Antiepileptic effects of botulinum neurotoxin E.
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.
Costantin
Laura
L
Scuola Normale Superiore, Consiglio Nazionale delle Ricerche, 56100 Pisa, Italy.
Bozzi
Yuri
Y
Richichi
Cristina
C
Viegi
Alessandro
A
Antonucci
Flavia
F
Funicello
Marcella
M
Gobbi
Marco
M
Mennini
Tiziana
T
Rossetto
Ornella
O
Montecucco
Cesare
C
Maffei
Lamberto
L
Vezzani
Annamaria
A
Caleo
Matteo
M
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000627:therapeutic use*; D001905:Botulinum Toxins / Q000008:administration & dosage / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control; D003292:Convulsants / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D004558:Electric Stimulation; D004569:Electroencephalography; D004828:Epilepsies, Partial / Q000188:drug therapy* / Q000503:physiopathology; D004829:Epilepsy, Generalized / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D015552:Injections, Intralesional; D007608:Kainic Acid / Q000633:toxicity; D007696:Kindling, Neurologic / Q000187:drug effects; D018782:Maze Learning / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D020318:Rats, Long-Evans; D013238:Stereotaxic Techniques; D050825:Synaptosomal-Associated Protein 25
D000927:Anticonvulsants; D003292:Convulsants; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C494210:Snap25 protein, rat; D050825:Synaptosomal-Associated Protein 25; D018698:Glutamic Acid; D001905:Botulinum Toxins; D007608:Kainic Acid; C096326:botulinum toxin type E
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