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. Here 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-min period by convection enhanced delivery (CED). Electrographic (EEG) and behavioral kindling measures were determined at selected times during the 3 to 64 day period after the infusion. BoNT/B was associated with a dose-dependent elevation in afterdischarge threshold and duration and a reduction in the seizure stage and duration of behavioral seizures that lasted for up to 50 days following 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 for the first time demonstrates 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.
- The American Society for Pharmacology and Experimental Therapeutics