RESUMEN
Experimental studies suggest that the delivery of antiepileptic agents into the seizure focus might be of potential utility for the treatment of focal-onset epilepsies. Botulinum neurotoxin E (BoNT/E) causes a prolonged inhibition of neurotransmitter release after its specific cleavage of the synaptic protein synaptosomal-associated protein of 25 kDa (SNAP-25). Here, we show that BoNT/E injected into the rat hippocampus inhibits glutamate release and blocks spike activity of pyramidal neurons. BoNT/E effects persist for at least 3 weeks, as determined by immunodetection of cleaved SNAP-25 and loss of intact SNAP-25. The delivery of BoNT/E to the rat hippocampus dramatically reduces both focal and generalized kainic acid-induced seizures as documented by behavioral and electrographic analysis. BoNT/E treatment also prevents neuronal loss and long-term cognitive deficits associated with kainic acid seizures. Moreover, BoNT/E-injected rats require 50% more electrical stimulations to reach stage 5 of kindling, thus indicating a delayed epileptogenesis. We conclude that BoNT/E delivery to the hippocampus is both antiictal and antiepileptogenic in experimental models of epilepsy.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Toxinas Botulínicas/uso terapéutico , Epilepsias Parciales/tratamiento farmacológico , Epilepsia Generalizada/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Animales , Anticonvulsivantes/administración & dosificación , Toxinas Botulínicas/administración & dosificación , Muerte Celular/efectos de los fármacos , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/prevención & control , Convulsivantes/toxicidad , Evaluación Preclínica de Medicamentos , Estimulación Eléctrica , Electroencefalografía , Epilepsias Parciales/fisiopatología , Epilepsia Generalizada/inducido químicamente , Epilepsia Generalizada/complicaciones , Epilepsia Generalizada/fisiopatología , Ácido Glutámico/metabolismo , Hipocampo/fisiopatología , Inyecciones Intralesiones , Ácido Kaínico/toxicidad , Excitación Neurológica/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Células Piramidales/efectos de los fármacos , Células Piramidales/patología , Células Piramidales/fisiología , Distribución Aleatoria , Ratas , Ratas Long-Evans , Técnicas Estereotáxicas , Proteína 25 Asociada a SinaptosomasRESUMEN
In humans, botulinum neurotoxin (BoNT) serotype A (BoNT/A) is a useful therapeutic tool, but different BoNT serotypes may be useful when a specific immune resistance related to BoNT/A is proved. BoNT serotype F (BoNT/F) was injected into human muscles but its effects are shorter compared to BoNT/A, whereas BoNT serotype B (BoNT/B) is effective in humans only if injected at very high doses. BoNT serotype C (BoNT/C) has a general profile of action similar to BoNT/A. Nevertheless, a comparison between these different BoNTs in human has not yet been reported. To establish the general profile of these different BoNTs in humans and the spread in near and untreated muscles we conducted an electrophysiological evaluation in 12 healthy volunteers by injecting BoNT/A (BOTOX 15MU), BoNT/B (NeuroBloc 1500MU), BoNT/F (15MU), BoNT/C (15MU) and a saline solution (placebo) in the abductor digiti minimi muscle (ADM) in a double-blind manner. The compound muscle action potential (CMAP) amplitude variation, before and at 2, 4, 6 and 8 weeks after the injections, was evaluated in the ADM, the fourth dorsal interosseus, the first dorsal interosseus and the abductor pollicis brevis APB. We detected an earlier recovery for BoNT/F when compared to the other BoNTs. No significant differences in the local or distant BoNT spread was observed among the different serotypes. We conclude that in humans, BoNT/B and BoNT/C have a general profile similar to BoNT/A and as such these serotypes could be alternative therapies to BoNT/A. BoNT/F might be useful when only a short duration of neuromuscular blockade is required.