Botulinum Neurotoxins beyond Neurons: Interplay with Glial Cells

Abstract

In recent years, numerous studies have highlighted the significant use of botulinum neurotoxins (BoNTs) in the human therapy of various motor and autonomic disorders. The therapeutic action is exerted with the selective cleavage of specific sites of the SNARE’s protein complex, which plays a key role in the vesicular neuroexocytosis which is responsible for neural transmission. The primary target of the BoNTs’ action is the peripheral neuromuscular junction (NMJ), where, by blocking cholinergic neurons releasing acetylcholine (ACh), they interfere with neural transmission. A great deal of experimental evidence has demonstrated that BoNTs are also effective in blocking the release of other neurotransmitters or neuromodulators, such as glutamate, substance-P, and CGRP, and they can interfere with the function of glial cells, both at the peripheral and central level. The purpose of this review is to provide an update on the available experimental data from animal models that suggest or confirm the direct interactions between BoNTs and glial cells. From the data collected, it appears evident that, through mechanisms that are not yet fully understood, BoNTs can block the activation of spinal glial cells and their subsequent release of pro-inflammatory factors. BoNTs are also able to promote peripheral regeneration processes after nerve injury by stimulating the proliferation of Schwann cells. The data will be discussed in consideration of the possible therapeutic implications of the use of BoNTs on those pathological conditions where the contribution of glial cell activation is fundamental, such as in peripheral and central neuropathies.

Improvement of neurogenic urinary dysfunctions in female rats treated with an injection of botulinum toxin A at the epicenter of the spinal cord injured site

“…It is important to note that the probability of administering BoNT/A immediately after an SCI in a person is complicated at the current time. However, the objective of this study was to evaluate, from the basic research perspective, whether an acute injection of BoNT/A at the epicenter of a SCI region can reduce the high neurotoxicity environment occurring just after the injury, 2,3,5,16,28 with the objective of improving spinal cell survival and the physiology of the lower urinary tract in female rats with severe SCI. Potential translational use in neurology is plausible due to the current therapeutic application of BoNT/A to treat different neurological conditions of the central nervous system in humans 27 …”

“…An important weakness of our study is the lack of a histological component for either the spinal cord or the lower urinary tract, however, it is possible to suggest that a compression SCI, whether with a spinal saline solution injection or not (Figure 5), may create an increase in the release of all types of neurotransmitters that require the SNARE complex for vesicle release, including both excitatory and inhibitory. 5 This condition may trigger glutamate-induced neurotoxicity affecting motoneurons, sensory neurons, and inter-neurons, but also promote and damage to oligodendrocytes and oligodendrocyteprecursor cells (OPC). 3,28 Under these conditions, reduced opportunities for spinal cell survival may promote the loss of sensory responses, impaired locomotion, altered voiding behavior, and declined physiology of the lower urinary tract (Figure 5).…”

“…In this sense, the action mechanism for botulinum toxin type A (BoNT/A) involves the hydrolysis of the soluble N-ethylmaleimide sensitive factor attachment protein (SNARE) complex 4 to reduce the release of acetylcholine and other neurotransmitters in skeletal muscle and the central nervous system. 5 Furthermore, the use of BoNT/A as intradetrusor injections for the treatment of neurogenic bladder after SCI has been clinically established, 6 while the intrathecal application of BoNT/A can improve neurogenic overactivity of the detrusor in SCI rats. 7 Other studies have shown that a spinal injection of BoNT/A shortly after inducing a severe SCI at the thoracic level in mice, can improve locomotor function, axon reconnection, and further prevent spinal cell death.…”

Neurotoxins Acting at Synaptic Sites: A Brief Review on Mechanisms and Clinical Applications

“…(3) SNAREs, the target molecules of BoNT and TeNT, are expressed in the neuronal cells of almost all vertebrate phylla [ 30 , 31 , 32 ]. However, the neuroselectivity of BoNT is not absolute and it can act on the non-neuronal cells to exert some functions, such as glial cells [ 33 ].…”

Safety of Onabotulinumtoxin A in Chronic Migraine: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

“…In addition to the inhibition of neurotransmitter release from primary sensory neurons [ 31 ], mechanisms explaining its analgesic activity may include the reduction in mechanical hypersensitivity of sensitized C-units via interference with the expression of high threshold mechanosensitive ion channels [ 32 ]. In particular, there is a great deal of evidence in favor of the blockade of the neuronal release of neuromediators, such as acetylcholine in the peripheral neuromuscular junction, but also substance P and glutamate [ 33 ]. A Cochrane systematic review completed in 2018 highlighted several factors that downgrade the quality of the evidence for the efficacy of botulinum toxins in comparison with placebo or active treatment for the prevention or frequency reduction in chronic or episodic migraine: the lack of long-term data, the small size of trials with high risk of bias and unexplained heterogeneity [ 34 ].…”