title: Spinal Central Effects of Peripherally Applied Botulinum Neurotoxin A in Comparison between Its Subtypes A1 and A2.
abstract: Because of its unique ability to exert long-lasting synaptic transmission blockade, botulinum neurotoxin A (BoNT/A) is used to treat a wide variety of disorders involving peripheral nerve terminal hyperexcitability. However, it has been a matter of debate whether this toxin has central or peripheral sites of action. We employed a rat model in which BoNT/A1 or BoNT/A2 was unilaterally injected into the gastrocnemius muscle. On time-course measurements of compound muscle action potential (CMAP) amplitudes after injection of BoNT/A1 or BoNT/A2 at doses ranging from 1.7 to 13.6 U, CMAP amplitude for the ipsilateral hind leg was markedly decreased on the first day, and this muscle flaccidity persisted up to the 14th day. Of note, both BoNT/A1 and BoNT/A2 administrations also resulted in decreased CMAP amplitudes for the contralateral leg in a dose-dependent manner ranging from 1.7 to 13.6 U, and this muscle flaccidity increased until the fourth day and then slowly recovered. Immunohistochemical results revealed that BoNT/A-cleaved synaptosomal-associated protein of 25 kDa (SNAP-25) appeared in the bilateral ventral and dorsal horns 4 days after injection of BoNT/A1 (10 U) or BoNT/A2 (10 U), although there seemed to be a wider spread of BoNT/A-cleaved SNAP-25 associated with BoNT/A1 than BoNT/A2 in the contralateral spinal cord. This suggests that the catalytically active BoNT/A1 and BoNT/A2 were axonally transported via peripheral motor and sensory nerves to the spinal cord, where they spread through a transcytosis (cell-to-cell trafficking) mechanism. Our results provide evidence for the central effects of intramuscularly administered BoNT/A1 and BoNT/A2 in the spinal cord, and a new insight into the clinical effects of peripheral BoNT/A applications.
authors.affiliation: Department of Clinical Neuroscience, Institute of Health Biosciences, Graduate School of Medical Sciences, University of Tokushima , Tokushima , Japan ; Department of Motor Neuroscience and Neurotherapeutics, Institute of Health Biosciences, Graduate School of Medical Sciences, University of Tokushima , Tokushima , Japan.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Koizumi
authors.affiliation: Department of Motor Neuroscience and Neurotherapeutics, Institute of Health Biosciences, Graduate School of Medical Sciences, University of Tokushima , Tokushima , Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Goto
authors.affiliation: Department of Motor Neuroscience and Neurotherapeutics, Institute of Health Biosciences, Graduate School of Medical Sciences, University of Tokushima , Tokushima , Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Okita
authors.affiliation: Department of Motor Neuroscience and Neurotherapeutics, Institute of Health Biosciences, Graduate School of Medical Sciences, University of Tokushima , Tokushima , Japan.
authors.forename: Ryoma
authors.initials: R
authors.lastname: Morigaki
authors.affiliation: Research Division for Life Science, Kumamoto Health Science University , Kumamoto , Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Akaike
authors.affiliation: The Chemo-Sero-Therapeutic Research Institute (KAKETSUKEN) , Kumamoto , Japan ; Graduate School of Medicine, Osaka University , Osaka , Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Torii
authors.affiliation: The Chemo-Sero-Therapeutic Research Institute (KAKETSUKEN) , Kumamoto , Japan.
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Harakawa
authors.affiliation: The Chemo-Sero-Therapeutic Research Institute (KAKETSUKEN) , Kumamoto , Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ginnaga
authors.affiliation: Department of Clinical Neuroscience, Institute of Health Biosciences, Graduate School of Medical Sciences, University of Tokushima , Tokushima , Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kaji
keywords: SNAP-25; axonal transport; botulinum neurotoxin; central effects; spinal cord