Long-Lasting Attenuation of Amygdala-Kindled Seizures after Convection-Enhanced Delivery of Botulinum Neurotoxins A and B into the Amygdala in Rats

Abstract

Botulinum neurotoxins (BoNTs) are well recognized to cause potent, selective, and long-lasting neuroparalytic actions by blocking cholinergic neurotransmission to muscles and glands. There is evidence that BoNT isoforms can also inhibit neurotransmission in the brain. In this study, we examined whether locally delivered BoNT/A and BoNT/B can attenuate kindling measures in amygdala-kindled rats. Male rats were implanted with a combination infusion cannula-stimulating electrode assembly into the right basolateral amygdala. Fully kindled animals received a single infusion of vehicle or BoNT/A or BoNT/B at doses of 1, 3.2, or 10 ng over a 20-minute period by convection-enhanced delivery. Electrographic (EEG) and behavioral kindling measures were determined at selected times during the 3- to 64-day period after the infusion. BoNT/B produced a dose-dependent elevation in after-discharge threshold and duration and a reduction in the seizure stage and duration of behavioral seizures that lasted for up to 50 days after infusion. BoNT/A had similar effects on EEG measures; behavioral seizure measures were also reduced, but the effect did not reach statistical significance. The effects of both toxins on EEG and behavioral measures progressively resolved during the latter half of the observation period. Animals gained weight normally, maintained normal body temperature, and did not show altered behavior. This study demonstrates for the first time that locally delivered BoNTs can produce prolonged inhibition of brain excitability, indicating that they could be useful for the treatment of brain disorders, including epilepsy, that would benefit from long-lasting suppression of neurotransmission within a circumscribed brain region.