Botulinum toxin: mechanisms of action

Abstract

-This review describes therapeutically relevant mechanisms of action of botulinum toxin (BT). B T 's molecular mode of action includes extracellular binding to glycoproteine structures on cholinergic nerve terminals and intracellular blockade of the acetylcholine secretion. BT affects the spinal stretch reflex by blockade of intrafusal muscle fibres with consecutive reduction of Ia/II afferent signals and muscle tone without affecting muscle strength (reflex inhibition). This mechanism allows for antidystonic effects not only caused by target muscle paresis. BT also blocks efferent autonomic fibres to smooth muscles and to exocrine glands. Direct central nervous system effects are not observed, since BT does not cross the bloodbrain-barrier and since it is inactivated during its retrograde axonal transport. Indirect central nervous system effects include reflex inhibition, normalisation of reciprocal inhibition, intracortical inhibition and somatosensory evoked potentials. Reduction of formalin-induced pain suggests direct analgesic BT effects possibly mediated through blockade of substance P, glutamate and calcitonin gene related peptide.KEY WORDS: botulinum toxin, mechanisms of action, acetylcholine, muscle spindles, stretch reflex, smooth muscles, exocrine glands, retrograde axonal transport, blood-brain-barrier, substance P.Toxina botulínica: mecanismos de ação RESUMO -O propósito deste artigo é uma revisão dos mecanismos de ação da toxina botulínica (TB) relevantes para a compreensão do seu uso terapêutico. A ação da TB a nível molecular consiste na sua ligação extracelular a estruturas glicoprotéicas em terminais nervosos colinérgicos e no bloqueio intracelular da secreção de acetilcolina. A TB interfere no reflexo espinal de estiramento através do bloqueio de fibras musculares intrafusais causando redução da sinalização aferente veiculada por fibras Ia e II e do tono muscular. Portanto, o efeito da TB pode estar relacionado não somente à paresia muscular mas também à inibição reflexa espinal. A TB promove ainda o bloqueio de fibras autonômicas para músculos lisos e glândulas exócrinas. Apesar de ocorrer alguma difusão sistêmica após a aplicação intramuscular a TB não atinge o sistema nervoso central (SNC) devido ao seu peso molecular (não atravessa a barreira hematoencefálica) e à lentidão do seu transporte axonal retrógrado que permite a sua inativação. Os efeitos indiretos sobre o SNC são: inibição reflexa, reversão das alterações da inibição recíproca, da inibição intracortical e de potenciais evocados somatosensoriais. A redução da dor induzida por formalina sugere que a TB tenha efeito analgésico direto possivelmente mediado por bloqueio da substância P, do glutamato e do peptídeo relacionado ao gene da calcitonina.PA L AV R A S -C H AVE: toxina botulínica, mecanismos de ação, acetilcolina, fusos musculares; reflexo de estiramento, músculos lisos, glândulas exócrinas, transporte axonal retrógrado, barreira hematoencefálica, substância P.

Proteomic changes in rat thyroarytenoid muscle induced by botulinum neurotoxin injection

“…Botulinum neurotoxin (BoNT) is a potent agent that induces muscle paresis or paralysis by entering neurons and disrupting acetylcholine (ACh) release into the neuromuscular junction [1,2]. Seven BoNT serotypes are known to exist (A-G), all of which are produced by strains of the bacterium Clostridium botulinum.…”

Achalasia: What is the best treatment?

“…The toxins specifically bind the presynaptic membrane and enter the cystol of the nerve terminal where they cleave different proteins involved in neuroexocytosis. 28,29 Botulinum toxin-A which is used for the treatment of achalasia cleaves the SNAP-25 molecule of the presynaptic membrane, thus blocking acetylcholine (ACH) release. 29,30 In the early nineties, Pasrich and colleagues evaluated the usefulness of intrasphincteric injection of BTox in achalasia patients.…”

“…28,29 Botulinum toxin-A which is used for the treatment of achalasia cleaves the SNAP-25 molecule of the presynaptic membrane, thus blocking acetylcholine (ACH) release. 29,30 In the early nineties, Pasrich and colleagues evaluated the usefulness of intrasphincteric injection of BTox in achalasia patients. 31,32 The rationale was that the selective loss of inhibitory nerves in achalasia upset the excitatory cholinergic influences on the LES.…”

“…31,32 The rationale was that the selective loss of inhibitory nerves in achalasia upset the excitatory cholinergic influences on the LES. 29 Thus by blocking the release of ACH, locally injected BTox might reduce the LES pressure and improve passive esophageal emptying. 29,33 The toxin is injected through a standard schelerotherapy needle during an upper endoscopy performed under conscious sedation.…”

“…29 Thus by blocking the release of ACH, locally injected BTox might reduce the LES pressure and improve passive esophageal emptying. 29,33 The toxin is injected through a standard schelerotherapy needle during an upper endoscopy performed under conscious sedation. 34 Usually, 80 to 100 units of BTox-A are injected in each quadrant of the LES in 0.5 to 1ml aliquots.…”