Botulinum Neurotoxins in Central Nervous System: An Overview from Animal Models to Human Therapy

Luvisetto, Siro

doi:10.3390/toxins13110751

Cited by 24 publications

(22 citation statements)

References 140 publications

(159 reference statements)

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“…Except for peripheral mechanisms, we also explored the central mechanisms of perineural injection of BoNT/A-induced analgesia. It is well established that indirect central effects can be produced by peripherally injected BoNT/A through peripheral mechanisms of alteration of central sensorimotor integration [31]. Therefore, the results associated with peripheral protective effects of BoNT/A in this study suggested the indirect central effect of perineural injection of BoNT/A.…”

Section: Discussionsupporting

confidence: 56%

Analgesic Effect of Perineural Injection of BoNT/A on Neuropathic Pain Induced by Chronic Constriction Injury of Sciatic Nerve in Rats

Wei²,

Wu³

et al. 2023

Neurochem Res

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This study was designed to investigate the analgesic effect of perineural injection of BoNT/A on neuropathic pain induced by sciatic nerve chronic constriction injury (CCI) and possible mechanisms. SD rats were randomly divided into Sham group, CCI group and BoNT/A group. Paw mechanical withdrawal threshold (pMWT) and paw thermal withdrawal latency (pTWL) of each group were detected at different time points after surgery. The expression of myelin markers, autophagy markers and NLRP3 in ammasome-related molecules in injured sciatic nerves were examined at 12 days after surgery.Moreover, C-ber evoked potential in spinal dorsal horn was recorded. The expression of SNAP-25, neuroin ammation and synaptic plasticity in spinal dorsal horn of each group was examined. Then rats treated with BoNT/A were randomly divided into DMSO group and Wnt agonist group to further explore the regulatory effect of BoNT/A on Wnt pathway. We found that pMWT and pTWL of ipsilateral paw were signi cantly decreased in CCI group compared with Sham group, which could be improved by perineural injection of BoNT/A at days 7, 9 and 12 after surgery. The peripheral mechanisms of perineural injection of BoNT/A may be related to the protective effect on myelin sheath by inhibiting NLRP3 in ammasome and promoting autophagy ow, while the central mechanisms may be associated with inhibition of neuroin ammation and synaptic plasticity in spinal dorsal horn due to its ability to inhibit SNAP-25 and Wnt pathway. As a new route of administration, perineural injection of BoNT/A can relieve CCI induced neuropathic pain probably via both peripheral and central mechanisms.

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Section: Discussionsupporting

confidence: 56%

Analgesic Effect of Perineural Injection of BoNT/A on Neuropathic Pain Induced by Chronic Constriction Injury of Sciatic Nerve in Rats

Wei²,

Wu³

et al. 2023

Neurochem Res

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“…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 [ 68 ], 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.…”

Section: Interactions Between Bonts Microglia and Astrocytesmentioning

confidence: 99%

Botulinum Neurotoxins beyond Neurons: Interplay with Glial Cells

Luvisetto

2022

Toxins

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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.

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“…The central effects of BoNTs, following their peripheral administration, have been the subject of debate in the literature, and a consensus has not yet been reached as to their direct or indirect effects [ 190 , 191 , 192 ]. A 2018 review by Caleo and Restani [ 191 ] summarizes studies that have so far provided evidence of the retrograde transport of BoNTA after its peripheral injection and that this process might contribute to the clinical effects of BoNTA through a direct action on the central circuits [ 191 ].…”

Section: Mechanisms Underlying the Antipruritic Effect Of Bontsmentioning

confidence: 99%

How Does Botulinum Toxin Inhibit Itch?

Gazerani

2022

Toxins

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Two decades after reports of the anti-pruritic effects of botulinum neurotoxins (BoNTs), there is still no approved product for the anti-itch indication of BoNTs, and most clinical case reports still focus on the off-label use of BoNTs for various itchy conditions. Few randomized clinical trials have been conducted with controversial results, and the beneficial effects of BoNTs against itch are mainly based on case studies and case series. These studies are valuable in presenting the potential application of BoNTs in chronic pruritic conditions, but due to the nature of these studies, they are categorized as providing lower levels of evidence or lower grades of recommendation. To obtain approval for the anti-pruritic indication of BoNTs, higher levels of evidence are required, which can be achieved through conducting large-scale and well-designed studies with proper control groups and established careful and reliable primary and secondary outcomes. In addition to clinical evidence, presenting the mechanism-based antipruritic action of BoNTs can potentially strengthen, accelerate, and facilitate the current efforts towards further investments in accelerating the field towards the potential approval of BoNTs for itchy conditions. This review, therefore, aimed to provide the state-of-the-art mechanisms underlying the anti-itch effect of BoNTs from basic studies that resemble various clinical conditions with itch as a hallmark. Evidence of the neuronal, glial, and immune modulatory actions of BoNTs in reducing the transmission of itch are presented, and future potential directions are outlined.

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Botulinum Neurotoxins in Central Nervous System: An Overview from Animal Models to Human Therapy

Cited by 24 publications

References 140 publications

Analgesic Effect of Perineural Injection of BoNT/A on Neuropathic Pain Induced by Chronic Constriction Injury of Sciatic Nerve in Rats

Analgesic Effect of Perineural Injection of BoNT/A on Neuropathic Pain Induced by Chronic Constriction Injury of Sciatic Nerve in Rats

Botulinum Neurotoxins beyond Neurons: Interplay with Glial Cells

How Does Botulinum Toxin Inhibit Itch?

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