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Special Issue "Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications"

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Bacterial Toxins".

Deadline for manuscript submissions: 31 March 2018

Special Issue Editor

Guest Editor
Dr. Siro Luvisetto

National Research Council (CNR) of Italy, Institute of Cell Biology and Neurobiology, Monterotondo Scalo, Roma 00015, Italy
Website | E-Mail

Special Issue Information

Dear Colleagues,

Botulinum toxins (BoNTs) are a true wonder of nature. Like Dr. Jekyll and Mr Hide, they have a double "personality" that makes them unique among toxins of bacterial origin. On the one hand, BoNTs are key components of several widely-used drugs, approved for a variety of clinical conditions, difficult to treat with other medicine. On the other hand, BoNTs are the causal agent of botulism and, with its highest toxicity among natural products, are one of the most dangerous bioterrorism agents. Both animal and clinical studies have extensively investigated the therapeutics effects for BoNTs, evidencing a variety of apparently different mechanisms which have in common the block of the cholinergic transmission at the neuromuscular junction. This discovery gave an extraordinary consensus to the clinical use of BoNTs in human pathologies characterized by excessive muscle contractions, i.e., the hypercholinergic dysfunctions going from torticollis, blepharospasms, dystonias, and so on. In recent years, a number of studies have provided evidence for the efficacy of BoNTs in alleviating human pain, including pain disorders associated with migraine. The list of human disorders in which treatments with BoNTs have produced, or are expected to produce, favorable results is long and continuously growing. This Special Issue “Botulinum Neurotoxins in Nervous System: Future Challenges for Novel Indications” is particularly devoted to collecting the most recent research on the effects of BoNTs in all cases where the expected therapeutic action is not attributable only to the its canonical mechanism, but also to the interaction of the toxins with other structures, including peripheral nerves, spinal cord, central neurons, non-neural cells, and so on. Both review and research articles are welcome, not only on animal studies, but also on clinical reports. The ambitious purpose of this Special Issue is to provide an up-to-date picture of the state-of-the-art on the possible development of novel BoNT applications for future therapeutic indications.

Dr. Siro Luvisetto
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1500 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Botulinum
  • Peripheral nervous system
  • Central nervous system
  • Sensory motor system
  • Nerve regeneration
  • Spinal cord
  • Glial cells
  • Animal models
  • Clinical studies

Published Papers (5 papers)

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Research

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Open AccessArticle The Effect of Botulinum Neurotoxin Serotype a Heavy Chain on the Growth Related Proteins and Neurite Outgrowth after Spinal Cord Injury in Rats
Toxins 2018, 10(2), 66; doi:10.3390/toxins10020066
Received: 23 November 2017 / Revised: 31 January 2018 / Accepted: 31 January 2018 / Published: 2 February 2018
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Abstract
(1) Background: The botulinum toxin A (BoNT-A) heavy chain (HC) can stimulate the growth of primary motor neurites. (2) Methods: A recombinant BoNT/A HC was injected locally plus interval intrathecal catheter of BoNT/A HC to rats with ipsilateral semi-dissociated lumbar spinal cord injuries
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(1) Background: The botulinum toxin A (BoNT-A) heavy chain (HC) can stimulate the growth of primary motor neurites. (2) Methods: A recombinant BoNT/A HC was injected locally plus interval intrathecal catheter of BoNT/A HC to rats with ipsilateral semi-dissociated lumbar spinal cord injuries (SCIs). First, 2D gel with a silver nitrate stain was applied to detect the general pattern of protein expression. Growth associated protein 43 (GAP-43) and superior cervical ganglion 10 (SCG10) were chosen to represent the altered proteins, based on their molecular weight and pI, and were used to further detect their expression. Meanwhile, the neuronal processes were measured. The measurements of thermal hyperalgesia and grasp power at the ipsilateral hindlimb were used to evaluate spinal sensory and motor function, respectively. (3) Results: The local injection of BoNT/A HC followed by its intrathecal catheter intervally altered the spinal protein expression pattern after an SCI; protein expression was similar to normal levels or displayed a remarkable increase. The changes in the expression and distribution of phosphorylated growth associated protein 43(p-GAP 43) and superior cervical ganglion 10 (SCG 10) indicated that the administration of BoNT/A HC to the SCI significantly amplified the expression of p-GAP43 and SCG10 (p < 0.05). Meanwhile, the positive immunofluorescent staining for both p-GAP43 and SCG10 was mainly present near the rostral aspect of the injury, both in the cytoplasm and the neuronal processes. Moreover, the outgrowth of neurites was stimulated by the BoNT/A HC treatment; this was evident from the increase in neurite length, number of branches and the percentage of cells with neuronal processes. The results from the spinal function tests suggested that the BoNT/A HC did not affect sensation, but had a large role in improving the ipsilateral hindlimb grasp power (p < 0.05). (4) Conclusions: The local injection with the intermittent intrathecal administration of BoNT/A heavy chain to rats with SCI increased the local expression of GAP-43 and SCG 10, which might be affiliated with the regeneration of neuronal processes surrounding the injury, and might also be favorable to the relief of spinal motor dysfunction. Full article
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Open AccessArticle Botulinum Toxin A for Sialorrhoea Associated with Neurological Disorders: Evaluation of the Relationship between Effect of Treatment and the Number of Glands Treated
Toxins 2018, 10(2), 55; doi:10.3390/toxins10020055
Received: 21 December 2017 / Revised: 22 January 2018 / Accepted: 22 January 2018 / Published: 27 January 2018
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Abstract
Background: Sialorrhoea and drooling are disabling manifestations of different neurological disorders. The aim of this study was to evaluate the effects of botulinum neurotoxin type A (BoNT/A) injection on hypersalivation in 90 patients with neurological diseases of different aetiologies, and to define
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Background: Sialorrhoea and drooling are disabling manifestations of different neurological disorders. The aim of this study was to evaluate the effects of botulinum neurotoxin type A (BoNT/A) injection on hypersalivation in 90 patients with neurological diseases of different aetiologies, and to define the minimum number of injected salivary glands to reduce sialorrhoea. Determining the minimum number of glands that need to be engaged in order to have a significant reduction in drooling may be very useful for establishing the minimum total dosage of BoNT/A that may be considered effective in the treatment of hypersalivation. Methods: Twenty-five mouse units (MU) of BoNT/A (onabotulinumtoxin A, Botox; Allergan, Irvine, CA, USA; 100 MU/2 mL, 0.9% saline; or incobotulinumtoxin A, Xeomin; Merz Pharma, Germany; 100 MU/2 mL, 0.9% saline) were percutaneously injected into the parotid (p) glands and/or submandibular (s) glands under ultrasound control. On this basis, patients were divided into three groups. In group A (30 patients), BoNT/A injections were performed into four glands; in group B (30 patients), into three glands, and in group C (30 patients), into two glands. Patients treated in three glands (group B) were divided into two subgroups based on the treated glands (2 p + 1 s = 15 patients; 2 s + 1 p = 15 patients). Similarly, patients being injected in two glands (group C) were subdivided into three groups (2 p = 10 patients; 1 p + 1 s = 10 patients; 2 s = 10 patients). In patients who were injected in three and two salivary glands, saline solution was injected into the remaining one and two glands, respectively. Assessments were performed at baseline and at 2 weeks after the injections. Results: BoNT/A significantly reduced sialorrhoea in 82 out of 90 patients. The effect was more evident in patients who had four glands injected than when three or two glands were injected. The injections into three glands were more effective than injections into two glands. Conclusions: Our results have shown that BoNT/A injections induced a significant reduction in sialorrhoea in most patients (91%). In addition, we demonstrated that sialorrhoea associated with different neurological diseases was better controlled when the number of treated glands was higher. Full article
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Review

Jump to: Research

Open AccessReview Correction of Malocclusion by Botulinum Neurotoxin Injection into Masticatory Muscles
Toxins 2018, 10(1), 27; doi:10.3390/toxins10010027
Received: 1 December 2017 / Revised: 29 December 2017 / Accepted: 31 December 2017 / Published: 2 January 2018
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Abstract
Botulinum toxin (BTX) is a neurotoxin, and its injection in masticatory muscles induces muscle weakness and paralysis. This paralytic effect of BTX induces growth retardation of the maxillofacial bones, changes in dental eruption and occlusion state, and facial asymmetry. Using masticatory muscle paralysis
[...] Read more.
Botulinum toxin (BTX) is a neurotoxin, and its injection in masticatory muscles induces muscle weakness and paralysis. This paralytic effect of BTX induces growth retardation of the maxillofacial bones, changes in dental eruption and occlusion state, and facial asymmetry. Using masticatory muscle paralysis and its effect via BTX, BTX can be used for the correction of malocclusion after orthognathic surgery and mandible fracture. The paralysis of specific masticatory muscles by BTX injection reduces the tensional force to the mandible and prevents relapse and changes in dental occlusion. BTX injection in the anterior belly of digastric and mylohyoid muscle prevents the open-bite and deep bite of dental occlusion and contributes to mandible stability after orthognathic surgery. The effect of BTX injection in masticatory muscles for maxillofacial bone growth and dental occlusion is reviewed in this article. The clinical application of BTX is also discussed for the correction of dental malocclusion and suppression of post-operative relapse after mandibular surgery. Full article
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Open AccessReview Botulinum Toxin in the Field of Dermatology: Novel Indications
Toxins 2017, 9(12), 403; doi:10.3390/toxins9120403
Received: 20 November 2017 / Revised: 13 December 2017 / Accepted: 14 December 2017 / Published: 16 December 2017
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Abstract
Since its approval by the US Food and Drug Administration in 2002 for glabellar wrinkles, botulinum toxin (BTX) has been widely used to correct facial wrinkles. As a result, many consider BTX synonymous with cosmetic dermatology. Recent studies indicate that BTX elicits biological
[...] Read more.
Since its approval by the US Food and Drug Administration in 2002 for glabellar wrinkles, botulinum toxin (BTX) has been widely used to correct facial wrinkles. As a result, many consider BTX synonymous with cosmetic dermatology. Recent studies indicate that BTX elicits biological effects on various skin cell types via the modulation of neurotransmitter release, and it seems that BTX has a wider zone of dermatologic influence than originally understood. Clinicians and researchers are now beginning to explore the potential of BTX beyond the amelioration of facial lines and encouraging results are seen with BTX in a variety of skin conditions. In this paper, we review novel dermatological indications of BTX which includes (but not limited to) scar prevention, facial flushing, post-herpetic neuralgia and itch. These areas show great promise, but there is definite need for larger, double-blinded, randomized control trials against established treatments before BTX becomes a clinical reality. Full article
Open AccessFeature PaperReview Botulinum Toxin in Management of Limb Tremor
Toxins 2017, 9(11), 365; doi:10.3390/toxins9110365
Received: 24 October 2017 / Revised: 7 November 2017 / Accepted: 8 November 2017 / Published: 10 November 2017
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Abstract
Essential tremor is characterized by persistent, usually bilateral and symmetric, postural or kinetic activation of agonist and antagonist muscles involving either the distal or proximal upper extremity. Quality of life is often affected and one’s ability to perform daily tasks becomes impaired. Oral
[...] Read more.
Essential tremor is characterized by persistent, usually bilateral and symmetric, postural or kinetic activation of agonist and antagonist muscles involving either the distal or proximal upper extremity. Quality of life is often affected and one’s ability to perform daily tasks becomes impaired. Oral therapies, including propranolol and primidone, can be effective in the management of essential tremor, although adverse effects can limit their use and about 50% of individuals lack response to oral pharmacotherapy. Locally administered botulinum toxin injection has become increasingly useful in the management of essential tremor. Targeting of select muscles with botulinum toxin is an area of active research, and muscle selection has important implications for toxin dosing and functional outcomes. The use of anatomical landmarks with palpation, EMG guidance, electrical stimulation, and ultrasound has been studied as a technique for muscle localization in toxin injection. Earlier studies implemented a standard protocol for the injection of (predominantly) wrist flexors and extensors using palpation and EMG guidance. Targeting of muscles by selection of specific activators of tremor (tailored to each patient) using kinematic analysis might allow for improvement in efficacy, including functional outcomes. It is this individualized muscle selection and toxin dosing (requiring injection within various sites of a single muscle) that has allowed for success in the management of tremors. Full article

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

1. Title: Antipruritic effects of botulinum neurotoxins

Author: Parisa Gazerani
Abstract: This review would explore current evidence to demonstrate that botulinum neurotoxins exert antipruritic effects. Both experimental and clinical conditions in which botulinum neurotoxins have been applied for itch relieving effects will be presented and significant findings will be highlighted. Potential mechanisms underlying antipruritic effects will also be discussed and ongoing challenges and unmet needs will be listed.
2. Title: Exploiting Botulinum neurotoxins for the study of brain pathologies
Authors:
Matteo Caleo and Laura Restani
Abstract: Botulinum neurotoxins are metalloproteases that specifically cleave SNARE proteins in synaptic terminals, resulting in a potent inhibition of vesicle fusion and transmitter release. The family comprises different serotypes (BoNT/A to /G). The natural target of these toxins is represented by the neuromuscular junction, where BoNTs block acetylcholine release. In this review, we describe the actions of botulinum toxins after direct delivery to the central nervous system (CNS), where BoNTs block exocytosis of several transmitters at central synapses, with near-complete silencing of neural networks. The use of clostridial neurotoxins in the CNS has allowed to investigate specifically the role of synaptic activity in several physiological and pathological processes. The silencing properties of BoNTs can be exploited for for therapeutic purposes, for example to counteract pathological hyperactivity and seizures in epileptogenic brain foci, or to investigate the role of activity in degenerative diseases like prion disease. Altogether, clostridial neurotoxins and their derivatives hold promise as powerful tools for both the basic understanding of brain function and the dissection and treatment of activity-dependent pathogenic pathways.
3. Title: Botulinum neurotoxin and neurorehabilitation: state of the art and future perspectives

Authors: Stefano Tamburin, Giorgio Sandrini and collaborators

Abstract: Botulinum neurotoxin (BoNT) is widely used for the treatment of excessive and/or undesired muscle tone, in particular spasticity and dystonia and its therapeutic indications have progressively expanded. BoNT was recently licensed for chronic migraine, and represents an emerging treatment for an increasing number of pain conditions, including primary headache, trigeminal neuralgia, and neuropathic pain. BoNT is also used to treat bladder dysfunction.
Patients with neurological diseases undergoing neurorehabilitation often have more than one conditions (e.g. patients with spinal cord injury are frequently affected by spasticity, central neuropathic pain, and bladder dysfunction), and thanks to its wide therapeutic effects may target more than one problem with limited or no side effects.
The association of an ad hoc rehabilitative program may improve the efficacy of BoNT in several clinical conditions (e.g., dystonia).
Here we will review the role of BoNT in the field of neurorehabilitation, and future areas of focus for clinical research, such as potential role of BoNT injection therapy in combination with systemic drugs and/or physical therapies.
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