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Toxins
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Botulinum Neurotoxin and Parkinson’s Disease
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Botulinum Neurotoxin and Parkinson’s Disease

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

Deadline for manuscript submissions: closed (15 December 2022) | Viewed by 19436

Special Issue Editors

Prof. Dr. Andreas Wree

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Guest Editor
Institute of Anatomy, Rostock University Medical Center, Gertrudenstrasse 9, 18057 Rostock, Germany
Interests: botulinum-neurotoxin; receptors; imaging; animal models of neurodegenerative diseases
Special Issues, Collections and Topics in MDPI journals
Dr. Veronica Alexandra Antipova

E-Mail Website
Guest Editor
Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Macroscopic and Clinical Anatomy, Medical University of Graz, A-8010 Graz, Austria
Interests: botulinum neurotoxin; brain; neurodegenerative disease; animal models of neurodegenerative diseases; parkinson disease; huntington disease; behavior; receptors; morphometry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Parkinson’s disease (PD) is a progressive neurodegenerative disease, and is the second most frequently occurring of this type. The main motor symptoms of PD, such as bradykinesia, akinesia, rest tremor, rigidity, postural instability, and gait disorders, are caused by axonal degeneration of dopaminergic fibers in the striatum and subsequent or parallel loss of dopaminergic neurons in the substantia nigra pars compacta. In addition to these motor symptoms, patients with PD often experience non-motor symptoms, including autonomic dysfunction, olfactory deficits, cognitive decline, sleep disorders, and neuropsychiatric symptoms such as depression, anxiety, and psychosis.

The non-motor symptoms often appear years before the motor symptoms are first noticed, but they can become major problems for the patients and adversely affect quality of life. Medications used to treat both motor and non-motor symptoms in PD are often inadequately effective and can cause intolerable side effects.

Botulinum toxins, produced by the anaerobic bacterium Clostridium botulinum, are among the most potent poisons present in nature. They inhibit the release of acetylcholine from the presynaptic terminal by affecting SNARE and SNAP proteins. In recent years botulinum neurotoxin (BoNT) has been used for the treatment over 100 different medical indications. Many of the symptoms for which BoNT has been found to be effective occur in a variety of neurological disorders. Especially in Parkinson’s disease, BoNT has been successfully applied to treat various motor symptoms (i.e., limb, cervical, pharyngeal, oromandibular dystonia and rigidity, bruxism, blepharospasm and lid apraxia, dysphagia, hand and jaw tremor, camptocormia, freezing of gait) and non-motor symptoms (i.e., drooling and sialorrhea, seborrhea, hyperhidrosis), gastroenterological symptoms including constipation and overactive bladder, gynecological disorders, pain, and so on.

In this Special Issue, we ask experts to contribute manuscripts that examine the current therapeutic indications and effectiveness of BoNT in PD or respective animal models.

Prof. Dr. Andreas Wree
Dr. Veronica Alexandra Antipova
Guest Editors

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 submissions that pass pre-check are 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 double-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 2700 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

  • Parkinson’s disease
  • botulinum neurotoxin
  • treatment of motor symptoms
  • treatment of non-motor symptoms
  • clinical studies
  • animal models
  • peripheral nervous system
  • central nervous system

Published Papers (6 papers)

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Research

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19 pages, 3504 KiB  
Article
Biological and Immunological Characterization of a Functional L-HN Derivative of Botulinum Neurotoxin Serotype F
by Zhiying Li, Bolin Li, Jiansheng Lu, Xuyang Liu, Xiao Tan, Rong Wang, Peng Du, Shuo Yu, Qing Xu, Xiaobin Pang, Yunzhou Yu and Zhixin Yang
Toxins 2023, 15(3), 200; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins15030200 - 06 Mar 2023
Cited by 3 | Viewed by 1510
Abstract
Botulinum neurotoxins (BoNTs) can cause nerve paralysis syndrome in mammals and other vertebrates. BoNTs are the most toxic biotoxins known and are classified as Class A biological warfare agents. BoNTs are mainly divided into seven serotypes A-G and new neurotoxins BoNT/H and BoNT/X, [...] Read more.
Botulinum neurotoxins (BoNTs) can cause nerve paralysis syndrome in mammals and other vertebrates. BoNTs are the most toxic biotoxins known and are classified as Class A biological warfare agents. BoNTs are mainly divided into seven serotypes A-G and new neurotoxins BoNT/H and BoNT/X, which have similar functions. BoNT proteins are 150 kDa polypeptide consisting of two chains and three domains: the light chain (L, catalytic domain, 50 kDa) and the heavy chain (H, 100 kDa), which can be divided into an N-terminal membrane translocation domain (HN, 50 kDa) and a C-terminal receptor binding domain (Hc, 50 kDa). In current study, we explored the immunoprotective efficacy of each functional molecule of BoNT/F and the biological characteristics of the light chain-heavy N-terminal domain (FL-HN). The two structure forms of FL-HN (i.e., FL-HN-SC: single chain FL-HN and FL-HN-DC: di-chain FL-HN) were developed and identified. FL-HN-SC could cleave the vesicle associated membrane protein 2 (VAMP2) substrate protein in vitro as FL-HN-DC or FL. While only FL-HN-DC had neurotoxicity and could enter neuro-2a cells to cleave VAMP2. Our results showed that the FL-HN-SC had a better immune protection effect than the Hc of BoNT/F (FHc), which indicated that L-HN-SC, as an antigen, provided the strongest protective effects against BoNT/F among all the tested functional molecules. Further in-depth research on the different molecular forms of FL-HN suggested that there were some important antibody epitopes at the L-HN junction of BoNT/F. Thus, FL-HN-SC could be used as a subunit vaccine to replace the FHc subunit vaccine and/or toxoid vaccine, and to develop antibody immune molecules targeting L and HN domains rather than the FHc domain. FL-HN-DC could be used as a new functional molecule to evaluate and explore the structure and activity of toxin molecules. Further exploration of the biological activity and molecular mechanism of the functional FL-HN or BoNT/F is warranted. Full article
(This article belongs to the Special Issue Botulinum Neurotoxin and Parkinson’s Disease)
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28 pages, 4411 KiB  
Article
Olfactory Bulb D2/D3 Receptor Availability after Intrastriatal Botulinum Neurotoxin-A Injection in a Unilateral 6-OHDA Rat Model of Parkinson’s Disease
by Teresa Alberts, Veronica Antipova, Carsten Holzmann, Alexander Hawlitschka, Oliver Schmitt, Jens Kurth, Jan Stenzel, Tobias Lindner, Bernd J. Krause, Andreas Wree and Martin Witt
Toxins 2022, 14(2), 94; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins14020094 - 25 Jan 2022
Cited by 4 | Viewed by 3381
Abstract
Olfactory deficits occur as early non-motor symptoms of idiopathic Parkinson’s disease (PD) in humans. The first central relay of the olfactory pathway, the olfactory bulb (OB), depends, among other things, on an intact, functional crosstalk between dopaminergic interneurons and dopamine receptors (D2 [...] Read more.
Olfactory deficits occur as early non-motor symptoms of idiopathic Parkinson’s disease (PD) in humans. The first central relay of the olfactory pathway, the olfactory bulb (OB), depends, among other things, on an intact, functional crosstalk between dopaminergic interneurons and dopamine receptors (D2/D3R). In rats, hemiparkinsonism (hemi-PD) can be induced by unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB), disrupting dopaminergic neurons of the substantia nigra pars compacta (SNpc). In a previous study, we showed that subsequent injection of botulinum neurotoxin-A (BoNT-A) into the striatum can reverse most of the pathological motor symptoms and normalize the D2/D3R availability. To determine whether this rat model is suitable to explain olfactory deficits that occur in humans with PD, we examined the availability of D2/D3R by longitudinal [18F]fallypride-PET/CT, the density of tyrosine hydroxylase immunoreactivity in the OB, olfactory performance by an orienting odor identification test adapted for rats, and a connectome analysis. PET/CT and immunohistochemical data remained largely unchanged after 6-OHDA lesion in experimental animals, suggesting that outcomes of the 6-OHDA hemi-PD rat model do not completely explain olfactory deficits in humans. However, after subsequent ipsilateral BoNT-A injection into the striatum, a significant 8.5% increase of the D2/D3R availability in the ipsilateral OB and concomitant improvement of olfactory performance were detectable. Based on tract-tracing meta-analysis, we speculate that this may be due to indirect connections between the striatum and the OB. Full article
(This article belongs to the Special Issue Botulinum Neurotoxin and Parkinson’s Disease)
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37 pages, 14760 KiB  
Article
Antidepressant-Like Properties of Intrastriatal Botulinum Neurotoxin-A Injection in a Unilateral 6-OHDA Rat Model of Parkinson’s Disease
by Veronica Antipova, Carsten Holzmann, Alexander Hawlitschka, Martin Witt and Andreas Wree
Toxins 2021, 13(7), 505; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13070505 - 20 Jul 2021
Cited by 9 | Viewed by 4042
Abstract
Parkinson’s patients often suffer from depression and anxiety, for which there are no optimal treatments. Hemiparkinsonian (hemi-PD) rats were used to test whether intrastriatal Botulinum neurotoxin-A (BoNT-A) application could also have antidepressant-like properties in addition to the known improvement of motor performance. To [...] Read more.
Parkinson’s patients often suffer from depression and anxiety, for which there are no optimal treatments. Hemiparkinsonian (hemi-PD) rats were used to test whether intrastriatal Botulinum neurotoxin-A (BoNT-A) application could also have antidepressant-like properties in addition to the known improvement of motor performance. To quantify depression- and anxiety-like behavior, the forced swim test, tail suspension test, open field test, and elevated plus maze test were applied to hemi-PD rats injected with BoNT-A or vehicle. Furthermore, we correlated the results in the forced swim test, open field test, and elevated plus maze test with the rotational behavior induced by apomorphine and amphetamine. Hemi-PD rats did not show significant anxiety-like behavior as compared with Sham 6-OHDA- + Sham BoNT-A-injected as well as with non-injected rats. However, hemi-PD rats demonstrated increased depression-like behaviors compared with Sham- or non-injected rats; this was seen by increased struggling frequency and increased immobility frequency. Hemi-PD rats intrastriatally injected with BoNT-A exhibited reduced depression-like behavior compared with the respective vehicle-receiving hemi-PD animals. The significant effects of intrastriatally applied BoNT-A seen in the forced swim test are reminiscent of those found after various antidepressant drug therapies. Our data correspond with the efficacy of BoNT-A treatment of glabellar frown lines in treating patients with major depression and suggest that also intrastriatal injected BoNT-A may have some antidepressant-like effect on hemi-PD. Full article
(This article belongs to the Special Issue Botulinum Neurotoxin and Parkinson’s Disease)
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Review

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14 pages, 419 KiB  
Review
Botulinum Toxin Treatment of Motor Disorders in Parkinson Disease—A Systematic Review
by Bahman Jabbari and Samira Marie Comtesse
Toxins 2023, 15(2), 81; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins15020081 - 17 Jan 2023
Cited by 4 | Viewed by 2804
Abstract
This review provides an up-to-date literature account on the efficacy of Botulinum toxin treatment for common motor disorders of Parkinson Disease. The reviewed disorders include the common motor disorders in PD such as tremor, focal foot dystonia, rigidity and freezing of gait (FOG). [...] Read more.
This review provides an up-to-date literature account on the efficacy of Botulinum toxin treatment for common motor disorders of Parkinson Disease. The reviewed disorders include the common motor disorders in PD such as tremor, focal foot dystonia, rigidity and freezing of gait (FOG). In the area of Parkinson tremor, two newly described evaluation/injection techniques (Yale method in USA and Western University method in Canada) offer efficacy with low incidence of hand and finger weakness as side effects. Blinded studies conducted on foot dystonia of PD indicate that botulinum toxin injections into toe flexors are efficacious in alleviating this form of dystonia. Small, blinded studies suggest improvement of Parkinson rigidity after botulinum toxin injection; proof of this claim, however, requires information from larger, blinded clinical trials. In FOG, the improvement reported in open label studies could not be substantiated in blinded investigations. However, there is room for further controlled studies that include the proximal lower limb muscles in the injection plan and/or use higher doses of the injected toxin for this indication. Full article
(This article belongs to the Special Issue Botulinum Neurotoxin and Parkinson’s Disease)
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13 pages, 890 KiB  
Review
Therapeutic Applications of Botulinum Neurotoxin for Autonomic Symptoms in Parkinson’s Disease: An Updated Review
by Steven D. Mitchell and Christos Sidiropoulos
Toxins 2021, 13(3), 226; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13030226 - 19 Mar 2021
Cited by 7 | Viewed by 3069
Abstract
Parkinson’s disease is the most common age-related motoric neurodegenerative disease. In addition to the cardinal motor symptoms of tremor, rigidity, bradykinesia, and postural instability, there are numerous non-motor symptoms as well. Among the non-motor symptoms, autonomic nervous system dysfunction is common. Autonomic symptoms [...] Read more.
Parkinson’s disease is the most common age-related motoric neurodegenerative disease. In addition to the cardinal motor symptoms of tremor, rigidity, bradykinesia, and postural instability, there are numerous non-motor symptoms as well. Among the non-motor symptoms, autonomic nervous system dysfunction is common. Autonomic symptoms associated with Parkinson’s disease include sialorrhea, hyperhidrosis, gastrointestinal dysfunction, and urinary dysfunction. Botulinum neurotoxin has been shown to potentially improve these autonomic symptoms. In this review, the varied uses of botulinum neurotoxin for autonomic dysfunction in Parkinson’s disease are discussed. This review also includes discussion of some additional indications for the use of botulinum neurotoxin in Parkinson’s disease, including pain. Full article
(This article belongs to the Special Issue Botulinum Neurotoxin and Parkinson’s Disease)
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16 pages, 1669 KiB  
Review
Use of Botulinum Neurotoxin in Parkinson’s Disease: A Critical Appraisal
by Wolfgang H. Jost
Toxins 2021, 13(2), 87; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13020087 - 25 Jan 2021
Cited by 11 | Viewed by 3578
Abstract
For well over 30 years, the botulinum neurotoxin (BoNT) has been used for a large number of indications, some of which however have not been licensed. Admittedly, approval varies in many countries and this permits a large spectrum for evaluation. Thus, BoNT is [...] Read more.
For well over 30 years, the botulinum neurotoxin (BoNT) has been used for a large number of indications, some of which however have not been licensed. Admittedly, approval varies in many countries and this permits a large spectrum for evaluation. Thus, BoNT is used for patients with Parkinson’s disease (PD) and other Parkinson’s syndromes (PS) in varying degrees of frequency. We have to distinguish between (1) indications that are either approved or (2) those not approved, (3) indications that might be a result of PS and (4) finally those which appear independent of PS. The most important indication for BoNT in PS patients is probably sialorrhea, for which approval has been granted in the majority of countries. Cervical dystonia is a frequent symptom in PS, with anterocollis as a specific entity. A further indication is blepharospasm in the different forms, especially the inhibition of eyelid opening in atypical PS. The use of BoNT in cases of camptocormia, the Pisa syndrome and neck rigidity is still a matter of debate. In dystonia of the extremities BoNT can be recommended, especially in dystonia of the feet. One well-known indication, for which however sufficient data are still lacking, involves treating tremor with BoNT. As to autonomic symptoms: Focal hyperhidrosis and detrusor hyperactivity can be mentioned, in this last case BoNT has already been approved. A number of further but rare indications such as freezing-of-gait, dyskinesia, and dysphagia will be discussed and evaluated. Full article
(This article belongs to the Special Issue Botulinum Neurotoxin and Parkinson’s Disease)
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