Botulinum Toxin: Mechanisms of Action

Abstract

Botulinum toxin (BT) has been perceived as a lethal threat for many centuries. In the early 1980s, this perception completely changed when BT’s therapeutic potential suddenly became apparent. We wish to give an overview over BT’s mechanisms of action relevant for understanding its therapeutic use. BT’s molecular mode of action includes extracellular binding to glycoprotein 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 blood-brain 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 by blockade of substance P, glutamate and calcitonin gene-related peptide.

Denervation suppresses gastric tumorigenesis

“…Botox enters into the axon terminal through vesicle internalization and cleaves synaptosomal-associated protein 25, leading to impaired exocytosis of neurotransmitters, including acetylcholine (24). Botox was injected subserosally along the greater curvature in the anterior side of the stomach (Fig.…”

Botulinum Neurotoxin: The Ugly Duckling

“…Neurotoxin action on the central nervous system (reflex inhibition) is not immediate since toxins do not cross the blood-brain barrier and are neutralized during retrograde axonal transport [7]. Apart from inhibition of acetylcholine release, it has been shown that botulinum neurotoxin also inhibits secretion of other neurotransmitters such as substance P, glutamate and noradrenaline.…”

“…Nevertheless, spinal cord neurons still receive excitatory signals from other sources, so that the innervated muscles may still twitch, though in an uncontrolled fashion which is frequently painful and prevents purposeful movements [44,45,46]. However, if a physiotherapeutic rehabilitation program is implemented immediately after stabilization, the patient may regain a substantial part of his/her previous abilities [7, 47, 48]. Therefore, a caring team should immediately intervene in the hope to prevent muscle rigidity and shortening [49].…”

“…Although the clinical effects of botulinum neurotoxins have been long known [7, 60, 61], it was not until 1985 that scientists used this substance off label to treat muscular disorders [62,63,64]. In 1989, the Food and Drug Administration of the USA granted American doctors the license to use these toxins for the treatment of strabismus and blepharospasm.…”

“…There are more than 10,000 interesting articles and the relevant papers published every week all over the world contain much more information than the average human brain can assimilate. Even the most recent part of the literature dealing with the impact and safety of botulinum toxin in clinical applications is rather enormous, including short [4], extended [5], classical [6] and new [7,8,9,10,11] articles. An additional difficulty originates from the fact that the research field is spread over a wide range of various and frequently not very much related disciplines such as biochemistry, bioterrorism, chemical synthesis, cosmetics, ecology, medicine, microbiology, neurology.…”