Beyond neuromuscular activity: botulinum toxin type A exerts direct central action on spinal control of movement

Scientific paper - Original scientific paper

• Author: Petra Šoštarić
• Author: Magdalena Matić
• Author: Dalia Nemanić
• Author: Željka Lučev Vasić
• Author: Mario Cifrek
• Author: Marco Pirazzini
• Author: Ivica Matak
• Author's institution: University of Zagreb; School of Medicine; (Croatian Institiute for Brain Research)
• Author's institution: University of Zagreb; School of Medicine; (Department of Pharmacology)
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Basic Medical Sciences; Pharmacology
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Basic Medical Sciences; Neuroscience

Abstract (english)

Overt muscle activity and impaired spinal locomotor control hampering coordinated movement is a hallmark of spasticity and movement disorders like dystonia. While botulinum toxin A (BoNT-A) standard therapy alleviates mentioned symptoms presumably due to its peripheral neuromuscular actions alone, the aim of present study was to examine for the first time the toxin's trans-synaptic activity within central circuits that govern the skilled movement. The rat hindlimb motor pools were targeted by BoNT-A intrasciatic bilateral injection (2 U per nerve), while its trans-synaptic action on premotor inputs was blocked by intrathecal BoNT-A-neutralising antitoxin (5 i.u.). Effects of BoNT-A on coordinated and high intensity motor tasks (rotarod, beamwalk swimming), and localised muscle weakness (digit abduction, gait ability) were followed until their substantial recovery by day 56 post BoNT-A. Later, (day 62-77) the BoNT-A effects were examined in unilateral calf muscle spasm evoked by tetanus toxin (TeNT, 1.5 ng). In comparison to peripheral effect alone, combined peripheral and central trans-synaptic BoNT-A action induced a more prominent and longer impairment of different motor tasks, as well as the localised muscle weakness. After near-complete recovery of motor functions, the BoNT-A maintained the ability to reduce the experimental calf spasm evoked by tetanus toxin (TeNT 1.5 ng, day 62) without altering the monosynaptic reflex excitability. These results indicate that, in addition to muscle terminals, BoNT-A-mediated control of hyperactive muscle activity in movement disorders and spasticity may involve the spinal premotor inputs and central circuits participating in the skilled locomotor performance.

• Keywords (english): Animals; Botulinum Toxins, Type A / pharmacology; Movement; Movement Disorders; Muscle Weakness; Neuromuscular Agents / pharmacology; Rats; Tetanus Toxin
• Language: english
• Publication type: Scientific paper - Original scientific paper
• Publication status: Published
• Peer review: Peer review
• Publication version: Accepted version
• Journal title: European Journal of Pharmacology
• Numbering: vol. 962, 176242
• p-ISSN: 0014-2999
• DOI: https://doi.org/10.1016/j.ejphar.2023.176242
• URN:NBN: urn:nbn:hr:105:410200
• Publication: 2024-01-05
• Project: Number: UIP-2019-04-8277; Title (croatian): Motorički učinci klostridijskih neurotoksina u središnjem živčanom sustavu; Title (english): Motor effects of clostridial neurotoxins in central nervous system; Acronym: MEFCLO; Leader: Ivica Matak; Jurisdiction: Croatia; Funding stream: UIP
• Document URL: https://linkinghub.elsevier.com/retrieve/pii/S0014299923007562
• Type of resource: Text
• Access conditions: Embargoed access; Embargo expiration date: 2025-01-06
• Created on: 2024-04-05 08:34:36