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Luvisetto, S. Botulinum Neurotoxins beyond Neurons. Encyclopedia. Available online: https://encyclopedia.pub/entry/31861 (accessed on 17 June 2024).
Luvisetto S. Botulinum Neurotoxins beyond Neurons. Encyclopedia. Available at: https://encyclopedia.pub/entry/31861. Accessed June 17, 2024.
Luvisetto, Siro. "Botulinum Neurotoxins beyond Neurons" Encyclopedia, https://encyclopedia.pub/entry/31861 (accessed June 17, 2024).
Luvisetto, S. (2022, October 29). Botulinum Neurotoxins beyond Neurons. In Encyclopedia. https://encyclopedia.pub/entry/31861
Luvisetto, Siro. "Botulinum Neurotoxins beyond Neurons." Encyclopedia. Web. 29 October, 2022.
Botulinum Neurotoxins beyond Neurons
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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.

botulinum glia peripheral nervous system central nervous system

1. Introduction

Botulinum neurotoxins (BoNTs) are produced by clostridium botulinum in the subtypes of seven serotypes, named from A to G [1][2], in addition to the recently characterized serotype X, and a certain number of chimeric neurotoxins [3][4]. The different types of BoNTs will be reported using the acronym BoNT/Y, where Y stands for serotypes A to X. If the subtype is not specified, then the acronym BoNTs will be used in a generic manner; where necessary, the commercial name will be used.
All BoNTs have similar structure, consisting of two chains (L-chain, 50 kDa, and H-chain, 100 kDa) that are linked by a single disulfide bridge, with the L-chain being the catalytic domain and the H-chain being the receptor-binding and translocation domain [5]. BoNTs act as powerful blockers of synaptic vesicle fusion at the peripheral neuromuscular junction (NMJ), where they block the release of acetylcholine (ACh). Inhibition of vesicular ACh release is achieved via the cleavage of SNARE proteins, which constitute the protein complex essential for the vesicular release evoked by the action potential at the NMJ. Different BoNT serotypes cleave different SNARE proteins: BoNT/B, D, F, G, and X cleave VAMP at single and different sites; BoNT/C cleaves both syntaxin and SNAP-25, whereas BoNT/A and E cleave SNAP-25 at different sites [6].
In recent years, many basic scientific studies, and a great deal of clinical evidence, demonstrated that, apart from the canonical anticholinergic effects at the NMJ, BoNTs are effective in inhibiting the ACh release at sites other than the NMJ, in addition to inhibiting the release of neurotransmitters other than ACh [7]. Currently, there is no doubt that BoNTs can block the release of excitatory neurotransmitters and neuropeptides, such as glutamate, substance-P, and CGRP. These substances, along with certain actions, are strongly involved in pain modulation [8]. Moreover, the finding that BoNTs may block their release provided studies, that were conducted on both animal models and in clinics [9][10], with the impetus to suggest the use of BoNTs as an analgesic for chronic pain conditions that did not respond to other analgesic drugs; therefore, BoNTs have been suggested as a third line analgesic treatment [11].
Many studies have provided evidence for the fact that, apart from the canonical action on neurons, BoNTs may interact also with glial cells, both in the central (CNS) and peripheral (PNS) nervous system. Historically, the first evidence for an interaction between BoNTs and glial cells, came from a series of in vitro studies in cultured astrocytes. Jeftinija et al. [12] demonstrated that the pre-treatment of cultured astrocytes with BoNT/A or BoNT/C decreased both the baseline and the bradykinin-evoked release of glutamate. Verderio et al. [13] demonstrated that BoNT/B and BoNT/F are internalized to culture astrocytes, whereas Araque et al. [14] demonstrated that a microinjection of cultured astrocytes with light chain BoNT/B strongly reduced SNARE protein-dependent glutamate releases. Moreover, it was demonstrated that BoNT/A also reduced the extracellular high K+-induced increase in glutamate that was released from the astrocytes [15]. Other in vitro studies showed that BoNT/A blocked the uridine triphosphate-stimulated ATP release from both cultured astrocytes that were isolated from rat cortexes [16] and Schwann cells (SCs) that were cultured from the sciatic nerve [17]. An additional effect of BoNT/A on cultured SCs was found by Marinelli et al. [18]; in ex vivo experiments, Marinelli et al. [18] found that, after a peripheral injection of BoNT/A in mice that were subjected to a ligature of the sciatic nerve, cleaved SNAP-25 co-localized with astrocytes. This finding has been considered as strong evidence for the possible transcytosis of BoNT/A from neuronal cells to astrocytes. Blocking the release of astrocytic glutamate from BoNT/A may contribute to the reduction of pain.

2. Interactions between BoNTs, Microglia, and Astrocytes

The main evidence for the interactions between BoNTs, astrocytes, and microglia comes from studies on pathological pain in animal models. Pathological pain is characterized by an amplified response to normally harmless stimuli and an amplified response to acute pain. With conditions that cause pathological pain, which results from a dysfunction in the neuronal activity of sensory neurons, the activation of spinal glial cells, microglia, and astrocytes, contributes to the development and maintenance of chronic pain [19][20][21][22]. Glial cells are activated by the neuronal release of neuromediators, including substance P, glutamate, and fractalkine. The activated glia may release other mediators that, via a feedback action on glia and neurons, produce an amplification of the pain signals. Critical mediators that sustain the amplification of pain have been demonstrated to be pro-inflammatory cytokines [23][24]. In a previous review, Rojewska et al. [25] provided a detailed analysis of the evidence that shows a modulatory interaction between BoNT/A and microglia, astrocytes, and neurons under neuropathic pain conditions; they had a particular interest in clarifying how BoNT/A may affect spinal neuron–glial interactions. Starting with the review of Rojewska et al. [25], which gives a comprehensive review on these topics before 2018, the current chapter aims to provide an update on the effects of BoNTs on microglia and/or astrocytes by using the findings of newer studies.
Before analyzing the interaction between BoNTs and microglia in detail, some preliminary fixed points must be addressed. It is well recognized that, under pathophysiological conditions, microglia can act in two different forms: a classic pro-inflammatory phenotype and an alternative anti-inflammatory phenotype [26][27]. As a pro-inflammatory phenotype, microglia release TNF-α, IL-1β, IL-12, IL-23, and pro-inflammatory cytokines, which exacerbate inflammation and tissue injury. In contrast, as an anti-inflammatory phenotype, they release TGF-β, IL-4, IL-10, Il-13, VEGF, BDNF, PDGF, anti-inflammatory cytokines, and growth factors, which suppress inflammation and promote tissue recovery, respectively [20]. Differentiation of microglia towards the pro-inflammatory phenotype often occurs during neuropathic pain, and a transition from a pro-inflammatory to an anti-inflammatory phenotype may represent an innovative therapeutic strategy for relieving neuropathic pain [20][25].
In a neuropathic pain model that involved a chronic constrictive injury (CCI) to the sciatic nerve of a rat, Gui et al. [28] found that the subcutaneous injection of BoNT/A (10–20 U/kg Botox® into the metatarsal surface; three days after CCI) promoted the polarization of a microglial to become an anti-inflammatory phenotype. This finding correlated with the decreased expression of the microglial purinergic P2X7 receptor, along with the increased mechanical withdrawal threshold and thermal withdrawal latency. The reduced expression of P2X7 receptors was also confirmed by in vitro assays performed in a microglial cell line stimulated by lipopolysaccharide (LPS). The exact mechanism by which BoNT/A reduced the expression of P2X7 receptors, and thus, the mechanism that caused the microglia to become an anti-inflammatory phenotype, remains unknown. In another report from the same laboratory [29], the authors confirmed that BoNT/A attenuated CCI-induced neuropathic pain in rats by slowing the release of pro-inflammatory factors from activated microglia, as well as mitigating the expression of SNAP-23. Reducing the SNAP-23 expression in microglia occurs by targeting toll-like receptor 2 (TLR2), and its adaptor protein, MyD88. Toll-like receptors are normally expressed in immune and glial cells, where they regulate innate and adaptive immunity.
It is worth considering that the Botox dose used in references [28][29] appear particularly high. In fact, the dose of 20 U/Kg would represent a dose of 1500 units for a 75 Kg adult, which is exceptionally high (15 vials of 100 U per vial). In light of this, translating the results in references [28][29] from rats to humans seems questionable; however, it should be also noted that doses of BoNT/A in animal models cannot be simply converted into therapeutic doses for humans on the basis of weight ratios, rather, they must be appropriately chosen on the basis of toxicity criteria.
The role of TLR2-mediated neuroinflammation was also evidenced by Chen et al. [30], who demonstrated that the unilateral subcutaneous facial injection of BoNT/A (0.18 U of Lanzhou manufactured BoNT/A into the whisker pad), in a trigeminal neuralgia model induced by CCI of the distal infraorbital nerve in mice, attenuated bilateral trigeminal neuropathic pain behaviors and inhibited the upregulation of microglia in TLR2 expression.
Altogether, these results are confirmed by the findings of Piotroska et al. [31], who revealed that BoNT/A inhibits the expression of pro-inflammatory factors through the modulation of NF-kB, p38, and ERK1/2. Moreover, it interacts with the TLR2/MyD88 signaling pathway, thus resulting in the decreased expression of SNAP-23 in LPS stimulated microglial cells. The results from Piotroska et al. [31] are in line with the results of Hepp et al. [32], who reported that SNAP-23 replaces SNAP-25 in microglia and oligodendrocytes. The effects of BoNT/A on SNAP-23 seem to contrast with the natural molecular targets of BoNT/A in neuronal cells (i.e., SNAP-25); however, when analyzing the structural features of SNAP-25, and its non-neuronal SNAP-23 isoforms, which include the murine mSNAP-23 and human hSNAP-23, Vaydianathan et al. [33] found that BoNT/A was effectively able to cleave the non-neuronal mSNAP-23, but not hSNAP-23. Additionally, BoNT/E was more efficient than BoNT/A in cleaving mSNAP-23. Notably, if BoNT/A was only able to block microglial mSNAP-23, this finding would pose an important limitation, in that it would highlight the difficulty in translating these results to a therapeutic setting for humans, from a pharmacological perspective (i.e., regarding the possibility of interacting BoNT/A with microglia as an alternative method to treat chronic pain). Further research is needed to clarify these points.
In a rat model involving a spinal cord injury (SCI), Yu et al. [34] observed that the combined application of BoNT/A (injection of two doses of 1.25 U of Botox® around the SCI site and forelimb muscle) and minocycline, an antibiotic agent that also has anti-inflammatory properties, synergistically reduced neuropathic pain and apoptosis by inactivating the glial cells. In further detail, the authors found that the combination of BoNT/A and minocycline promotes the expression of the SIRT1 cell signaling pathway, inactivates the NF-κB, P53, and PI3K/AKT signaling pathways, and attenuates an inflammatory response and oxidative stress. These combined effects greatly enhance the therapeutic effect of the two drugs.
Feng et al. [35] showed that a single intraplantar, or the intrathecal, pre-administration of BoNT/A (0.5–1 U/kg of Botox®), in a rat that was subjected to a partial sciatic nerve ligation (PSNL) pain model, significantly prevented PSNL-induced allodynia and thermal hyperalgesia, together with a reduced upregulation of pro-inflammatory cytokines in the spinal cord, dorsal horn, and dorsal root ganglions (DRGs). In order to determine the direct effect of BoNT/A on microglia and/or astrocytes, the authors also performed an in vitro experiment on the LPS-activated glial cells that were treated with BoNT/A (1–2 U/mL of Botox®). They found that BoNT/A significantly inhibited the activation of LPS-activated microglia and reduced the release of TNF-α, IL-6, Il-1β, iNOS, and MIP-1α, without any effect on the astrocytes’ activation. This latter result appears to be in contrast with findings that detect the cl-SNAP25 immunoreaction after treatment with BoNT/A, both in LPS-activated astrocytes [30] and in spinal astrocytes, either in CCI pain models [18][36] or in spinal cord injury models [37]. Interestingly, Finocchiaro et al. [38] reported a strong reduction in the activation of spinal astrocytes, a study which also involved CCI mice that were treated with BoNT/B (intraplantar injection of 7.5 pg/mouse of 150 KDa of purified BoNT/B). Conversely, no difference in the expression of resting and activated microglia were observed in CCI mice treated with BoNT/B. The discrepancies observed in the different BoNTs serotypes may depend on the different targets of the toxins, namely, SNAP-25 for BoNT/A and VAMP-2 for BoNT/B, and the different expressions of these targets in neuronal and non-neuronal cells.
The possible interaction between BoNTs and glial cells was not only analyzed in the context of neuropathic pain, but also in the context of inflammatory pain. In a chronic inflammatory pain model, which involved an intraarticular injection of a solution of complete Freund’s adjuvant (CFA) into the ankle joint cavity of the left leg of a rat, Shi et al. [39] observed that an intraarticular injection of BoNT/A (5–10 U/Kg of Botox® into ankle articular cavity) reduced CFA-induced pain-related behaviors in a dose dependent manner. Similar behavioral effects were achieved by blocking the activation of spinal microglia and reducing TNF-α. Furthermore, the authors found that the effect of BoNT/A on spinal microglial activation was associated with the inhibition of spinal microglial P2X4R–P38MAPK intracellular signaling pathways. Similarly, in a model that involved antigen-induced arthritis of the temporomandibular joint (TMJ) in rats, which was induced by injecting and emulsifying CFA and methylated serum albumin, Munoz-Lora et al. [40][41] found that the intra-TMJ injection of BoNT/A (7 U/Kg of Botox®, or 14 U/Kg of Dysport®) was able to reduce the P2X7/Cathepsin-S/Fractalkine microglia-activated pathway in the trigeminal subnucleus caudalis. Moreover, BoNT/A also reduced the protein level of IL-1β and TNF-α.
In all the studies presented thus far, the exact mechanism by which the peripherally injected BoNT/A reaches the spinal cord, where it may block both neuronal synaptic release and spinal glial activation, is not yet completely understood. As has been suggested in many studies that have used animal models [42], a direct central effect of the peripheral administration of BoNT/A is conceivable as a consequence of its retrograde transport along the axons of sensory neurons and its subsequent transcytosis to neuronal and non-neuronal spinal cells, where it can block both the release of neurotransmitters and the activation of spinal glia cells. It should be noted that, although the retrograde transport of the toxin can be evoked as a mechanism by which the peripheral toxin can reach the spinal cord in animal models, for obvious reasons, it is desirable that this does not happen in humans. The retrograde transport of the toxin from the peripheral injection site, which is an uncontrollable event, is an undesirable adverse effect, and in practical medicine, every effort is aimed at ensuring that this event does not occur. In light of this, it is unthinkable to consider the possibility of translating this type of mechanism, which concerns the toxin–glial cell interaction, for use in a clinical setting. Nonetheless, this problem could be circumvented by synthesizing new chimera toxins, which, if they are successfully designed to recognize specific receptors, may selectively target glial cells. In recent years, the development of engineered toxins has become the subject of intense research in the field of botulinum toxins, and it is desirable that this continues further [43][44][45].

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