title: More than at the neuromuscular synapse: actions of botulinum neurotoxin A in the central nervous system.
abstract: Botulinum neurotoxin type A (BoNT/A) is a metalloprotease that produces a sustained yet transitory blockade of transmitter release from peripheral nerve terminals. Local delivery of this neurotoxin is successfully employed in clinical practice to reduce muscle hyperactivity such as in spasticity and dystonia, and to relieve pain with long-lasting therapeutic effects. However, not all BoNT/A effects can be explained by an action at peripheral nerve terminals. Indeed, it appears that BoNT/A is endowed with trafficking properties similar to the parental tetanus neurotoxin and thus be able to directly affect the CNS. In this review, we present and discuss novel compelling evidence for a direct central effect of BoNT/A in both dorsal and ventral horns of the animal and human spinal cord after peripheral injection of the neurotoxin, with important consequences on pain and motor control. This new knowledge is expected to radically change the approach to the use of BoNT/A in the future. As BoNT/A central action appears to also contribute to functional improvement, for instance in human spastic gait, the challenge will be to develop new subtypes or BoNT derivatives with deliberate, cell-specific central effects in order to fully exploit the spectrum of BoNT/A therapeutic activity.
authors.affiliation: S.C. Neurologia e Neurofisiologia Clinica, Dipartimento di Scienze Neurologiche e Neurosensoriali, Azienda Ospedaliera Universitaria Senese, Viale Bracci, Siena, Italy mazzocchio@unisi.it.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Mazzocchio
authors.affiliation: CNR Neuroscience Institute, Pisa, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Caleo
mesh_terms: D000818:Animals; D019274:Botulinum Toxins, Type A / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects; D002491:Central Nervous System Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009465:Neuromuscular Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism; D010146:Pain / Q000188:drug therapy / Q000378:metabolism; D010525:Peripheral Nerves / Q000187:drug effects; D066148:Spinal Cord Dorsal Horn / Q000187:drug effects / Q000502:physiology; D066151:Spinal Cord Ventral Horn / Q000187:drug effects / Q000502:physiology; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism
chemical_list: D002491:Central Nervous System Agents; D009465:Neuromuscular Agents; D019274:Botulinum Toxins, Type A
keywords: SNAP-25; axonal transport; motoneurons; neurotransmitter release; pain; recurrent inhibition; transcytosis