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 convectionenhanced 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.

Proconvulsant actions of intrahippocampal botulinum neurotoxin B in the rat

“…However, we cannot exclude the possibility that the evolution of epileptic activity following intrahippocampal BoNT/B requires an epileptogenic process and is not simply the result of the pharmacological actions of the toxin. In the present study, we did not assess seizure threshold at time points greater than 2 weeks following BoNT/B so we do not know if heightened seizure susceptibility would continue for the prolonged duration (two or more months) seen in our previous study (Gasior et al, 2013). In addition, we do not know if the seizure activity would outlast the functional effects of the toxin and thus represent a true epileptogenic action.…”

“…Focal application of BoNTs has potential utility in the treatment of intractable localization-related epilepsy (Costantin et al, 2005; Antonucci et al, 2009; Gasior et al, 2013). This novel treatment strategy could provide an alternative to resective surgery (Rogawski, 2009).…”

“…We recently reported that intra-amygdala infusion of BoNT/B in fully amygdala-kindled rats causes a prolonged elevation of the after discharge threshold and a reduction of the after discharge duration (Gasior et al, 2013). We concluded that BoNT/B can cause long-lasting inhibition of amygdala excitability.…”

“…This suggests that unlike BoNT/A and BoNT/E, BoNT/B may not be selective for glutamatergic neurons. Nevertheless, there is evidence that BoNT/B can inhibit seizure activity when locally delivered into the amygdala (Gasior et al, 2013). In the present study, we sought to assess the actions of BoNT/B on seizure susceptibility following intrahippocampal delivery.…”

Novel Central Nervous System Drug Delivery Systems

“…In another preclinical study carried out by Gasior et al . , rats with kindled epilepsy were given botulinum neurotoxins A and B, which are anticonvulsants, into the amygdala using CED. Rats that were given neurotoxins showed attenuated seizure activity, gained weight, and behaved normally when compared to kindled rats that did not receive botulinum toxin via CED .…”