Peripheral and central effects of botulinum toxin type A in the rat motor nervous system

doctoral thesis

• Title (croatian): Perfierni i središnji učinci botulinum toksina tipa A u motoričkom živčanom sustavu štakora
• Author: Petra Šoštarić Mužić
• Mentor: Ivica Matak (mentor)
• Committee member: Melita Šalković-Petrišić (predsjednik povjerenstva)
• Committee member: Robert Likić (član povjerenstva)
• Committee member: Mario Habek (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; (Department of Pharmacology); Zagreb
• Defense date and country: 2024-09-24, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Basic Medical Sciences; Pharmacology
• Universal decimal classification (UDC): 615 - Pharmacology. Therapeutics. Toxicology

Abstract

Introduction: Intramuscular administration of botulinum toxin type A (BoNT-A) is used to treat
hyperkinetic disorders such as dystonia and spasticity. Our research suggests that BoNT-A, in
addition to its primary peripheral action, also exerts effects on the central nervous system, which
could explain its prolonged effect.
Methods: Studies were conducted on Wistar Han rats and primary cultures of rat cerebellar
neurons. Peripheral and central effects of BoNT-A were assessed using motor tests,
electromyography, intrathecal administration of antitoxin, and latrotoxin (LTX). The protease
activity of the toxin was analyzed using the Western blot method.
Results: The antispastic effect of BoNT-A was dose-dependent in the later phase, with higher
doses preventing spasm and improving motor performance. Intrathecal antitoxin accelerated
the recovery of muscle weakness. BoNT-A reduced muscle tone induced by tetanus toxin
(TeNT) without affecting the monosynaptic reflex. Central transsynaptic activity contributed to
the late antispastic effect, with the presence of BoNT-A enzymatic activity in muscles and the
spinal cord. LTX accelerated the recovery of neuroparalysis and reduced the late antispastic
effects of BoNT-A.
Conclusion: Peripheral and central activities of BoNT-A act synergistically, with the later
central effect dependent on the reduction of intense peripheral action. This is also confirmed by
the initial dominance of the flaccid neuroparalytic effect of TeNT on peripheral NMJ, in relation
to the central disinhibitory effect and the occurrence of spasms in cephalic tetanus.

Abstract (croatian)

Uvod: Intramuskularna primjena botulinum toksina tipa A (BoNT-A) koristi se za liječenje
hiperkinetičkih poremećaja poput distonije i spastičnosti. Naša istraživanja upućuju da BoNTA,
osim primarnog perifernog djelovanja, ostvaruje i učinke na središnji živčani sustav, što bi
moglo objasniti njegov produljeni učinak.
Metode: Istraživanja su provedena na štakorima soja Wistar Han i primarnoj kulturi neurona
malog mozga štakora. Periferni i središnji učinci BoNT-A procijenjeni su motoričkim
testovima, elektromiografijom, intratekalnom primjenom antitoksina i latrotoxinom (LTX).
Proteazna aktivnost toksina analizirana je Western blot metodom.
Rezultati: Antispastični učinak BoNT-A pokazao se ovisan o dozi u kasnijoj fazi, te su veće
doze spriječile spazam i poboljšale motoričke izvedbe. Intratekalni antitoksin ubrzao je
oporavak mišićne slabosti. BoNT-A je smanjio mišićni tonus induciran tetanus toksinom
(TeNT), bez utjecaja na monosinaptički refleks. Središnja transsinaptička aktivnost
pridonijela je kasnom antispastičkom učinku, uz prisutnost enzimske aktivnosti BoNT-A u
mišićima i leđnoj moždini. LTX je ubrzao oporavak neuroparalize i smanjio kasne
antispastične učinke BoNT-A.
Zaključci: Periferna i središnja aktivnost BoNT-A djeluju sinergistički, a kasniji središnji
učinak ovisi o smanjenju intenzivnog perifernog djelovanja, što također potvrđuje i početna
dominacija perifernog mlohavog neuroparalitičkog učinka TeNT u odnosu na središnji
dezinhibicijski učinak i nastanak spazma kod cefaličkog tetanusa.

• Keywords: Botulinum toxin; neuromuscular disorders; central motor regions; SNAP-25
• Keywords (english): Botulinum toksin; neuromuskularni poremećaji; središnja motorička regija; SNAP-25
• Language: english
• URN:NBN: urn:nbn:hr:105:216406
• Project: Number: UIP-2019-04-8277; Title: Motorički učinci klostridijskih neurotoksina u središnjem živčanom sustavu; Title: Motor effects of clostridial neurotoxins in central nervous system; Acronym: MEFCLO; Leader: Ivica Matak; Jurisdiction: Croatia; Funder: Hrvatska zaklada za znanost; Funding stream: Installation Research Projects
• Study programme: Title: Biomedicine and Health Sciences; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje biomedicine i zdravstvo (doktor/doktorica znanosti, područje biomedicine i zdravstvo)
• Type of resource: Text
• Extent: 152 str.
• File origin: Born digital
• Access conditions: Open access
• Created on: 2024-10-01 09:06:54