Abstract:
The cerebellum is a potent anti‑epileptic target for deep brain stimulation in patients with drug‑resistant epilepsy. The effects of such
stimulation, however, may also favor seizure activity. Our goal was to investigate the effect of cerebellar electrical stimulation (ES) alone
and in combination with the anti‑epileptic drug diazepam (DIA) on seizure outcome. We used a rat model of pentylenetetrazol kindling,
which is characterized by seizures followed by deteriorations in central benzodiazepine‑GABAA (BDZ‑GABAA) receptors. We tested the
effects of ES alone and in combination with DIA (0.1 and 1.0 mg/kg) on seizures. Our data demonstrated: 20 ES trials can prevent the
recurrence of clonic‑tonic kindled seizures, administration of either DIA‑0.1 or ES (5 trials) alone is ineffective on seizures, and combining
DIA‑0.1 and 5 ES or DIA‑1.0 and 5 ES caused an additive effect, prolonged the latency to seizure onset, and prevented recurrence of
clonic‑tonic seizures. We also observed that ES alone produced either facilitation or inhibition of seizures on EEG. In contrast, the
same ES inhibited EEG seizures when delivered after a combination of DIA‑1.0 and 5 ES and ultimately prevented the facilitation of the
discharges. Lastly, we demonstrated that seizure suppression is intensified when cortical ES is performed after DIA administration. Our
data supported the hypothesis that both BDZ‑GABAA receptor activity along with cerebellar output comprise the potential mechanisms
underlying the peculiar effects of deep brain stimulation in the cerebellum on seizures.
