (VPA) in a newly emerging rat model of neocortical epilepsy induced by tetanus toxin (TeT) plus cobalt chloride (CoCl2). Methods. In rats, VPA (n = 5) or sodium chloride (NaCl) (n = 5) containing polycaprolactone (PCL) implants were applied onto the right motor cortex treated before with a triple injection of 75 ng TeT plus 15 mg CoCl2. Video-EEG monitoring was performed with intracortical depth electrodes. Results. All rats randomized to the NaCl group died within one week after surgery. In contrast, the rats treated with local VPA survived significantly longer (P < 0.01). In both groups, witnessed deaths occurred in the context of seizures. At least 3/4 of the rats surviving the first postoperative day developed neocortical epilepsy with recurrent spontaneous seizures. Conclusions. The novel TeT/CoCl2 approach targets at a new model of neocortical epilepsy in rats and allows the investigation of local epilepsy therapy strategies. In this vehicle-controlled study, local application of VPA significantly enhanced survival in rats, possibly by focal antiepileptic or antiepileptogenic mechanisms.

Electrocorticographic and neurochemical findings after local cortical valproate application in patients with pharmacoresistant focal epilepsy

“…9 In a rat model of neocortical epilepsy, locally applied VPA has shown efficacy in decreasing interictal epileptiform potentials and enhanced survival. 7,10 In the present study we tried to transfer and replicate these findings in patients with pharmacoresistant neocortical focal epilepsy who were selected for epilepsy surgery.…”

Bypassing the Blood–Brain Barrier: Direct Intracranial Drug Delivery in Epilepsies

“…Implantation of a titania bioceramics reservoir containing valproate into the amygdala of chemically kindled rats suppressed seizures [154]. Neocortical valproate-containing polymer implants significantly enhanced survival in rats with tetanus toxin/cobalt neocortical epilepsy focus [155] and reduced epileptiform potentials [156].…”

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

“…In the present study, we did not produce overt seizures with the additional CoCl 2 treatment. In parallel experiments, however, we used a larger TeT dose (225 ng), a medium CoCl 2 dose (15 mg) and also implanted NaCl-or VPA-implants [44]. Then, the animals developed reliable seizures, but also had a high mortality rate, so that quantitative evaluation of ECoG activity was not possible [44].…”

“…In parallel experiments, however, we used a larger TeT dose (225 ng), a medium CoCl 2 dose (15 mg) and also implanted NaCl-or VPA-implants [44]. Then, the animals developed reliable seizures, but also had a high mortality rate, so that quantitative evaluation of ECoG activity was not possible [44]. The CoCl 2 -implanted animals in the present study, however, showed a stable activity of typical EPs, which enabled their quantification.…”

“…We were able to show a reduction in the rate of EPs after application of VPA directly on the epileptic focus. We hypothesize therefore that local administration of VPA might positively influence not only over-all survival [44], but also focal epilepsy. However, the rate of EPs was highest during the first two weeks.…”