|
1
|
He S, Liu Y, Zhang Z, Cai M, Hao Y, Hu H. Gene Editing in Ganoderma lucidum: Development, Challenges, and Future Prospects. J Fungi (Basel) 2025; 11:310. [PMID: 40278130 PMCID: PMC12029067 DOI: 10.3390/jof11040310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 04/05/2025] [Accepted: 04/09/2025] [Indexed: 04/26/2025] Open
Abstract
As an emerging and innovative technology, gene-editing technology has been widely applied in crop breeding, human disease treatment, animal model research, drug and vaccine development, and microbial engineering. We mainly introduce the development of gene-editing technology, the application of clustered regularly interspaced short palindromic repeat/Cas9 (CRISPR/Cas9) in Ganoderma lucidum breeding, the current challenges and optimization strategies in the use of gene-editing technology in Ganoderma breeding, as well as the current status of gene-editing technology in Ganoderma breeding. Finally, the future research directions and innovative strategies that gene editing may explore in Ganoderma breeding are prospects given the existing background, future research directions, and innovative strategies that gene editing may explore in Ganoderma breeding prospects.
Collapse
Affiliation(s)
- Shiqi He
- National Health Commission Science and Technology Innovation Platform for Nutrition and Safety of Microbial Food, Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China; (S.H.); (Y.L.); (Z.Z.); (M.C.); (Y.H.)
| | - Yuanchao Liu
- National Health Commission Science and Technology Innovation Platform for Nutrition and Safety of Microbial Food, Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China; (S.H.); (Y.L.); (Z.Z.); (M.C.); (Y.H.)
| | - Zhi Zhang
- National Health Commission Science and Technology Innovation Platform for Nutrition and Safety of Microbial Food, Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China; (S.H.); (Y.L.); (Z.Z.); (M.C.); (Y.H.)
- Guangdong Yuewei Biotechnology Co., Ltd., Shaoguan 512029, China
| | - Manjun Cai
- National Health Commission Science and Technology Innovation Platform for Nutrition and Safety of Microbial Food, Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China; (S.H.); (Y.L.); (Z.Z.); (M.C.); (Y.H.)
| | - Yufan Hao
- National Health Commission Science and Technology Innovation Platform for Nutrition and Safety of Microbial Food, Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China; (S.H.); (Y.L.); (Z.Z.); (M.C.); (Y.H.)
| | - Huiping Hu
- National Health Commission Science and Technology Innovation Platform for Nutrition and Safety of Microbial Food, Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China; (S.H.); (Y.L.); (Z.Z.); (M.C.); (Y.H.)
- Guangdong Yuewei Biotechnology Co., Ltd., Shaoguan 512029, China
| |
Collapse
|
|
2
|
Ayoub N. Botulinum Toxin Therapy: A Comprehensive Review on Clinical and Pharmacological Insights. J Clin Med 2025; 14:2021. [PMID: 40142828 PMCID: PMC11943293 DOI: 10.3390/jcm14062021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2025] [Revised: 03/10/2025] [Accepted: 03/12/2025] [Indexed: 03/28/2025] Open
Abstract
Background: Botulinum toxin (BoNT), produced by Clostridium botulinum, has transitioned from being a lethal neurotoxin to a versatile therapeutic agent. Its ability to inhibit neurotransmitter release by targeting Soluble N-ethylmaleimide-sensitive factor Attachment Protein Receptor (SNARE) proteins underpins its applications in treating conditions such as spasticity, dystonia, chronic pain, and overactive bladder. The clinical and pharmacological properties of BoNT have been extensively studied, with significant advancements in its therapeutic use, safety profile, and understanding of associated adverse effects. Objective: This comprehensive review aims to consolidate historical developments, molecular mechanisms, clinical applications, and challenges associated with BoNT, with a focus on expanding its therapeutic scope while ensuring safety and efficacy. Method: A narrative approach was used to analyze and synthesize insights from 155 references spanning experimental studies, clinical trials, and reviews. Key topics included BoNT's historical milestones, mechanisms of action, therapeutic applications, and adverse events. Findings: BoNT demonstrates remarkable efficacy in a wide range of medical and cosmetic applications. In movement disorders such as dystonia and spasticity, it reduces muscle overactivity and improves functional outcomes. In chronic pain management, including migraines and neuropathic pain, BoNT significantly alleviates symptoms by modulating neurotransmitter activity. Cosmetic use for conditions like glabellar lines and hyperhidrosis highlights its precision and safety when administered appropriately. For conditions like strabismus and blepharospasm, BoNT effectively restores muscle control, reducing involuntary contractions. In urological applications, BoNT has proven to be an effective therapy for overactive bladder, offering significant symptom relief in refractory cases. However, concerns about long-distance effects, where the toxin may spread beyond the injection site to affect distant muscles or systems, have been reported in certain high-dose or sensitive populations. These findings emphasize the importance of dose optimization and patient-specific approaches. Adverse effects such as localized pain, hematoma, dysphagia, and systemic effects, particularly in high-risk groups, underscore the need for careful monitoring. The development of immunogenicity, leading to neutralizing antibodies, remains a challenge that impacts long-term therapeutic efficacy. Emerging research on novel serotypes, including BoNT/X, and innovations in delivery mechanisms, offer promising avenues to address current limitations. Advances in optimizing dosing regimens and refining injection techniques have also contributed to minimizing complications and improving outcomes across diverse patient populations. Conclusions: BoNT remains a cornerstone in neurology and cosmetic medicine, with its therapeutic potential still expanding. The balance between efficacy and safety, driven by innovations in formulation and application, underscores the importance of continued research. Future directions should focus on minimizing adverse effects, reducing immunogenicity, and exploring novel indications to further enhance its clinical utility.
Collapse
Affiliation(s)
- Nahla Ayoub
- Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah 24375, Saudi Arabia
| |
Collapse
|
|
3
|
Marinelli S. BoNT/Action beyond neurons. Toxicon 2025; 255:108250. [PMID: 39862929 DOI: 10.1016/j.toxicon.2025.108250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 01/10/2025] [Accepted: 01/11/2025] [Indexed: 01/27/2025]
Abstract
Botulinum neurotoxin type A (BoNT/A) has expanded its therapeutic uses beyond neuromuscular disorders to include treatments for various pain syndromes and neurological conditions. Originally recognized for blocking acetylcholine release at neuromuscular junctions, BoNT/A's effects extend to both peripheral and central nervous systems. Its ability to undergo retrograde transport allows BoNT/A to modulate synaptic transmission and reduce pain centrally, influencing neurotransmitter systems beyond muscle control. BoNT/A also interacts with glial cells, such as Schwann cells, satellite glial cells, astrocytes, microglia, and oligodendrocytes. Schwann cells, key to peripheral nerve regeneration, are directly influenced by BoNT/A, which promotes their proliferation and enhances remyelination. Satellite glial cells, involved in sensory neuron regulation, show reduced glutamate release in response to BoNT/A, aiding in pain relief. In the CNS, BoNT/A modulates astrocyte activity, reducing excitotoxicity and inflammation, which is relevant in conditions like epilepsy. Microglia, the CNS's immune cells, shift from a pro-inflammatory to a neuroprotective state when treated with BoNT/A, enhancing tissue repair. Additionally, BoNT/A promotes oligodendrocyte survival and remyelination, especially after spinal cord injury. Overall, BoNT/A's ability to target both neurons and glial cells presents a multifaceted therapeutic strategy for neurological disorders, pain management, and CNS repair. Further research is necessary to fully elucidate its mechanisms and optimize its clinical application.
Collapse
Affiliation(s)
- Sara Marinelli
- National Research Council of Italy, Institute of Biochemistry and Cell Biology, 00015, Monterotondo, RM, Italy.
| |
Collapse
|
|
4
|
Schiavone G, Richter S, Henke T, Koch I, Thies L, Klöpper F, Megighian A, Pirazzini M, Binz T. Probing the properties of PTEN specific botulinum toxin type E mutants. J Neural Transm (Vienna) 2025:10.1007/s00702-025-02879-2. [PMID: 39849213 DOI: 10.1007/s00702-025-02879-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Accepted: 01/07/2025] [Indexed: 01/25/2025]
Abstract
Botulinum neurotoxins (BoNT) are established biopharmaceuticals for neuromuscular and secretory conditions based on their ability to block neurotransmitter release from neurons by proteolyzing specific soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. Recently, a mutant catalytic domain of serotype E (LC/E) exhibiting 16 mutations was reported to cleave the phosphatase and tensin homolog (PTEN). This molecule represents an attractive new target in neurons as several reports support PTEN knockdown as a strategy to stimulate axonal regeneration after injury. Though this LC/E mutant was shown to cleave PTEN in primary neurons through lentivirus-based expression, its expression and functionality as mutated full-length BoNT/E have not been studied. Hence, we assembled the 16 mutations stepwise in a bacterial expression plasmid for LC/E and purified several multiple mutants of LC/E. Biochemical characterization showed that the 16-fold mutant did not exhibit a detectable activity toward SNAP-25 up to 10 µM final concentration while it displayed an EC50 of approximately 200 nM for PTEN, exceeding 1000-fold that for LC/E-wt on the native substrate SNAP-25. Unexpectedly, expression of the full length 16-fold mutated BoNT/E did not provide soluble protein, possibly due to an interference of the interaction between LC and the translocation domain. Reversion of individual mutations revealed the E159L and S162Q substitutions, critical for redirecting LC/E activity toward PTEN, as main culprits for the solubility issue. To overcome this problem, we applied a methodology proved successful years ago, harnessing a proteolytically inactive variant of BoNT type D (BoNT/Di) as neurospecific delivery system for cargo proteins. The fusion protein LCE-16x-BoNT/Di could be produced in sufficient yields. Activity tests using rat cerebellar granule neurons showed BoNT/E-like activity for LC/E-wt-BoNT/Di, but no PTEN-directed activity for LC/E-16x-BoNT/Di.
Collapse
Affiliation(s)
- Giorgia Schiavone
- Department of Biomedical Sciences, University of Padova, Padova, 35131, Italy
| | - Sandy Richter
- Department of Biomedical Sciences, University of Padova, Padova, 35131, Italy
| | - Tina Henke
- Institut für Zellbiochemie, OE 4310, Medizinische Hochschule Hannover, 30623, Hannover, Germany
| | - Ineke Koch
- Institut für Zellbiochemie, OE 4310, Medizinische Hochschule Hannover, 30623, Hannover, Germany
| | - Linda Thies
- Institut für Zellbiochemie, OE 4310, Medizinische Hochschule Hannover, 30623, Hannover, Germany
| | - Fiete Klöpper
- Institut für Zellbiochemie, OE 4310, Medizinische Hochschule Hannover, 30623, Hannover, Germany
| | - Aram Megighian
- Department of Biomedical Sciences, University of Padova, Padova, 35131, Italy
- Padova Neuroscience Center, University of Padova, Padova, 35131, Italy
| | - Marco Pirazzini
- Department of Biomedical Sciences, University of Padova, Padova, 35131, Italy.
| | - Thomas Binz
- Institut für Zellbiochemie, OE 4310, Medizinische Hochschule Hannover, 30623, Hannover, Germany.
| |
Collapse
|
|
5
|
Maytharakcheep S, Bhidayasiri R. Botulinum toxin treatment for hemifacial spasm: harmonising neurological and aesthetic outcomes. J Neural Transm (Vienna) 2025; 132:23-38. [PMID: 39174752 DOI: 10.1007/s00702-024-02821-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 08/07/2024] [Indexed: 08/24/2024]
Abstract
Hemifacial spasm (HFS) represents a challenging cranial movement disorder primarily affecting the facial nerve innervated muscles, with significant prevalence among Asians. Botulinum toxin type A (BoNT/A) injections, established as a primary therapeutic intervention since FDA approval, offer considerable effectiveness in alleviating spasms, albeit accompanied by challenges such as temporary effects and potential adverse events including facial asymmetry. This comprehensive review underscores the crucial need for harmonising neurological benefits and aesthetic outcomes in HFS management. The discussion delves into the interplay between facial aesthetics and neurological objectives in BoNT/A injections, emphasising precise techniques, dosages, and site considerations. Distinct aspects in neurological and aesthetic domains are also examined, including detailing the targeted muscles and injection methodologies for optimal therapeutic and aesthetic results. Importantly, evidence regarding various BoNT/A formulations, recommendations, and reconstitution guidelines in both neurology and aesthetics contexts are provided, along with a schematic approach outlining the stepwise process for BoNT/A injection in HFS treatment, addressing critical areas such as orbicularis oculi muscle sites, eyebrow correction strategies, mid- and lower-face considerations, contralateral injection sites, and post-injection follow-up and complication management. By highlighting the culmination of neurological efficacy and facial esthetics in BoNT/A treatment for HFS patients, this review proposes a holistic paradigm to achieve balanced symptomatic relief and natural aesthetic expression, ultimately enhancing quality of life for individuals grappling with HFS.
Collapse
Affiliation(s)
- Suppata Maytharakcheep
- Chulalongkorn Centre of Excellence for Parkinson's Disease and Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Roongroj Bhidayasiri
- Chulalongkorn Centre of Excellence for Parkinson's Disease and Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.
- The Academy of Science, The Royal Society of Thailand, Bangkok, Thailand.
| |
Collapse
|
|
6
|
Amrutha Lakshmi M, B R A, Manyam P, Javeedvali S, Khan AS, Palnam DW, Kandan A. Traditional to technological advancements in Ganoderma detection methods in oil palm. Folia Microbiol (Praha) 2024; 69:953-973. [PMID: 38976188 DOI: 10.1007/s12223-024-01177-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 05/19/2024] [Indexed: 07/09/2024]
Abstract
Ganoderma sp., the fungal agent causing basal stem rot (BSR), poses a severe threat to global oil palm production. Alarming increases in BSR occurrences within oil palm growing zones are attributed to varying effectiveness in its current management strategies. Asymptomatic progression of the disease and the continuous monoculture of oil palm pose challenges for prompt and effective management. Therefore, the development of precise, early, and timely detection techniques is crucial for successful BSR management. Conventional methods such as visual assessments, culture-based assays, and biochemical and physiological approaches prove time-consuming and lack specificity. Serological-based diagnostic methods, unsuitable for fungal diagnostics due to low sensitivity, assay affinity, cross-contamination which further underscores the need for improved techniques. Molecular PCR-based assays, utilizing universal, genus-specific, and species-specific primers, along with functional primers, can overcome the limitations of conventional and serological methods in fungal diagnostics. Recent advancements, including real-time PCR, biosensors, and isothermal amplification methods, facilitate accurate, specific, and sensitive Ganoderma detection. Comparative whole genomic analysis enables high-resolution discrimination of Ganoderma at the strain level. Additionally, omics tools such as transcriptomics, proteomics, and metabolomics can identify potential biomarkers for early detection of Ganoderma infection. Innovative on-field diagnostic techniques, including remote methods like volatile organic compounds profiling, tomography, hyperspectral and multispectral imaging, terrestrial laser scanning, and Red-Green-Blue cameras, contribute to a comprehensive diagnostic approach. Ultimately, the development of point-of-care, early, and cost-effective diagnostic techniques accessible to farmers is vital for the timely management of BSR in oil palm plantations.
Collapse
Affiliation(s)
- M Amrutha Lakshmi
- Plant Pathology, ICAR-Indian Institute of Oil Palm Research, India, Andhra Pradesh.
| | - Ajesh B R
- Tamil Nadu Agricultural University, Coimbatore, Tamil Nadu, India
| | - Pradeep Manyam
- Acharya N. G, Ranga Agricultural University, Guntur, Andhra Pradesh, India
| | - Shaik Javeedvali
- Tamil Nadu Agricultural University, Coimbatore, Tamil Nadu, India
| | - Amjada S Khan
- Tamil Nadu Agricultural University, Coimbatore, Tamil Nadu, India
| | - Dauda Wadzani Palnam
- Crop Science Unit, Department of Agronomy, Federal University, Yobe State, Gashua, Nigeria
| | - A Kandan
- ICAR-National Bureau of Agricultural Insect Resources, Bangalore, India
| |
Collapse
|
|
7
|
Crisafulli S, Ciccimarra F, Khan Z, Maccarrone F, Trifirò G. Understanding Clinical Effectiveness and Safety Implications of Botulinum Toxin in Children: A Narrative Review of the Literature. Toxins (Basel) 2024; 16:306. [PMID: 39057946 PMCID: PMC11281390 DOI: 10.3390/toxins16070306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 06/20/2024] [Accepted: 07/01/2024] [Indexed: 07/28/2024] Open
Abstract
Since its first approval by the Food and Drug Administration in 1989 for strabismus, botulinum toxin indications of use have been widely expanded. Due to its anticholinergic properties, this toxin is currently approved in adult patients for the treatment of a wide range of neuromuscular, otolaryngologic, orthopedic, gastrointestinal, and urologic disorders. Approved pediatric indications of use include the treatment of blepharospasm associated with dystonia, strabismus, lower-limb spasticity, focal spasticity in patients with cerebral palsy, and neurogenic detrusor overactivity. Alongside these approved indications, botulinum toxin is extensively used off-label. Although several clinical studies have shown that botulinum toxin is effective and well-tolerated in children, uncertainties persist regarding its long-term effects on growth and appropriate dosing in this population. As such, further research is needed to better define the botulinum toxin risk-benefit profile and expand approved uses in pediatrics. This narrative review aimed to provide a broad overview of the evidence concerning the clinical effectiveness and safety of BoNT with respect to its principal authorized and non-authorized pediatric therapeutic indications, as well as to describe perspectives on its future use in children.
Collapse
Affiliation(s)
| | - Francesco Ciccimarra
- Department of Diagnostics and Public Health, University of Verona, 37124 Verona, Italy; (F.C.); (F.M.)
| | - Zakir Khan
- Department of Pharmacy Practice, Riphah Institute of Pharmaceutical Sciences, Riphah International University, Gulberg Green Campus, Islamabad 44000, Pakistan;
| | - Francesco Maccarrone
- Department of Diagnostics and Public Health, University of Verona, 37124 Verona, Italy; (F.C.); (F.M.)
| | - Gianluca Trifirò
- Department of Diagnostics and Public Health, University of Verona, 37124 Verona, Italy; (F.C.); (F.M.)
| |
Collapse
|
|
8
|
Bagues A, Hu J, Alshanqiti I, Chung MK. Neurobiological mechanisms of botulinum neurotoxin-induced analgesia for neuropathic pain. Pharmacol Ther 2024; 259:108668. [PMID: 38782121 PMCID: PMC11182613 DOI: 10.1016/j.pharmthera.2024.108668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 05/15/2024] [Accepted: 05/20/2024] [Indexed: 05/25/2024]
Abstract
Botulinum neurotoxins (BoNTs) are a family of neurotoxins produced by Clostridia and other bacteria that induce botulism. BoNTs are internalized into nerve terminals at the site of injection and cleave soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins to inhibit the vesicular release of neurotransmitters. BoNTs have been approved for multiple therapeutic applications, including the treatment of migraines. They have also shown efficacies for treating neuropathic pain, such as diabetic neuropathy, and postherpetic and trigeminal neuralgia. However, the mechanisms underlying BoNT-induced analgesia are not well understood. Peripherally administered BoNT is taken up by the nerve terminals and reduces the release of glutamate, calcitonin gene-related peptide, and substance P, which decreases neurogenic inflammation in the periphery. BoNT is retrogradely transported to sensory ganglia and central terminals in a microtubule-dependent manner. BoNTs decrease the expression of pronociceptive genes (ion channels or cytokines) from sensory ganglia and the release of neurotransmitters and neuropeptides from primary afferent central terminals, which likely leads to decreased central sensitization in the dorsal horn of the spinal cord or trigeminal nucleus. BoNT-induced analgesia is abolished after capsaicin-induced denervation of transient receptor potential vanilloid 1 (TRPV1)-expressing afferents or the knockout of substance P or the neurokinin-1 receptor. Although peripheral administration of BoNT leads to changes in the central nervous system (e.g., decreased phosphorylation of glutamate receptors in second-order neurons, reduced activation of microglia, contralateral localization, and cortical reorganization), whether such changes are secondary to changes in primary afferents or directly mediated by trans-synaptic, transcytotic, or the hematogenous transport of BoNT is controversial. To enhance their therapeutic potential, BoNTs engineered for specific targeting of nociceptive pathways have been developed to treat chronic pain. Further mechanistic studies on BoNT-induced analgesia can enhance the application of native or engineered BoNTs for neuropathic pain treatment with improved safety and efficacy.
Collapse
Affiliation(s)
- Ana Bagues
- Área de Farmacología, Nutrición y Bromatología, Dpto. C.C. Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Unidad Asociada I+D+i al Instituto de Química Médica (CSIC), Alcorcón, Spain; High Performance Research Group in Experimental Pharmacology (PHARMAKOM), Spain
| | - Jiaxin Hu
- Department of Neural and Pain Sciences, School of Dentistry, University of Maryland Baltimore, Baltimore, MD 21201, USA
| | - Ishraq Alshanqiti
- Department of Neural and Pain Sciences, School of Dentistry, University of Maryland Baltimore, Baltimore, MD 21201, USA; Program in Dental Biomedical Sciences, University of Maryland Baltimore, School of Dentistry, Baltimore, MD 21201, USA; Department of Basic and Clinical Sciences, School of Dentistry, Umm Al-Qura University, Makkah 24382, Kingdom of Saudi Arabia
| | - Man-Kyo Chung
- Department of Neural and Pain Sciences, School of Dentistry, University of Maryland Baltimore, Baltimore, MD 21201, USA; Program in Dental Biomedical Sciences, University of Maryland Baltimore, School of Dentistry, Baltimore, MD 21201, USA; Center to Advance Chronic Pain Research, University of Maryland Baltimore, Baltimore, MD 21201, USA.
| |
Collapse
|
|
9
|
Buzatu R, Luca MM, Castiglione L, Sinescu C. Efficacy and Safety of Botulinum Toxin in the Management of Temporomandibular Symptoms Associated with Sleep Bruxism: A Systematic Review. Dent J (Basel) 2024; 12:156. [PMID: 38920857 PMCID: PMC11203296 DOI: 10.3390/dj12060156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 05/11/2024] [Accepted: 05/21/2024] [Indexed: 06/27/2024] Open
Abstract
Sleep bruxism, characterized by involuntary grinding or clenching of teeth during sleep, poses significant challenges in management due to its potential to induce temporomandibular joint disorders (TMDs) and other related symptoms. The use of Botulinum toxin Type A (BoNT-A), also known as Botox®, has been proposed as a therapeutic intervention. This systematic review aims to evaluate the efficacy and safety of BoNT-A in the management of sleep bruxism, focusing on pain reduction, improvement in jaw function, reduction in bruxism episodes, and the incidence of adverse effects. An exhaustive search was conducted across PubMed, Scopus, and Embase databases up to January 2024, adhering to the PRISMA guidelines. Nine randomized clinical trials (RCTs) involving 137 participants were analyzed for efficacy and safety outcomes. The studies demonstrated a significant reduction in mean pain scores (from 7.1 to 0.2 at 6 months and 1 year post-treatment in one study) and a notable decrease in the number of bruxism events (from 4.97/h to 1.70/h in the BoNT-A group in another study). Additionally, improvements were observed in jaw stiffness and total sleep time. Adverse effects varied but were generally mild and transient, including injection site pain in 20% of participants in one study and cosmetic changes in smile in 15.4% of patients in another. These findings suggest that BoNT-A injections may provide some benefits for treating nocturnal bruxism, potentially reducing TMD symptoms like pain and improving jaw function. However, these findings are preliminary due to variability in study designs and the absence of detailed statistical analysis.
Collapse
Affiliation(s)
- Roxana Buzatu
- Department of Dental Aesthetics, Faculty of Dental Medicine, “Victor Babes” University of Medicine and Pharmacy Timisoara, Revolutiei Boulevard 9, 300041 Timisoara, Romania;
| | - Magda Mihaela Luca
- Department of Pediatric Dentistry, Faculty of Dental Medicine, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square 2, 300041 Timisoara, Romania
| | - Luca Castiglione
- Doctoral School, Faculty of General Medicine, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square 2, 300041 Timisoara, Romania;
| | - Cosmin Sinescu
- Department of Prostheses Technology and Dental Materials, Faculty of Dental Medicine, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square 2, 300041 Timisoara, Romania;
| |
Collapse
|
|
10
|
Yamagata A, Ito K, Suzuki T, Dohmae N, Terada T, Shirouzu M. Structural basis for antiepileptic drugs and botulinum neurotoxin recognition of SV2A. Nat Commun 2024; 15:3027. [PMID: 38637505 PMCID: PMC11026379 DOI: 10.1038/s41467-024-47322-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 03/26/2024] [Indexed: 04/20/2024] Open
Abstract
More than one percent of people have epilepsy worldwide. Levetiracetam (LEV) is a successful new-generation antiepileptic drug (AED), and its derivative, brivaracetam (BRV), shows improved efficacy. Synaptic vesicle glycoprotein 2a (SV2A), a putative membrane transporter in the synaptic vesicles (SVs), has been identified as a target of LEV and BRV. SV2A also serves as a receptor for botulinum neurotoxin (BoNT), which is the most toxic protein and has paradoxically emerged as a potent reagent for therapeutic and cosmetic applications. Nevertheless, no structural analysis on AEDs and BoNT recognition by full-length SV2A has been available. Here we describe the cryo-electron microscopy structures of the full-length SV2A in complex with the BoNT receptor-binding domain, BoNT/A2 HC, and either LEV or BRV. The large fourth luminal domain of SV2A binds to BoNT/A2 HC through protein-protein and protein-glycan interactions. LEV and BRV occupy the putative substrate-binding site in an outward-open conformation. A propyl group in BRV creates additional contacts with SV2A, explaining its higher binding affinity than that of LEV, which was further supported by label-free spectral shift assay. Numerous LEV derivatives have been developed as AEDs and positron emission tomography (PET) tracers for neuroimaging. Our work provides a structural framework for AEDs and BoNT recognition of SV2A and a blueprint for the rational design of additional AEDs and PET tracers.
Collapse
Affiliation(s)
- Atsushi Yamagata
- Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, Japan.
| | - Kaori Ito
- Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, Japan
| | - Takehiro Suzuki
- Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama, Japan
| | - Naoshi Dohmae
- Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama, Japan
| | - Tohru Terada
- Department of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, Japan
| | - Mikako Shirouzu
- Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, Japan
| |
Collapse
|
|
11
|
Zhantleuova A, Leese C, Andreou AP, Karimova A, Carpenter G, Davletov B. Recent Developments in Engineering Non-Paralytic Botulinum Molecules for Therapeutic Applications. Toxins (Basel) 2024; 16:175. [PMID: 38668600 PMCID: PMC11054698 DOI: 10.3390/toxins16040175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 04/01/2024] [Accepted: 04/02/2024] [Indexed: 04/29/2024] Open
Abstract
This review discusses the expanding application of botulinum neurotoxin in treating neurological conditions. The article specifically explores novel approaches to using non-paralytic botulinum molecules. These new molecules, such as BiTox or el-iBoNT, offer an alternative for patients who face limitations in using paralytic forms of botulinum neurotoxin due to concerns about muscle function loss. We highlight the research findings that confirm not only the effectiveness of these molecules but also their reduced paralytic effect. We also discuss a potential cause for the diminished paralytic action of these molecules, specifically changes in the spatial parameters of the new botulinum molecules. In summary, this article reviews the current research that enhances our understanding of the application of new botulinum neurotoxins in the context of common conditions and suggests new avenues for developing more efficient molecules.
Collapse
Affiliation(s)
- Aisha Zhantleuova
- Department of Biophysics, Biomedicine and Neuroscience, Al-Farabi Kazakh National University, Almaty A15E3C7, Kazakhstan; (A.Z.); (A.K.)
| | - Charlotte Leese
- Department of Biomedical Science, University of Sheffield, Sheffield S10 2JA, UK;
| | - Anna P. Andreou
- Headache Research, Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE1 1UL, UK;
- Neuresta, Inc., San Diego, CA 91991, USA
| | - Altynay Karimova
- Department of Biophysics, Biomedicine and Neuroscience, Al-Farabi Kazakh National University, Almaty A15E3C7, Kazakhstan; (A.Z.); (A.K.)
| | - Guy Carpenter
- Salivary Research, Centre for Host-Microbiome Interactions, Faculty of Dental, Oral & Craniofacial Sciences, King’s College London, London SE1 1UL, UK;
| | - Bazbek Davletov
- Department of Biomedical Science, University of Sheffield, Sheffield S10 2JA, UK;
- Neuresta, Inc., San Diego, CA 91991, USA
| |
Collapse
|
|
12
|
Lee ST, Kim D, Park JH, Kwon TG. Ultrasound-guided intraoral botulinum toxin injection into the lateral pterygoid muscle for chronic temporomandibular joint dislocation. J Korean Assoc Oral Maxillofac Surg 2024; 50:41-48. [PMID: 38419520 PMCID: PMC10910006 DOI: 10.5125/jkaoms.2024.50.1.41] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 02/02/2024] [Accepted: 02/04/2024] [Indexed: 03/02/2024] Open
Abstract
Objectives Botulinum toxin type A (BTX), a powerful neurotoxin, can be an effective treatment choice for diverse muscular disorders and can reduce abnormal muscle activities. Abnormal movements of the mandible can be caused by involuntary and uncontrolled contractions of the lateral pterygoid muscle (LP) in various pathological situations. Previous reports have shown that BTX can reduce abnormal contractions of the LP. However, needle placement into the LP for BTX injection requires skill, experience, and sufficient anatomical knowledge. To place the needle precisely into the LP, ultrasonography (USG) can be used as an effective needle-guidance modality. USG is a non-invasive imaging modality able to create real-time images without any potential risks, including radiation exposure. Patients and. Methods The patients who had been performed USG-guided BTX injection into the LP using an intraoral approach were included in this study with a literature review and case presentations. Using the USG, four patients received BTX injections to treat recurrent temporomandibular dislocation and oromandibular dystonia resulting from involuntary LP activity. Result Involuntary movements of the mandible were improved successfully in all patients, and showed satisfactory results without significant complication. Conclusion The intraoral approach could prevent potential complications during needle placement. USG-guided BTX injection is an effective, convenient, and safe method that provides real-time imaging without unnecessary pain to the patient.
Collapse
Affiliation(s)
- Sung-Tak Lee
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Kyungpook National University, Daegu, Korea
| | - Dohyoung Kim
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Kyungpook National University, Daegu, Korea
| | - Jae-Hyeong Park
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Kyungpook National University, Daegu, Korea
| | - Tae-Geon Kwon
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Kyungpook National University, Daegu, Korea
| |
Collapse
|
|
13
|
Flores-Holguín N, Salas-Leiva JS, Núñez-Vázquez EJ, Tovar-Ramírez D, Glossman-Mitnik D. Marine Toxins as Pharmaceutical Treasure Troves: A Focus on Saxitoxin Derivatives from a Computational Point of View. Molecules 2024; 29:275. [PMID: 38202857 PMCID: PMC10780485 DOI: 10.3390/molecules29010275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 12/30/2023] [Accepted: 12/31/2023] [Indexed: 01/12/2024] Open
Abstract
This work highlights the significant potential of marine toxins, particularly saxitoxin (STX) and its derivatives, in the exploration of novel pharmaceuticals. These toxins, produced by aquatic microorganisms and collected by bivalve mollusks and other filter-feeding organisms, offer a vast reservoir of chemical and biological diversity. They interact with sodium channels in physiological processes, affecting various functions in organisms. Exposure to these toxins can lead to symptoms ranging from tingling sensations to respiratory failure and cardiovascular shock, with STX being one of the most potent. The structural diversity of STX derivatives, categorized into carbamate, N-sulfocarbamoyl, decarbamoyl, and deoxydecarbamoyl toxins, offers potential for drug development. The research described in this work aimed to computationally characterize 18 STX derivatives, exploring their reactivity properties within marine sponges using conceptual density functional theory (CDFT) techniques. Additionally, their pharmacokinetic properties, bioavailability, and drug-likeness scores were assessed. The outcomes of this research were the chemical reactivity parameters calculated via CDFT as well as the estimated pharmacokinetic and ADME properties derived using computational tools. While they may not align directly, the integration of these distinct datasets enriches our comprehensive understanding of the compound's properties and potential applications. Thus, this study holds promise for uncovering new pharmaceutical candidates from the considered marine toxins.
Collapse
Affiliation(s)
- Norma Flores-Holguín
- Centro de Investigación en Materiales Avanzados, Miguel de Cervantes 120, Complejo Industrial Chihuahua, Chihuahua 31136, Chih, Mexico; (J.S.S.-L.); (D.G.-M.)
| | - Joan S. Salas-Leiva
- Centro de Investigación en Materiales Avanzados, Miguel de Cervantes 120, Complejo Industrial Chihuahua, Chihuahua 31136, Chih, Mexico; (J.S.S.-L.); (D.G.-M.)
| | - Erick J. Núñez-Vázquez
- Centro de Investigaciones Biológicas del Noroeste, Av. Instituto Politécnico Nacional 195, Col. Playa Palo de Santa Rita Sur, La Paz 23096, BCS, Mexico; (E.J.N.-V.); (D.T.-R.)
| | - Dariel Tovar-Ramírez
- Centro de Investigaciones Biológicas del Noroeste, Av. Instituto Politécnico Nacional 195, Col. Playa Palo de Santa Rita Sur, La Paz 23096, BCS, Mexico; (E.J.N.-V.); (D.T.-R.)
| | - Daniel Glossman-Mitnik
- Centro de Investigación en Materiales Avanzados, Miguel de Cervantes 120, Complejo Industrial Chihuahua, Chihuahua 31136, Chih, Mexico; (J.S.S.-L.); (D.G.-M.)
| |
Collapse
|
|
14
|
Zhang K, Ren Y, Lv J, Mao P, Zhou W, Shi Y, Zhou K, Wang L, Zhang C, Zhang H. Exploring the Biomarkers and Potential Mechanisms of Botulinum Toxin Type A in the Treatment of Microglial Inflammatory Activation through P2X7 Receptors based on Transcriptome Sequencing. Curr Pharm Des 2024; 30:3038-3053. [PMID: 39177140 DOI: 10.2174/0113816128318908240730093036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 06/22/2024] [Accepted: 07/05/2024] [Indexed: 08/24/2024]
Abstract
AIMS This study aims to explore the potential mechanism by which Botulinum toxin type A (BoNT/ A) inhibits microglial inflammatory activation through P2X7 receptors (P2X7R). BACKGROUND BoNT/A is a promising analgesic drug, and previous studies have established that it alleviates Neuropathic Pain (NP) by inhibiting microglial inflammatory activation. This study examined the biomarkers and potential mechanisms by which BoNT/A relieves neuropathic pain by mediating microglial P2X7R and analyzing transcriptome sequencing data from mouse BV-2 microglial cells. OBJECTIVE The P2X7R agonist Bz-ATP was used to induce microglial inflammatory activation, whilst RNAseq technology was used to explore the biomarkers and potential mechanisms through which BoNT/A suppresses microglial inflammation. METHODS RNA sequencing was performed on three BV-2 cell samples treated with a P2X7R specific activator (Bz-ATP) and three BV-2 cell samples pre-treated with BoNT/A. Only data that successfully passed quality control measures were included in subsequent analysis. Initially, Differentially Expressed Genes (DEGs) were identified from BoNT/A and control samples, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Biomarkers were then identified by constructing a Protein- Protein Interaction (PPI) network and utilizing the CytoHubba plug-in in Cytoscape software. Lastly, enrichment analysis and regulatory network analysis were performed to elucidate the potential mechanism of BoNT/A in the treatment of NP. RESULTS 93 DEGs related to the "cell component size regulation" GO term and enriched in the "axon guidance" KEGG pathway were identified. Subsequently, 6 biomarkers were identified, namely PTPRF, CHDH, CKM, Ky, Sema3b, and Sema3f, which were enriched in pathways related to biosynthesis and metabolism, disease progression, signal transduction, and organelle function, including the "ribosome" and "Wnt signaling pathway." Finally, a competing endogenous RNA (ceRNAs) network was constructed from 6 mRNAs, 66 miRNAs, and 31 lncRNAs, forming a complex relationship network. CONCLUSION Six genes (PTPRF, Sema3b, Sema3f, CHDH, CKM, and Ky) were identified as biomarkers of microglial inflammatory activation following BoNT/A treatment. This finding may provide a valuable reference for the relief and treatment of neuropathic pain.
Collapse
Affiliation(s)
- Kai Zhang
- Department of Spine Surgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Yi Ren
- Department of Spine Surgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Jiayang Lv
- Department of Spine Surgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Peng Mao
- Department of Spine Surgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Wenming Zhou
- Department of Spine Surgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Yongqiang Shi
- Department of Spine Surgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Kaisheng Zhou
- Department of Spine Surgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Linna Wang
- Department of Drug Development, Lanzhou Biotechnique Development Co., LTD, Lanzhou, China
| | - Chengjun Zhang
- Department of Drug Development, Lanzhou Biotechnique Development Co., LTD, Lanzhou, China
| | - Haihong Zhang
- Department of Spine Surgery, Lanzhou University Second Hospital, Lanzhou, China
| |
Collapse
|
|
15
|
Hosseindoost S, Askari Rad M, Inanloo SH, Rahimi M, Dehghan S, Orandi A, Dehpour AR, Majedi H. The analgesic effects of botulinum neurotoxin by modulating pain-related receptors; A literature review. Mol Pain 2024; 20:17448069241275099. [PMID: 39093638 PMCID: PMC11339750 DOI: 10.1177/17448069241275099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 08/12/2024] [Accepted: 07/24/2024] [Indexed: 08/04/2024] Open
Abstract
Botulinum neurotoxins (BoNTs), produced by Clostridium botulinum, have been used for the treatment of various central and peripheral neurological conditions. Recent studies have suggested that BoNTs may also have a beneficial effect on pain conditions. It has been hypothesized that one of the mechanisms underlying BoNTs' analgesic effects is the inhibition of pain-related receptors' transmission to the neuronal cell membrane. BoNT application disrupts the integration of synaptic vesicles with the cellular membrane, which is responsible for transporting various receptors, including pain receptors such as TRP channels, calcium channels, sodium channels, purinergic receptors, neurokinin-1 receptors, and glutamate receptors. BoNT also modulates the opioidergic system and the GABAergic system, both of which are involved in the pain process. Understanding the cellular and molecular mechanisms underlying these effects can provide valuable insights for the development of novel therapeutic approaches for pain management. This review aims to summarize the experimental evidence of the analgesic functions of BoNTs and discuss the cellular and molecular mechanisms by which they can act on pain conditions by inhibiting the transmission of pain-related receptors.
Collapse
Affiliation(s)
- Saereh Hosseindoost
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
- Pain Research Center, Neuroscience Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Maziyar Askari Rad
- Anesthesia, Critical Care, and Pain Management Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Hassan Inanloo
- Department of Urology, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Mojgan Rahimi
- Anesthesia, Critical Care, and Pain Management Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Samaneh Dehghan
- Stem Cell and Regenerative Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran
- Eye Research Center, The Five Senses Institute, Rassoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Amirhossein Orandi
- Anesthesia, Critical Care, and Pain Management Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Reza Dehpour
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Majedi
- Pain Research Center, Neuroscience Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
- Anesthesia, Critical Care, and Pain Management Research Center, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
16
|
Karian V, Morton H, Schefter ZJ, Smith A, Rogan H, Morse B, LeBel A. OnabotulinumtoxinA for Pediatric Migraine. Pain Manag Nurs 2023; 24:610-616. [PMID: 37183070 DOI: 10.1016/j.pmn.2023.04.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 04/08/2023] [Indexed: 05/16/2023]
Abstract
BACKGROUND Migraine is a painful, prevalent, and problematic condition among children. Children need access to safe and effective treatment options to alleviate the impact of this chronic condition on their wellbeing. CLINICAL IMPLICATIONS Nurses have a crucial role in supporting patient access to BTX-A. Given the results of this and other studies demonstrating the safety and efficacy of BTX-A in children, nurses can support policy change for health plans to fund this intervention for pediatric migraineurs. Allowing children to receive the safe and effective BTX-A injections will lessen the already significant impact of chronic migraine on their physical, emotional and mental health. Nurses can also play a key role in providing education to patients regarding safe administration of BTX-A for migraine. AIM The objective of this study was to define the experiences, effects, and clinical response of children to onabotulinumtoxinA (BTX-A) for migraine prevention. METHODS Clinical documentation for patients aged 13-17 years presenting for BTX-A treatment for chronic migraine between 2016-2022 in a community-based specialty clinic within a large, urban, pediatric academic medical center were included. A series of one-way repeated measures (analysis of variance [ANOVA]) were conducted to compare headache frequency, severity, and duration at baseline, and following first and second injections of BTX-A. RESULTS Of 32 eligible participants, administration of BTX-A demonstrated a decrease in headache frequency and severity. Participants reported nearly seven fewer headache days per month. Participants reported neck stiffness, fever or flu-like symptoms, fatigue, and worsening pain following BTX-A administration. CONCLUSIONS Pediatric migraineurs need therapies that are safe, effective, and accessible. BTX-A was a safe and effective treatment for migraine among the children included in this study.
Collapse
Affiliation(s)
- Victoria Karian
- Pediatric Headache Program, Division of Pain Medicine, Department of Anesthesiology, Perioperative & Pain Medicine, Boston Children's Hospital, Boston, Massachusetts
| | - Hannah Morton
- Pediatric Headache Program, Division of Pain Medicine, Department of Anesthesiology, Perioperative & Pain Medicine, Boston Children's Hospital, Boston, Massachusetts
| | - Zoë J Schefter
- Pediatric Headache Program, Division of Pain Medicine, Department of Anesthesiology, Perioperative & Pain Medicine, Boston Children's Hospital, Boston, Massachusetts
| | - Allison Smith
- Pediatric Headache Program, Division of Pain Medicine, Department of Anesthesiology, Perioperative & Pain Medicine, Boston Children's Hospital, Boston, Massachusetts
| | - Hannah Rogan
- Pediatric Headache Program, Division of Pain Medicine, Department of Anesthesiology, Perioperative & Pain Medicine, Boston Children's Hospital, Boston, Massachusetts
| | - Brenna Morse
- Pediatric Headache Program, Division of Pain Medicine, Department of Anesthesiology, Perioperative & Pain Medicine, Boston Children's Hospital, Boston, Massachusetts; School of Nursing, MGH Institute of Health Professions, Boston, Massachusetts.
| | - Alyssa LeBel
- Pediatric Headache Program, Division of Pain Medicine, Department of Anesthesiology, Perioperative & Pain Medicine, Boston Children's Hospital, Boston, Massachusetts; Department of Anesthesia, Harvard Medical School, Boston, Massachusetts
| |
Collapse
|
|
17
|
Rawson AM, Dempster AW, Humphreys CM, Minton NP. Pathogenicity and virulence of Clostridium botulinum. Virulence 2023; 14:2205251. [PMID: 37157163 PMCID: PMC10171130 DOI: 10.1080/21505594.2023.2205251] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/10/2023] Open
Abstract
Clostridium botulinum, a polyphyletic Gram-positive taxon of bacteria, is classified purely by their ability to produce botulinum neurotoxin (BoNT). BoNT is the primary virulence factor and the causative agent of botulism. A potentially fatal disease, botulism is classically characterized by a symmetrical descending flaccid paralysis, which is left untreated can lead to respiratory failure and death. Botulism cases are classified into three main forms dependent on the nature of intoxication; foodborne, wound and infant. The BoNT, regarded as the most potent biological substance known, is a zinc metalloprotease that specifically cleaves SNARE proteins at neuromuscular junctions, preventing exocytosis of neurotransmitters, leading to muscle paralysis. The BoNT is now used to treat numerous medical conditions caused by overactive or spastic muscles and is extensively used in the cosmetic industry due to its high specificity and the exceedingly small doses needed to exert long-lasting pharmacological effects. Additionally, the ability to form endospores is critical to the pathogenicity of the bacteria. Disease transmission is often facilitated via the metabolically dormant spores that are highly resistant to environment stresses, allowing persistence in the environment in unfavourable conditions. Infant and wound botulism infections are initiated upon germination of the spores into neurotoxin producing vegetative cells, whereas foodborne botulism is attributed to ingestion of preformed BoNT. C. botulinum is a saprophytic bacterium, thought to have evolved its potent neurotoxin to establish a source of nutrients by killing its host.
Collapse
Affiliation(s)
- Alexander M Rawson
- Clostridia Research Group, BBSRC/EPSRC Synthetic Biology Research Centre (SBRC), School of Life Sciences, The Biodiscovery Institute, The University of Nottingham, Nottingham, UK
| | - Andrew W Dempster
- Clostridia Research Group, BBSRC/EPSRC Synthetic Biology Research Centre (SBRC), School of Life Sciences, The Biodiscovery Institute, The University of Nottingham, Nottingham, UK
| | - Christopher M Humphreys
- Clostridia Research Group, BBSRC/EPSRC Synthetic Biology Research Centre (SBRC), School of Life Sciences, The Biodiscovery Institute, The University of Nottingham, Nottingham, UK
| | | |
Collapse
|
|
18
|
Mousavi Ghahfarrokhi SS, Mahdigholi FS, Amin M. Collateral beauty in the damages: an overview of cosmetics and therapeutic applications of microbial proteases. Arch Microbiol 2023; 205:375. [PMID: 37935975 DOI: 10.1007/s00203-023-03713-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 10/14/2023] [Accepted: 10/16/2023] [Indexed: 11/09/2023]
Abstract
Microbial proteases are enzymes secreted by a variety of microorganisms, including bacteria and fungi, and have attracted significant attention due to their versatile applications in the food and pharmaceutical industries. In addition, certain proteases have been used in the development of skin health products and cosmetics. This article provides a review of microbial proteases in terms of their classification, sources, properties, and applications. Moreover, different pharmacological and molecular investigations have been reviewed. Various biological activities of microbial proteases, such as Arazyme, collagenase, elastin, and Nattokinase, which are involved in the digestion of dietary proteins, as well as their potential anti-inflammatory, anti-cancer, antithrombotic, and immunomodulatory effects have been included. Furthermore, their ability to control infections and treat various disorders has been discussed. Finally, this review highlights the potential applications and future perspectives of microbial proteases in biotechnology and biomedicine, and proposes further studies to develop new perspectives for disease control and health-promoting strategies using microbial resources.
Collapse
Affiliation(s)
- Seyed Sadeq Mousavi Ghahfarrokhi
- Department of Drug and Food Control, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Pharmaceutical Microbiology Group, Pharmaceutical Quality Assurance Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
- Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Fateme Sadat Mahdigholi
- Department of Biomaterials, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohsen Amin
- Department of Drug and Food Control, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
- Pharmaceutical Microbiology Group, Pharmaceutical Quality Assurance Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.
- Room No. 1-221, Faculty of Pharmacy, 16th Azar Street, Tehran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
19
|
Raman S, Yamamoto Y, Suzuki Y, Matsuka Y. Mechanism and clinical use of botulinum neurotoxin in head and facial region. J Prosthodont Res 2023; 67:493-505. [PMID: 36740263 DOI: 10.2186/jpr.jpr_d_22_00238] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE Botulinum neurotoxin (BoNT) is a biological toxin produced by Clostridium botulinum. BoNT is a potent toxin extensively used in therapeutic interventions. This review provides an updated overview of the mechanisms of action and clinical applications of BoNT in head and facial region. STUDY SELECTION MEDLINE/PubMed searches were conducted using the terms "botulinum neurotoxin" and "dentistry" along with a combination of other related terms. In addition, studies were manually selected from reference lists of the selected articles. RESULTS The Food and Drug Administration in the United States initially approved BoNT to treat strabismus, blepharospasm, and hemifacial spasms. The use of BoNT in dermatology and cosmetics has been widely established and has created a revolution in these fields. Over the years, its applications in various medical specialties have expanded widely. Owing to its safety, efficacy, and long duration of action, it is well-accepted by patients. BoNT/A and BoNT/B are widely used in clinical practice. Several off-label uses of BoNT in the dental fraternity have yielded promising results. We have elaborated on the speculated mechanism of action, dosage, effective sites of injection, and adverse effects of each therapeutic application. The various clinical indications for BoNT include bruxism, myofascial pain, temporomandibular joint dislocation, hemifacial pain, orofacial dystonia, facial paralysis, chronic migraine, and trigeminal neuralgia. CONCLUSIONS BoNT is a safe treatment that can be used effectively, provided that the clinician has adequate knowledge regarding the mechanism, injection techniques, and local and systemic side effects and that it is administered cautiously and purposefully.
Collapse
Affiliation(s)
- Swarnalakshmi Raman
- Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Yumiko Yamamoto
- Department of Bacteriology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Yoshitaka Suzuki
- Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Yoshizo Matsuka
- Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| |
Collapse
|
|
20
|
Poenaru D, Sandulescu MI, Cinteza D. Pain Modulation in Chronic Musculoskeletal Disorders: Botulinum Toxin, a Descriptive Analysis. Biomedicines 2023; 11:1888. [PMID: 37509527 PMCID: PMC10376837 DOI: 10.3390/biomedicines11071888] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 06/25/2023] [Accepted: 07/01/2023] [Indexed: 07/30/2023] Open
Abstract
Botulinum neurotoxin (BoNT), a product of Clostridium botulinum, reversibly inhibits the presynaptic release of the neurotransmitter acetylcholine at the neuromuscular junction. In addition, BoNT blocks the transmission of other substances involved in pain perception and, together with a soft-tissue anti-inflammatory effect, may play a role in analgesia. When first-line treatment fails, second-line therapies might include BoNT. Studies on chronic and recurrent pain using different mechanisms offer heterogenous results that must be validated and standardized. Plantar fasciitis, severe knee osteoarthritis, painful knee and hip arthroplasty, antalgic muscular contractures, and neuropathic and myofascial pain syndromes may benefit from the administration of BoNT. Research on this topic has revealed the main musculoskeletal conditions that can benefit from BoNT, stressing the effects, modalities of administration, doses, and schedule.
Collapse
Affiliation(s)
- Daniela Poenaru
- Rehabilitation Department 1, Carol Davila University of Medicine and Pharmacy, 4192910 Bucharest, Romania
| | - Miruna Ioana Sandulescu
- Doctoral School, Carol Davila University of Medicine and Pharmacy, 4192910 Bucharest, Romania
| | - Delia Cinteza
- Rehabilitation Department 1, Carol Davila University of Medicine and Pharmacy, 4192910 Bucharest, Romania
| |
Collapse
|
|
21
|
Shi Y, Gong C, Nan W, Zhou W, Lei Z, Zhou K, Wang L, Zhao G, Zhang H. Intrathecal administration of botulinum toxin type a antagonizes neuropathic pain by countering increased vesicular nucleotide transporter expression in the spinal cord of chronic constriction injury of the sciatic nerve rats. Neuropeptides 2023; 100:102346. [PMID: 37178626 DOI: 10.1016/j.npep.2023.102346] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/28/2023] [Accepted: 05/02/2023] [Indexed: 05/15/2023]
Abstract
Botulinum toxin type A (BoNT/A) induces direct analgesic effects in neuropathic pain by inhibiting the release of substance P, calcitonin gene-related peptide (CGRP) and glutamate. Vesicular nucleotide transporter (VNUT) was responsible for the storage and release of ATP in vivo, and one of the mechanisms underlying neuropathic pain is VNUT-dependent release of extracellular ATP from dorsal horn neurons. However, the analgesic effect of BoNT/A by affecting the expression of VNUT remained largely unknown. Thus, in this study, we aimed to elucidate the antinociceptive potency and analgesic mechanism of BoNT/A in chronic constriction injury of the sciatic nerve (CCI) induced neuropathic pain. Our results showed that a single intrathecal injection of 0.1 U BoNT/A seven days after CCI surgery produced significant analgesic activity and decreased the expression of VNUT in the spinal cord of CCI rats. Similarly, BoNT/A inhibited the CCI-induced increase in ATP content in the rat spinal cord. Overexpression of VNUT in the spinal cord of CCI-induced rats markedly reversed the antinociceptive effect of BoNT/A. Furthermore, 33 U/mL BoNT/A dramatically reduced the expression of VNUT in pheochromocytoma (PC12) cells but overexpressing SNAP-25 increased VNUT expression in PC12 cells. Our current study is the first to demonstrate that BoNT/A is involved in neuropathic pain by regulating the expression of VNUT in the spinal cord in rats.
Collapse
Affiliation(s)
- Yongqiang Shi
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, China; The Second Clinical Medical College, Lanzhou University, Lanzhou, China; Orthopaedics Key Laboratory of Gansu Province, Lanzhou University, Lanzhou, China
| | - Chaoyang Gong
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, China; The Second Clinical Medical College, Lanzhou University, Lanzhou, China; Orthopaedics Key Laboratory of Gansu Province, Lanzhou University, Lanzhou, China
| | - Wei Nan
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, China; The Second Clinical Medical College, Lanzhou University, Lanzhou, China; Orthopaedics Key Laboratory of Gansu Province, Lanzhou University, Lanzhou, China
| | - Wenming Zhou
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, China; The Second Clinical Medical College, Lanzhou University, Lanzhou, China; Orthopaedics Key Laboratory of Gansu Province, Lanzhou University, Lanzhou, China
| | - Zeyuan Lei
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, China; The Second Clinical Medical College, Lanzhou University, Lanzhou, China; Orthopaedics Key Laboratory of Gansu Province, Lanzhou University, Lanzhou, China
| | - Kaisheng Zhou
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, China; The Second Clinical Medical College, Lanzhou University, Lanzhou, China; Orthopaedics Key Laboratory of Gansu Province, Lanzhou University, Lanzhou, China
| | - Linna Wang
- Lanzhou Biotechnique Development Co.LTD, China
| | - Guanghai Zhao
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, China.
| | - Haihong Zhang
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, China.
| |
Collapse
|
|
22
|
Tereshko Y, Belgrado E, Lettieri C, Gigli GL, Valente M. Botulinum Toxin Type A for the Treatment of Auriculotemporal Neuralgia-A Case Series. Toxins (Basel) 2023; 15:toxins15040274. [PMID: 37104212 PMCID: PMC10141838 DOI: 10.3390/toxins15040274] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 03/23/2023] [Accepted: 03/30/2023] [Indexed: 04/28/2023] Open
Abstract
Auriculotemporal neuralgia is a rare pain disorder in which anesthetic nerve blockade is usually effective but not always resolutive. Botulinum toxin type A has proven to be effective in treating neuropathic pain, and patients with auriculotemporal neuralgia could also benefit from this treatment. We described nine patients with auriculotemporal neuralgia treated with botulinum toxin type A in the territory of auriculotemporal nerve innervation. We compared the basal NRS and Penn facial pain scale scores with those obtained 1 month after BoNT/A injections. Both Penn facial pain scale (96.67 ± 24.61 vs. 45.11 ± 36.70, p 0.004; mean reduction 52.57 ± 36.50) and NRS scores (8.11 ± 1.27 vs. 4.22 ± 2.95, p 0.009; mean reduction 3.89 ± 2.52) improved significantly at one month after treatment. The mean duration of the effect of BoNT/A on pain was 95.00 ± 53.03 days and no adverse effects were reported.
Collapse
Affiliation(s)
- Yan Tereshko
- Clinical Neurology Unit, Udine University Hospital, Piazzale Santa Maria della Misericordia 15, 33100 Udine, Italy
| | - Enrico Belgrado
- Neurology Unit, Udine University Hospital, Piazzale Santa Maria della Misericordia 15, 33100 Udine, Italy
| | - Christian Lettieri
- Neurology Unit, Udine University Hospital, Piazzale Santa Maria della Misericordia 15, 33100 Udine, Italy
| | - Gian Luigi Gigli
- Clinical Neurology Unit, Udine University Hospital, Piazzale Santa Maria della Misericordia 15, 33100 Udine, Italy
| | - Mariarosaria Valente
- Clinical Neurology Unit, Udine University Hospital, Piazzale Santa Maria della Misericordia 15, 33100 Udine, Italy
| |
Collapse
|
|
23
|
Fang Y, Chang AY, Verma D, Miyashita SI, Eszterhas S, Lee PG, Shen Y, Davis LR, Dong M, Bailey-Kellogg C, Griswold KE. Functional Deimmunization of Botulinum Neurotoxin Protease Domain via Computationally Driven Library Design and Ultrahigh-Throughput Screening. ACS Synth Biol 2023; 12:153-163. [PMID: 36623275 PMCID: PMC9872818 DOI: 10.1021/acssynbio.2c00426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Indexed: 01/11/2023]
Abstract
Botulinum neurotoxin serotype A (BoNT/A) is a widely used cosmetic agent that also has diverse therapeutic applications; however, adverse antidrug immune responses and associated loss of efficacy have been reported in clinical uses. Here, we describe computational design and ultrahigh-throughput screening of a massive BoNT/A light-chain (BoNT/A-LC) library optimized for reduced T cell epitope content and thereby dampened immunogenicity. We developed a functional assay based on bacterial co-expression of BoNT/A-LC library members with a Förster resonance energy transfer (FRET) sensor for BoNT/A-LC enzymatic activity, and we employed high-speed fluorescence-activated cell sorting (FACS) to identify numerous computationally designed variants having wild-type-like enzyme kinetics. Many of these variants exhibited decreased immunogenicity in humanized HLA transgenic mice and manifested in vivo paralytic activity when incorporated into full-length toxin. One variant achieved near-wild-type paralytic potency and a 300% reduction in antidrug antibody response in vivo. Thus, we have achieved a striking level of BoNT/A-LC functional deimmunization by combining computational library design and ultrahigh-throughput screening. This strategy holds promise for deimmunizing other biologics with complex superstructures and mechanisms of action.
Collapse
Affiliation(s)
- Yongliang Fang
- Thayer
School of Engineering, Dartmouth, Hanover, New Hampshire 03755, United States
- Department
of Urology, Boston Children’s Hospital, Boston, Massachusetts 02115, United States
- Department
of Microbiology and Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Andrew Y. Chang
- Thayer
School of Engineering, Dartmouth, Hanover, New Hampshire 03755, United States
| | - Deeptak Verma
- Department
of Computer Science, Dartmouth, Hanover, New Hampshire 03755, United States
| | - Shin-Ichiro Miyashita
- Department
of Urology, Boston Children’s Hospital, Boston, Massachusetts 02115, United States
- Department
of Microbiology and Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115, United States
- Department
of Food, Aroma and Cosmetic Chemistry, Tokyo
University of Agriculture, 196 Yasaka, Abashiri 099-2493, Japan
| | - Susan Eszterhas
- Thayer
School of Engineering, Dartmouth, Hanover, New Hampshire 03755, United States
| | - Pyung-Gang Lee
- Department
of Urology, Boston Children’s Hospital, Boston, Massachusetts 02115, United States
- Department
of Microbiology and Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Yi Shen
- Department
of Urology, Boston Children’s Hospital, Boston, Massachusetts 02115, United States
- Department
of Microbiology and Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Lydia R. Davis
- Thayer
School of Engineering, Dartmouth, Hanover, New Hampshire 03755, United States
| | - Min Dong
- Department
of Urology, Boston Children’s Hospital, Boston, Massachusetts 02115, United States
- Department
of Microbiology and Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Chris Bailey-Kellogg
- Department
of Computer Science, Dartmouth, Hanover, New Hampshire 03755, United States
| | - Karl E. Griswold
- Thayer
School of Engineering, Dartmouth, Hanover, New Hampshire 03755, United States
| |
Collapse
|
|
24
|
Peng F, Xia TB. Effects of Intradermal Botulinum Toxin Injections on Herpes Zoster Related Neuralgia. Infect Drug Resist 2023; 16:2159-2165. [PMID: 37077249 PMCID: PMC10106788 DOI: 10.2147/idr.s401972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 03/17/2023] [Indexed: 04/21/2023] Open
Abstract
Background Postherpetic neuralgia (PHN), which represents the most common chronic complication of herpes zoster, is characterized by intense pain and is difficult to treat. In fact, no treatments are currently available that can effectively reduce the pain associated with PHN. Recent evidence has been presented indicating that Botulinum toxin (BoNT-A) can serve as an effective and safe treatment for peripheral neuropathic pain. Objective The effects of intradermal BoNT-A injections on herpes zoster related neuralgia were investigated in this study. Methods Patients diagnosed with herpes zoster related acute neuralgia (N=13 - acute group) and those diagnosed with postherpetic neuralgia (N=17 - PHN group) were enrolled in this study. The two groups were treated with intradermal injections of BoNT-A at the site of their affected pain areas and were then assessed at 1 day, 1 week, 2 weeks, 1 month, 2 months and 3 months after their BoNT-A treatments. Results When compared with pre-treatment values, Visual Analogue Scores (VAS) in all patients were all significantly decreased at all times tested following BoNT-A injection. Before treatment, PHN patients had significantly higher VAS than those in the acute group. However, after 1 day of treatment, there was no difference in VAS between the two groups. None of the patients in the acute phase treated with BoNT-A developed PHN. Conclusion BoNT-A injections significantly reduced herpetic-related pain and proved to be a more effective treatment for the PHN versus acute pain group. Moreover, an early application of BoNT-A can alleviate the probability of developing PHN.
Collapse
Affiliation(s)
- Fen Peng
- Department of Dermatology, Peking University Third Hospital, Beijing, People’s Republic of China
| | - Tian-Bao Xia
- Department of Dermatology, People’s Liberation Army Strategic Support Force Characteristic Medical Center, Beijing, People’s Republic of China
- Correspondence: Tian-Bao Xia, Department of Dermatology, People’s Liberation Army Strategic Support Force Characteristic Medical Center, No. 9th Anxiang Beili Road, Chaoyang District, Beijing, 100101, People’s Republic of China, Email
| |
Collapse
|
|
25
|
Shikhkerimov RK, Istomina EV. Recombinant botulinum toxin as a new stage in the development of botulinum toxin therapy. Possibilities and perspectives of use in neurological practice. NEUROLOGY, NEUROPSYCHIATRY, PSYCHOSOMATICS 2022. [DOI: 10.14412/2074-2711-2022-6-103-109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
|
|
26
|
Botulinum Neurotoxin Type A Directly Affects Sebocytes and Modulates Oleic Acid-Induced Lipogenesis. Toxins (Basel) 2022; 14:toxins14100708. [PMID: 36287976 PMCID: PMC9609209 DOI: 10.3390/toxins14100708] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/27/2022] [Accepted: 10/12/2022] [Indexed: 11/04/2022] Open
Abstract
Excess sebum (seborrhea) results in oily skin and is associated with large pore size and acne. Studies in healthy, seborrheic volunteers have reported that intradermal injection of commercial preparations of botulinum neurotoxin type A (BoNT/A) (onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA) reduced sebum production, and thus, skin oiliness and pore size. The mechanism for these effects has not been fully elucidated; however, several theories involving direct or indirect effects of BoNT/A on neuronal and/or dermal cells (e.g., sebocytes) have been proposed. In the present study, we evaluated the direct effect of native research grade BoNT/A complex, a commercial preparation of BoNT/A (onabotA), and BoNT/A variants on sebocyte lipogenesis using an in vitro sebocyte cell model. We show that picomolar concentrations of BoNT/A (BoNT/A complex: half maximal effective concentration [EC50] = 24 pM; BoNT/A 150 kDa: EC50 = 34 pM) modulate sebocyte lipogenesis and reduce oleic acid-induced sebocyte differentiation, lipogenesis, and holocrine-like secretion. Comparative studies with the binding domain of BoNT/A, which lacks enzymatic activity, show that this effect is independent of the enzymatic activity of BoNT/A and likely occurs via sebocyte cell surface receptors (e.g., fibroblast growth factor receptors). Overall, these results shed light on the potential mechanism of action and rationale for use of BoNT/A for treatment of sebum-related conditions.
Collapse
|
|
27
|
Gazerani P. How Does Botulinum Toxin Inhibit Itch? Toxins (Basel) 2022; 14:701. [PMID: 36287970 PMCID: PMC9610088 DOI: 10.3390/toxins14100701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 10/06/2022] [Accepted: 10/10/2022] [Indexed: 12/04/2022] Open
Abstract
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.
Collapse
Affiliation(s)
- Parisa Gazerani
- Department of Life Sciences and Health, Faculty of Health Sciences, Oslo Metropolitan University, 0130 Oslo, Norway; or
- Department of Health Science and Technology, Faculty of Medicine, Aalborg University, 9220 Aalborg East, Denmark
| |
Collapse
|
|
28
|
Botulinum Toxin Use for Modulating Neuroimmune Cutaneous Activity in Psoriasis. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58060813. [PMID: 35744076 PMCID: PMC9228985 DOI: 10.3390/medicina58060813] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 06/11/2022] [Accepted: 06/13/2022] [Indexed: 11/17/2022]
Abstract
Psoriasis is a complex immune-mediated inflammatory disorder that generates enormous interest within the scientific communities worldwide, with new therapeutic targets being constantly identified and tested. Despite the numerous topical and systemic medications available for the treatment of psoriasis, alternative therapies are still needed for the optimal management of some patients who present with localized, resistant lesions. Novel insights into the contribution of cutaneous neurogenic inflammation in the pathogenesis of psoriasis have yielded exciting new potential roles of nerve-targeting treatments, namely botulinum toxin type A (BoNT-A), for the management of this disease. This paper aims to review the existing literature on knowledge regarding the potential role of BoNT-A in psoriasis treatment, with a focus on its ability to interfere with the immunopathogenetic aspects of psoriatic disease. Furthermore, in our paper, we are also including the first report of psoriatic lesions remission following local BoNT-A injections that were administered for treating upper limb spasticity, in a patient that concomitantly suffered from psoriasis and post-stroke spasticity.
Collapse
|
|
29
|
Adler M, Pellett S, Sharma SK, Lebeda FJ, Dembek ZF, Mahan MA. Preclinical Evidence for the Role of Botulinum Neurotoxin A (BoNT/A) in the Treatment of Peripheral Nerve Injury. Microorganisms 2022; 10:microorganisms10050886. [PMID: 35630331 PMCID: PMC9148055 DOI: 10.3390/microorganisms10050886] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 03/29/2022] [Accepted: 04/17/2022] [Indexed: 01/27/2023] Open
Abstract
Traumatic peripheral nerve injuries tend to be more common in younger, working age populations and can lead to long-lasting disability. Peripheral nerves have an impressive capacity to regenerate; however, successful recovery after injury depends on a number of factors including the mechanism and severity of the trauma, the distance from injury to the reinnervation target, connective tissue sheath integrity, and delay between injury and treatment. Even though modern surgical procedures have greatly improved the success rate, many peripheral nerve injuries still culminate in persistent neuropathic pain and incomplete functional recovery. Recent studies in animals suggest that botulinum neurotoxin A (BoNT/A) can accelerate nerve regeneration and improve functional recovery after injury to peripheral nerves. Possible mechanisms of BoNT/A action include activation or proliferation of support cells (Schwann cells, mast cells, and macrophages), increased angiogenesis, and improvement of blood flow to regenerating nerves.
Collapse
Affiliation(s)
- Michael Adler
- Neuroscience Department, Medical Toxicology Division, U.S. Army Medical Research Institute of Chemical Defense, 8350 Ricketts Point Rd., Aberdeen Proving Ground, MD 21010, USA
- Correspondence: ; Tel.: +1-410-436-1913
| | - Sabine Pellett
- Department of Bacteriology, University of Wisconsin-Madison, 1550 Linden Drive, Madison, WI 53706, USA;
| | - Shashi K. Sharma
- Division of Microbiology, Center for Food Safety and Applied Nutrition, Food and Drug Administration, College Park, MD 20740, USA;
| | - Frank J. Lebeda
- Biotechnology, Protein Bioinformatics, Zanvyl Krieger School of Arts & Sciences, Johns Hopkins University, Advanced Academic Programs, 9601 Medical Center Drive, Rockville, MD 20850, USA;
| | - Zygmunt F. Dembek
- Department of Military and Emergency Medicine, Uniformed Services University of Health Sciences, 3154 Jones Bridge Rd., Bethesda, MD 20814, USA;
| | - Mark A. Mahan
- Department of Neurosurgery, Clinical Neurosciences, University of Utah, 175 N Medical Drive East, Salt Lake City, UT 84132, USA;
| |
Collapse
|
|
30
|
Afshani SM, Samadi A, Ayatollahi A, Kashani MN, Ahmad Nasdrollahi S, Hosseini H, Rezagholi Z, Hedayatjoo B, Fetratjoo DH, Ghobadi MA, Anari A, Saeedifar S, Firooz A. Evaluation of the Safety and Efficacy of a Biosimilar Abobotulinum Toxin Type A in Treating Moderate to Severe Glabellar Lines: A Non-Inferiority Double Blinded Randomized Controlled Trial. J Cosmet Dermatol 2022; 21:2398-2406. [PMID: 35340107 DOI: 10.1111/jocd.14939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 03/21/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Injection of botulinum toxin for cosmetic purposes is a well-established practice. OBJECTIVES This study was conducted to compare the safety and efficacy of Dyston® (investigational biosimilar abobotulinumtoxinA) with Dysport® (abobotulinumtoxinA, Ipsen) in the treatment of moderate to severe glabellar lines. METHODS Out of 193 screened subjects, 126 volunteers with moderate to severe glabellar lines fulfilling eligibility criteria were randomized in a 1:1 ratio to receive either an intramuscular injection of 40-60 units of Dyston® or Dysport® . The primary objective was to test the non-inferiority of Dyston® compared to Dysport® as measured by the percentage of volunteers who achieved no or mild glabellar lines at maximum frown assessed by the physicians based on the Glabellar Line Severity Score (GLSS) at day 30. Secondary endpoints included the improvement in the glabellar lines at maximum frown and rest states at days 14, 60, 90 and 120 as well as the side effects of the treatment. RESULTS Response rates at maximum frown were 75.44% (43/57) in the Dyston® group and 76.67% (46/60) in the Dysport® group on day 30 (P value: 0.88, 95%CI: -14.24 to 16.70, diff: 1.23) as per-protocol set, and were 75.81% (47/62) and 76.19 (48/63) (P value: 0.96, 95%CI: -14.59 to 15.35, diff: 0.3) in the Dyston® and the Dysport® groups, respectively, based on modified intention to treat population. Adverse events were similar in both groups and mostly mild and well-tolerated. CONCLUSION Treatment of moderate to severe glabellar lines with Dyston® was effective, tolerable, and non-inferior compared to Dysport® .
Collapse
Affiliation(s)
- Seyyedeh Maryam Afshani
- Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.,Medical Department, Arta pharmed Company, Tehran, Iran
| | - Aniseh Samadi
- Center for Research and Training in Skin diseases and Leprosy, Tehran University of Medical Sciences, Tehran, Iran
| | - Azin Ayatollahi
- Center for Research and Training in Skin diseases and Leprosy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mansour Nassiri Kashani
- Center for Research and Training in Skin diseases and Leprosy, Tehran University of Medical Sciences, Tehran, Iran
| | - Saman Ahmad Nasdrollahi
- Center for Research and Training in Skin diseases and Leprosy, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Hosseini
- Center for Research and Training in Skin diseases and Leprosy, Tehran University of Medical Sciences, Tehran, Iran.,Clinical Trial Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Rezagholi
- Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.,Medical Department, Arta pharmed Company, Tehran, Iran
| | | | - Delara Hazegh Fetratjoo
- Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.,Medical Department, Arta pharmed Company, Tehran, Iran
| | | | - AmirHossein Anari
- Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.,Medical Department, Arta pharmed Company, Tehran, Iran
| | - Sajjad Saeedifar
- Imen Vaccine Alborz, Biotechnology Research Center, Tehran, Iran
| | - Alireza Firooz
- Center for Research and Training in Skin diseases and Leprosy, Tehran University of Medical Sciences, Tehran, Iran.,Clinical Trial Center, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
31
|
Crook JL, Hamidian Jahromi A, Konofaos P. Long-term Effects of Repeated Botulinum Toxin Injection in Cosmetic Therapeutics. Ann Plast Surg 2022; 88:345-352. [PMID: 34611099 DOI: 10.1097/sap.0000000000002994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Botulinum toxin (BT), a potent neurotoxin, has been used in clinical medicine since the 1970s for cosmetic and therapeutic purposes. Studies have consistently shown positive outcomes with a very limited adverse effect profile and a conventional understanding that results dissipate after 3 to 5 months. However, more recent evidence suggests that changes in muscle composition, function, and appearance persist for much longer, even years. To examine the potential implications of these findings on cosmetic use of BT injections in reduction of skin lines and wrinkles, we first needed to further our understanding of the current literature on long-term outcomes after repeated BT injections. METHODS A comprehensive review of the literature on long-term outcomes after repeated BT injections for cosmetic indications was performed. We evaluated the study designs, and results were compared. RESULTS A total of 22 publications met our inclusion criteria, of which 14 were clinical trials. Few studies extended outcome measurement past 6 months postinjection, and many were funded or supported by industry. However, the studies that extended follow-up saw persistent changes after BT injection, in some cases as far as 4 years postinjection. CONCLUSION The current body of knowledge on the long-term results after repeated cosmetic BT injections is very limited, and the available literature provides insufficient evidence on how prolonged effects could alter clinical use of BT. Further clinical studies with extended follow-up periods with inclusion of both subjective and objective measured outcomes of appearance and muscle function are required to better understand the long-term impacts of repeated BT injections.
Collapse
Affiliation(s)
- Jennifer L Crook
- From the College of Medicine, University of Tennessee Health Science Center, Memphis, TN
| | | | - Petros Konofaos
- Department of Plastic Surgery, University of Tennessee Health Science Center, Memphis, TN
| |
Collapse
|
|
32
|
Kang WH, Ryu HJ, Kwak S, Yun HY. Model-Based Anticancer Effect of Botulinum Neurotoxin Type A1 on Syngeneic Melanoma Mice. Front Pharmacol 2022; 12:793349. [PMID: 35058777 PMCID: PMC8763961 DOI: 10.3389/fphar.2021.793349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 11/22/2021] [Indexed: 11/13/2022] Open
Abstract
In recent, Botulinum Neurotoxin A1 (BoNT/A1) has been suggested as a potential anticancer agent due to neuronal innervation in tumor cells. Although potential BoNT/A1's mechanism of action for the tumor suppression has been gradually revealed so far, there were no reports to figure out the exposure-response relationships because of the difficulty of its quantitation in the biological matrix. The main objectives of this study were to measure the anticancer effect of BoNT/A1 using a syngeneic mouse model transplanted with melanoma cells (B16-F10) and developed a kinetic-pharmacodynamic (K-PD) model for quantitative exposure-response evaluation. To overcome the lack of exposure information, the K-PD model was implemented by the virtual pharmacokinetic compartment link to the pharmacodynamic compartment of Simeoni's tumor growth inhibition model and evaluated using curve-fitting for the tumor growth-time profile after intratumoral injection of BoNT/A1. The final K-PD model was adequately explained for a pattern of tumor growth depending on represented exposure parameters and simulation studies were conducted to determine the optimal dose under various scenarios considering dose strength and frequency. The optimal dose range and regimen of ≥13.8 units kg-1 once a week or once every 3 days was predicted using the final model in B16-F10 syngeneic model and it was demonstrated with an extra in-vivo experiment. In conclusion, the K-PD model of BoNT/A1 was well developed to optimize the dosing regimen for evaluation of anticancer effect and this approach could be expandable to figure out quantitative interpretation of BoNT/A1's efficacy in various xenograft and/or syngeneic models.
Collapse
Affiliation(s)
- Won-Ho Kang
- Department of Pharmacology and Toxicology, Gwangyo R&D Center, Medytox Inc., Suwon, South Korea.,Department of Pharmacy, College of Pharmacy, Chungnam National University, Deajon, South Korea
| | - Hyo-Jeong Ryu
- Department of Pharmacology and Toxicology, Gwangyo R&D Center, Medytox Inc., Suwon, South Korea.,Department of Pharmacy, College of Pharmacy, Chungnam National University, Deajon, South Korea
| | - Seongsung Kwak
- Department of Pharmacology and Toxicology, Gwangyo R&D Center, Medytox Inc., Suwon, South Korea
| | - Hwi-Yeol Yun
- Department of Pharmacy, College of Pharmacy, Chungnam National University, Deajon, South Korea
| |
Collapse
|
|
33
|
Neuschäfer-Rube F, Pathe-Neuschäfer-Rube A, Püschel GP. Discrimination of the Activity of Low-Affinity Wild-Type and High-Affinity Mutant Recombinant BoNT/B by a SIMA Cell-Based Reporter Release Assay. Toxins (Basel) 2022; 14:toxins14010065. [PMID: 35051041 PMCID: PMC8780439 DOI: 10.3390/toxins14010065] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 01/05/2022] [Accepted: 01/13/2022] [Indexed: 12/12/2022] Open
Abstract
Botulinum neurotoxin (BoNT) is used for the treatment of a number of ailments. The activity of the toxin that is isolated from bacterial cultures is frequently tested in the mouse lethality assay. Apart from the ethical concerns inherent to this assay, species-specific differences in the affinity for different BoNT serotypes give rise to activity results that differ from the activity in humans. Thus, BoNT/B is more active in mice than in humans. The current study shows that the stimulus-dependent release of a luciferase from a differentiated human neuroblastoma–based reporter cell line (SIMA-hPOMC1-26-Gluc) was inhibited by clostridial and recombinant BoNT/A to the same extent, whereas both clostridial and recombinant BoNT/B inhibited the release to a lesser extent and only at much higher concentrations, reflecting the low activity of BoNT/B in humans. By contrast, the genetically modified BoNT/B-MY, which has increased affinity for human synaptotagmin, and the BoNT/B protein receptor inhibited luciferase release effectively and with an EC50 comparable to recombinant BoNT/A. This was due to an enhanced uptake into the reporter cells of BoNT/B-MY in comparison to the recombinant wild-type toxin. Thus, the SIMA-hPOMC1-26-Gluc cell assay is a versatile tool to determine the activity of different BoNT serotypes providing human-relevant dose-response data.
Collapse
|
|
34
|
Alvandipour M, Tavallaei M, Rezaei F, Khodabakhsh H. Postoperative outcomes of intrasphincteric botox injection during hemorrhoidectomy: A double-blind clinical trial. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2021; 26:53. [PMID: 34729061 PMCID: PMC8506240 DOI: 10.4103/jrms.jrms_612_18] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 08/15/2018] [Accepted: 12/30/2020] [Indexed: 11/04/2022]
Abstract
Background Pain is the most common postoperative complication of hemorrhoidectomy. We evaluated the effectiveness of intrasphincteric Botox injection on posthemorrhoidectomy complications including pain reduction and wound healing. Materials and Methods In this randomized, double-blind clinical trial, patients with Grades 3 or 4 symptomatic hemorrhoids who underwent open (Milligan-Morgan) hemorrhoidectomy were enrolled. The experimental group received intrasphincteric Botox injection during hemorrhoidectomy, while the controls received normal saline injection. Hemorrhoid grades, constipation status, history of hemorrhoidectomy, duration of operation, pain at rest and after defecation in six follow-up periods (6, 12, 24, and 48 h and 7 and 14 days after operation), wound healing (during follow-up after discharge with a 2-week period), analgesic use, and Botox side effects were evaluated and compared in the two experimental and control groups. Results In this trial, 34 and 33 patients were randomly allocated in the experimental and control groups, respectively. Operation time was significantly higher in Botox group (P = 0.009). Mean dose of analgesics use in Botox was significantly lower (P < 0.001). Rate of wound healing during follow-ups was significantly higher in Botox group in the fifth follow-up (P = 0.009). Frequency of urinary retention (P = 0.02) and moderate itching (P = 0.01) was significantly higher in placebo than Botox group. Mean of postoperative pain at rest in Botox group was significantly lower at 12th, 24th, and 48th h and 7th and 14th days after operation (P < 0.01). Mean of postoperative pain in Botox group was significantly lower at 3rd to 5th defecation (P < 0.01). Conclusion Our findings indicated that a single-dose injection of Botox during Milligan-Morgan hemorrhoidectomy is associated with less postsurgical pain at rest and during defecation and improved wound healing. It is suggested that it is a safe and effective procedure during hemorrhoidectomy regarding the procedure-related complications.
Collapse
Affiliation(s)
- Mina Alvandipour
- Department of Surgery, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Mazandaran Province, Iran
| | - Mehdi Tavallaei
- Department of Surgery, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fatemeh Rezaei
- Department of Medical Surgical Nursing, School of Nursing and Midwifery, Mazandaran University of Medical Sciences, Sari, Iran
| | - Hamed Khodabakhsh
- Department of Emergency Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| |
Collapse
|
|
35
|
Naik PP. Utilities of Botulinum Toxins in Dermatology and Cosmetology. Clin Cosmet Investig Dermatol 2021; 14:1319-1330. [PMID: 34584436 PMCID: PMC8464334 DOI: 10.2147/ccid.s332247] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 09/04/2021] [Indexed: 12/22/2022]
Abstract
Botulinum toxin (BoNT) is a neurotoxin produced by the Clostridium botulinum bacterium with a well-known efficacy and safety profile in the focal idiopathic hyperhidrosis treatment. BoNT comprises seven different neurotoxins; however, only toxins A and B are clinically employed. BoNT is lately practiced in off-label therapies for a variety of skin diseases. Scar prevention, hyperhidrosis, rhytides, eccrine nevus, alopecia, psoriasis, Darier disease, bullous skin disease, pompholyx and Raynaud's phenomenon are some of the novel indications for BoNT in cosmetic and notably non-cosmetic aspects of dermatology. To employ BoNT correctly in clinical practice, we must have a thorough understanding of the functional anatomy of the mimetic muscles. An intensive literature search was conducted to update all dermatology-oriented experiments and clinical trials on the described element of BoNT for this general overview of BoNT use in dermatology. This review aims to analyse the role of BoNT in dermatology and cosmetology.
Collapse
Affiliation(s)
- Piyu Parth Naik
- Department of Dermatology, Saudi German Hospital and Clinic, Dubai, United Arab Emirates
| |
Collapse
|
|
36
|
Marchitto MC, Chien AL. Mast Cell Stabilizers in the Treatment of Rosacea: A Review of Existing and Emerging Therapies. Dermatol Ther (Heidelb) 2021; 11:1541-1549. [PMID: 34476755 PMCID: PMC8484408 DOI: 10.1007/s13555-021-00597-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Indexed: 12/11/2022] Open
Abstract
Rosacea is a chronic inflammatory skin disease characterized by centrofacial erythema, papules, pustules, and telangiectasias. The onset of rosacea typically occurs after 30 years of age. It is estimated that approximately 2–5% of adults worldwide are affected. While the exact etiology of rosacea remains unknown, its pathogenesis is thought to be multifactorial with both environmental and genetic factors implicated. Ultraviolet radiation, heat, steam, ingested agents, including spicy foods and alcohol, host vasculature, dermal matrix degeneration, genetic susceptibility, and microbial organisms, including Demodex mites and Heliobacter pylori, have been implicated in the development of rosacea. Recently, mast cells (MCs) have emerged as key players in the pathogenesis of rosacea through the release of pro-inflammatory cytokines, chemokines, proteases, and antimicrobial peptides leading to cutaneous vasodilation, angiogenesis, and tissue fibrosis. Several existing and emerging topical, oral, and injectable therapeutics have been associated with improvement of rosacea symptoms based on their ability to stabilize and downregulate activated MCs. Herein, we review the data implicating MCs in the pathogenesis of rosacea and discuss interventions that may stabilize this pathway.
Collapse
Affiliation(s)
- Mark C Marchitto
- Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Anna L Chien
- Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
| |
Collapse
|
|
37
|
Nestor MS, Han H, Gade A, Fischer D, Saban Y, Polselli R. Botulinum toxin-induced blepharoptosis: Anatomy, etiology, prevention, and therapeutic options. J Cosmet Dermatol 2021; 20:3133-3146. [PMID: 34378298 PMCID: PMC9290925 DOI: 10.1111/jocd.14361] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/16/2021] [Accepted: 07/21/2021] [Indexed: 11/30/2022]
Abstract
Background Botulinum toxin A (BoNT‐A) has grown tremendously in aesthetic dermatology since 2002 when the United States Food and Drug Administration (FDA) first approved its use for treating moderate‐to‐severe glabellar lines. Blepharoptosis, due to local spread of toxin, is a reported side effect of BoNT‐A which, although rare, more frequently occurs among inexperienced practitioners. Objectives The purpose of this review is to highlight the causes and management of eyelid ptosis secondary to BoNT‐A administration including new anatomic pathways for BoNT‐A spread from the brow area to the levator palpebrae superioris muscle. Methods A literature search was conducted using electronic databases (PubMed, Science Direct, MEDLINE, Embase, CINAHL, EBSCO) regarding eyelid anatomy and the underlying pathogenesis, presentation, prevention, and treatment of eyelid ptosis secondary to BoNT‐A. Anatomic dissection has been performed to assess the role of neurovascular pedicles and supraorbital foramen anatomic variations. Results Blepharoptosis occurs due to weakness of the levator palpebrae superioris muscle. Mean onset is 3–14 days after injection and eventually self‐resolves after the paralytic effect of BoNT‐A wanes. Administration of medications, such as oxymetazoline hydrochloride or apraclonidine hydrochloride eye drops, anticholinesterase agents, or transdermal BoNT‐A injections to the pre‐tarsal orbicularis, can at least partially reverse eyelid ptosis. Anatomic study shows that a supraorbital foramen may be present in some patients and constitutes a shortcut from the brow area directly into the orbital roof, following the supraorbital neurovascular pedicle. Conclusion Providers should understand the anatomy and be aware of the causes and treatment for blepharoptosis when injecting BoNT‐A for the reduction of facial wrinkles. Thorough anatomic knowledge of the supraorbital area and orbital roof is paramount to preventing incorrect injection into “danger zones,” which increase the risk of eyelid ptosis.
Collapse
Affiliation(s)
- Mark S Nestor
- Center for Clinical and Cosmetic Research, Aventura, Florida, USA.,Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA.,Division of Plastic Surgery, Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Haowei Han
- Center for Clinical and Cosmetic Research, Aventura, Florida, USA
| | - Anita Gade
- Center for Clinical and Cosmetic Research, Aventura, Florida, USA
| | - Daniel Fischer
- Center for Clinical and Cosmetic Research, Aventura, Florida, USA
| | - Yves Saban
- Facial Plastic and Maxillofacial Surgery, Facial Anatomist, Nice, France.,European Academy of Facial Plastic Surgery (EAFPS), Lübeck, France.,Rhinoplasty Focus Group, Chennai, India
| | - Roberto Polselli
- Ear Nose Throat, Facial Plastic Surgery, Private Practice in Marina di Carrara, Marina di Carrara, Italy
| |
Collapse
|
|
38
|
Zargaran D, Zoller FE, Zargaran A, Mosahebi A. Complications of facial cosmetic botulinum toxin A injection: analysis of the UK Medicines & Healthcare Products Regulatory Agency registry and literature review. J Plast Reconstr Aesthet Surg 2021; 75:392-401. [PMID: 34456155 DOI: 10.1016/j.bjps.2021.05.074] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 05/29/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND Botulinum toxin A (BoNT-A) injection is one of the most frequently undertaken procedures in aesthetic medicine. The Medicines & Healthcare products Regulatory Agency (MHRA) is the government body in the United Kingdom (UK) mandated to ensure that the provision and administration of medicines is safe. We analyzed adverse events of facial cosmetic BoNT-A injections reported to the MHRA and assessed whether the incidence of reported adverse events in this government registry is comparable to published retrospective and prospective studies. METHODS A freedom of information (FOI) request was submitted to the MHRA to obtain recorded complications of BoNT- A. Complications reported to the MHRA between 1991 and 2020 were analyzed. Only cases with BoNT-A where the indication was specified as for facial cosmetics were included in the analysis. Additionally, the literature was reviewed on adverse events of facial cosmetic BoNT- A injections, and a statistical meta-analysis of complication rates was carried out. RESULTS A total of 188 adverse events of aesthetic BoNT-A injections were reported to the MHRA. The literature search resulted in 30 studies and a total of 17,352 injection sessions, where the complication rate was 16% (95% CI = 8% to 25%). Frequent adverse events included localized skin reactions such as bruising with an incidence of 5% (95% CI = 3% to 7%), headache in 3% (95% CI = from 1% to 5% ), and facial paresis in 2% (95% CI = 1% to 3%) of injection sessions. CONCLUSIONS This is the first paper to obtain and evaluate data on adverse events of BoNT-A from the MHRA. An estimate of the likely complication rate of aesthetic BoNT-A in the UK, according to the MHRA database, is significantly lower than the rate recorded from our meta-analysis of the international literature. This suggests that the MHRA may be underestimating the adverse events of aesthetic BoNT-A treatment, which would have implications for patient safety and informed consent. Therefore, legislative changes may be required to ensure more robust reporting of aesthetic BoNT-A in the UK.
Collapse
Affiliation(s)
- David Zargaran
- Department of Plastic Surgery, Royal Free Hospital, Pond Street, London, NW3 2QG.
| | - Florence E Zoller
- Department of Plastic Surgery, Royal Free Hospital, Pond Street, London, NW3 2QG
| | - Alexander Zargaran
- Department of Medicine, St Thomas' Hospital, Westminster Bridge Road, London, SE1 7EH, United Kingdom
| | - Afshin Mosahebi
- Department of Plastic Surgery, Royal Free Hospital, Pond Street, London, NW3 2QG
| |
Collapse
|
|
39
|
Mooney SS, Readman E, Hiscock RJ, Francis A, Fraser E, Ellett L. Botulinum toxin A (Botox) injection into muscles of pelvic floor as a treatment for persistent pelvic pain secondary to pelvic floor muscular spasm: A pilot study. Aust N Z J Obstet Gynaecol 2021; 61:777-784. [PMID: 34128537 DOI: 10.1111/ajo.13396] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/12/2021] [Accepted: 05/09/2021] [Indexed: 11/26/2022]
Abstract
BACKGROUND Persistent pelvic pain (PPP) remains an important cause of morbidity. Pelvic floor muscle spasm is an important contributor to PPP. AIMS The study's primary aim was to assess if botulinum toxin (BoNT) injection to pelvic floor muscles altered pain scores or quality of life (QoL) at six, 12 and 26 weeks. Secondary aims included investigating the impact of BoNT on opiate usage, examining the role of pain catastrophising, and assessing for complications. MATERIALS AND METHODS A single-centre prospective cohort study enrolled 21 patients with PPP who had failed physiotherapy techniques. Each participant underwent BoNT injection to muscles of the pelvic floor and pudendal nerve block. Questionnaires and digital vaginal examinations were conducted at baseline, six, 12 and 26 weeks. Pain score quantification used visual analogue scales (VAS) and numerical rating scales (NRS). Other outcome assessments included The World Health Organization Quality of Life instrument (WHOQoL-BREF), Pain Catastrophising Scale (PCS), and modified Australian Pelvic Floor Questionnaire (APFQ). ACTRN12620000067976. RESULTS Following BoNT injection, median VAS scores decreased for all domains at six and 12 weeks, with VAS for dyspareunia significant at six weeks (P = 0.026). Scores returned to baseline by 26 weeks. Opiate usage was significantly less following BoNT injection, with a percentage reduction of 23.8% (95% CI -48.3 to 0.7, P = 0.06). Sexual function improved significantly (P < 0.01), and at six months, four previously apareunic participants reported successful penetrative vaginal intercourse. Health-related QoL and PCS demonstrated sustained improvement (P = 0.02-0.05). NRS for muscle tenderness decreased for all assessed muscle groups (P < 0.001). CONCLUSIONS BoNT requires further assessment as a treatment modality for select women with PPP.
Collapse
Affiliation(s)
- Samantha S Mooney
- Endosurgery Department, Mercy Hospital for Women, Melbourne, Victoria, Australia
| | - Emma Readman
- Endosurgery Department, Mercy Hospital for Women, Melbourne, Victoria, Australia
| | - Richard J Hiscock
- Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Heidelberg, Victoria, Australia
| | - Alaina Francis
- Endosurgery Department, Mercy Hospital for Women, Melbourne, Victoria, Australia
| | - Elise Fraser
- Department of Physiotherapy, Mercy Hospital for Women, Melbourne, Victoria, Australia
| | - Lenore Ellett
- Endosurgery Department, Mercy Hospital for Women, Melbourne, Victoria, Australia
| |
Collapse
|
|
40
|
Characterization of clostridium botulinum neurotoxin serotype A (BoNT/A) and fibroblast growth factor receptor interactions using novel receptor dimerization assay. Sci Rep 2021; 11:7832. [PMID: 33837264 PMCID: PMC8035261 DOI: 10.1038/s41598-021-87331-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 03/24/2021] [Indexed: 01/03/2023] Open
Abstract
Clostridium botulinum neurotoxin serotype A (BoNT/A) is a potent neurotoxin that serves as an effective therapeutic for several neuromuscular disorders via induction of temporary muscular paralysis. Specific binding and internalization of BoNT/A into neuronal cells is mediated by its binding domain (HC/A), which binds to gangliosides, including GT1b, and protein cell surface receptors, including SV2. Previously, recombinant HC/A was also shown to bind to FGFR3. As FGFR dimerization is an indirect measure of ligand-receptor binding, an FCS & TIRF receptor dimerization assay was developed to measure rHC/A-induced dimerization of fluorescently tagged FGFR subtypes (FGFR1-3) in cells. rHC/A dimerized FGFR subtypes in the rank order FGFR3c (EC50 ≈ 27 nM) > FGFR2b (EC50 ≈ 70 nM) > FGFR1c (EC50 ≈ 163 nM); rHC/A dimerized FGFR3c with similar potency as the native FGFR3c ligand, FGF9 (EC50 ≈ 18 nM). Mutating the ganglioside binding site in HC/A, or removal of GT1b from the media, resulted in decreased dimerization. Interestingly, reduced dimerization was also observed with an SV2 mutant variant of HC/A. Overall, the results suggest that the FCS & TIRF receptor dimerization assay can assess FGFR dimerization with known and novel ligands and support a model wherein HC/A, either directly or indirectly, interacts with FGFRs and induces receptor dimerization.
Collapse
|
|
41
|
Memariani H, Memariani M, Moravvej H, Shahidi-Dadras M. Emerging and Novel Therapies for Keloids: A compendious review. Sultan Qaboos Univ Med J 2021; 21:e22-e33. [PMID: 33777420 PMCID: PMC7968901 DOI: 10.18295/squmj.2021.21.01.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 07/27/2020] [Accepted: 08/13/2020] [Indexed: 12/31/2022] Open
Abstract
Keloids are abnormal fibroproliferative scars with aggressive dermal growth expanding beyond the borders of the original injury. Different therapeutic modalities, such as corticosteroids, surgical excision, topical silicone gel sheeting, laser therapy, cryotherapy, photodynamic therapy and radiotherapy, have been used to treat keloids; however, none of these modalities has proven completely effective. Recently, researchers have devised several promising anti-keloid therapies including anti-hypertensive pharmaceuticals, calcineurin inhibitors, electrical stimulation, mesenchymal stem cell therapy, microneedle physical contact and ribonucleic acid-based therapies. The present review summarises emerging and novel treatments for keloids. PubMed® (National Library of Medicine, Bethesda, Maryland, USA), EMBASE (Elsevier, Amsterdam, Netherlands) and Web of Science (Clarivate Analytics, Philadelphia, Pennsylvania, USA) were searched for relevant literature published between January 1987 to June 2020. A total of 118 articles were included in this review. A deeper understanding of the molecular mechanisms underlying keloid scarring pathogenesis would open further avenues for developing innovative treatments.
Collapse
Affiliation(s)
- Hamed Memariani
- Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mojtaba Memariani
- Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamideh Moravvej
- Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | |
Collapse
|
|
42
|
Non-invasive Intrauterine Administration of Botulinum Toxin A Enhances Endometrial Angiogenesis and Improves the Rates of Embryo Implantation. Reprod Sci 2021; 28:1671-1687. [PMID: 33650094 PMCID: PMC8144131 DOI: 10.1007/s43032-021-00496-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 02/08/2021] [Indexed: 10/26/2022]
Abstract
Endometrial angiogenesis plays crucial roles in determining the endometrial receptivity. Defects in endometrial receptivity often cause repeated implantation failure, which is one of the major unmet needs for infertility and contributes a major barrier to the assisted reproductive technology. Despite the numerous extensive research work, there are currently no effective evidence-based treatments to prevent or cure this condition. As a non-invasive treatment strategy, botulinum toxin A (BoTA) was administered into one side of mouse uterine horns, and saline was infused into the other side of horns for the control. Impact of BoTA was assessed in the endometrium at 3 or 8 days after infusion. We demonstrated that BoTA administration enhances the capacity of endothelial cell tube formation and sprouting. The intrauterine BoTA administration significantly induced endometrial angiogenesis displaying increased numbers of vessel formation and expression levels of related marker genes. Moreover, BoTA intrauterine application promoted the endometrial receptivity, and the rates of embryo implantation were improved with BoTA treatment with no morphologically retarded embryos. Intrauterine BoTA treatment has a beneficial effect on vascular reconstruction of functional endometrium prior to embryo implantation by increasing endometrial blood flow near the uterine cavity suggesting BoTA treatment as a potential therapeutic strategy for patients who are suffering from repeated implantation failure with the problems with endometrial receptivity.
Collapse
|
|
43
|
Sikorra S, Donald S, Elliott M, Schwede S, Coker SF, Kupinski AP, Tripathi V, Foster K, Beard M, Binz T. Engineering an Effective Human SNAP-23 Cleaving Botulinum Neurotoxin A Variant. Toxins (Basel) 2020; 12:toxins12120804. [PMID: 33352834 PMCID: PMC7766560 DOI: 10.3390/toxins12120804] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/11/2020] [Accepted: 12/13/2020] [Indexed: 12/13/2022] Open
Abstract
Botulinum neurotoxin (BoNT) serotype A inhibits neurotransmitter release by cleaving SNAP-25 and represents an established pharmaceutical for treating medical conditions caused by hyperactivity of cholinergic nerves. Oversecretion from non-neuronal cells is often also the cause of diseases. Notably, excessive release of inflammatory messengers is thought to contribute to diseases such as chronic obstructive pulmonary disease, asthma, diabetes etc. The expansion of its application to these medical conditions is prevented because the major non-neuronal SNAP-25 isoform responsible for exocytosis, SNAP-23, is, in humans, virtually resistant to BoNT/A. Based on previous structural data and mutagenesis studies of SNAP-23 we optimized substrate binding pockets of the enzymatic domain for interaction with SNAP-23. Systematic mutagenesis and rational design yielded the mutations E148Y, K166F, S254A, and G305D, each of which individually increased the activity of LC/A against SNAP-23 between 3- to 23-fold. The assembled quadruple mutant showed approximately 2000-fold increased catalytic activity against human SNAP-23 in in vitro cleavage assays. A comparable increase in activity was recorded for the full-length BoNT/A quadruple mutant tested in cultivated primary neurons transduced with a fluorescently tagged-SNAP-23 encoding gene. Equipped with a suitable targeting domain this quadruple mutant promises to complete successfully tests in cells of the immune system.
Collapse
Affiliation(s)
- Stefan Sikorra
- Institut für Zellbiochemie, OE 4310, Medizinische Hochschule Hannover, 30623 Hannover, Germany; (S.S.); (S.S.)
| | - Sarah Donald
- Ipsen Bioinnovation, 102 Park Drive, Milton Park, Abingdon OX14 4RY, UK; (S.D.); (M.E.); (S.-F.C.); (A.P.K.); (V.T.); (K.F.)
| | - Mark Elliott
- Ipsen Bioinnovation, 102 Park Drive, Milton Park, Abingdon OX14 4RY, UK; (S.D.); (M.E.); (S.-F.C.); (A.P.K.); (V.T.); (K.F.)
| | - Susan Schwede
- Institut für Zellbiochemie, OE 4310, Medizinische Hochschule Hannover, 30623 Hannover, Germany; (S.S.); (S.S.)
| | - Shu-Fen Coker
- Ipsen Bioinnovation, 102 Park Drive, Milton Park, Abingdon OX14 4RY, UK; (S.D.); (M.E.); (S.-F.C.); (A.P.K.); (V.T.); (K.F.)
| | - Adam P. Kupinski
- Ipsen Bioinnovation, 102 Park Drive, Milton Park, Abingdon OX14 4RY, UK; (S.D.); (M.E.); (S.-F.C.); (A.P.K.); (V.T.); (K.F.)
| | - Vineeta Tripathi
- Ipsen Bioinnovation, 102 Park Drive, Milton Park, Abingdon OX14 4RY, UK; (S.D.); (M.E.); (S.-F.C.); (A.P.K.); (V.T.); (K.F.)
| | - Keith Foster
- Ipsen Bioinnovation, 102 Park Drive, Milton Park, Abingdon OX14 4RY, UK; (S.D.); (M.E.); (S.-F.C.); (A.P.K.); (V.T.); (K.F.)
| | - Matthew Beard
- Ipsen Bioinnovation, 102 Park Drive, Milton Park, Abingdon OX14 4RY, UK; (S.D.); (M.E.); (S.-F.C.); (A.P.K.); (V.T.); (K.F.)
- Correspondence: (M.B.); (T.B.); Tel.: +44(0)7850-910340 (M.B.); +49(0)511-532-2859 (T.B.)
| | - Thomas Binz
- Institut für Zellbiochemie, OE 4310, Medizinische Hochschule Hannover, 30623 Hannover, Germany; (S.S.); (S.S.)
- Correspondence: (M.B.); (T.B.); Tel.: +44(0)7850-910340 (M.B.); +49(0)511-532-2859 (T.B.)
| |
Collapse
|
|
44
|
McLean T, Norbury L, Conduit R, Shepherd N, Coloe P, Sasse A, Smooker P. Inactivated tetanus as an immunological smokescreen: A major step towards harnessing tetanus-based therapeutics. Mol Immunol 2020; 127:164-174. [PMID: 33002728 DOI: 10.1016/j.molimm.2020.09.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 09/01/2020] [Accepted: 09/08/2020] [Indexed: 11/24/2022]
Abstract
BACKGROUND AND PURPOSE Tetanus neurotoxin has many potential therapeutic applications, due to its ability to increase localised muscle tone when injected directly into a muscle. It is a closely related molecule to botulinum neurotoxin (most commonly known as Botox), which has been widely used to release muscle tension for therapeutic and cosmetic applications. However, tetanus toxin has been relegated to the "maybe pile" for protein therapeutics - as most of the population is vaccinated, leading to highly effective antibody-mediated protection against the toxin. The potential for tetanus-based therapeutics remains substantial if the problem of pre-existing immunity can be resolved. EXPERIMENTAL APPROACH A well-established murine model of localised muscular contraction was utilised. We administered functional tetanus toxin combined with an immunogenic, but functionally inactive, decoy molecule. KEY RESULTS Incorporation of the decoy molecule greatly reduces the dose of active toxin required to induce a localised increase in muscle tone in mice vaccinated with the human toxoid vaccine. CONCLUSION AND IMPLICATIONS Our results clearly demonstrate that the barriers to developing a tetanus toxin therapeutic are not insurmountable and the technology presented here is the first major step towards realising the therapeutic potential of this powerful neurotoxin. Opening the therapeutic potential of tetanus toxin will have huge implications for the wide range of diseases caused by low-tone muscle.
Collapse
Affiliation(s)
- Thomas McLean
- Bioscience and Food Technology, School of Science, Plenty Road, Building 223 Bundoora West campus, RMIT University, Bundoora, VIC 3083, Australia.
| | - Luke Norbury
- Bioscience and Food Technology, School of Science, Plenty Road, Building 223 Bundoora West campus, RMIT University, Bundoora, VIC 3083, Australia.
| | - Russell Conduit
- School of Health and Biomedical Sciences, College of Science, Engineering and Health, RMIT University, Bundoora, VIC 3083, Australia.
| | - Natalie Shepherd
- Bioscience and Food Technology, School of Science, Plenty Road, Building 223 Bundoora West campus, RMIT University, Bundoora, VIC 3083, Australia
| | - Peter Coloe
- Bioscience and Food Technology, School of Science, Plenty Road, Building 223 Bundoora West campus, RMIT University, Bundoora, VIC 3083, Australia.
| | - Anthony Sasse
- Bioscience and Food Technology, School of Science, Plenty Road, Building 223 Bundoora West campus, RMIT University, Bundoora, VIC 3083, Australia; Latrobe Regional Hospital, Gippsland, Australia.
| | - Peter Smooker
- Bioscience and Food Technology, School of Science, Plenty Road, Building 223 Bundoora West campus, RMIT University, Bundoora, VIC 3083, Australia.
| |
Collapse
|
|
45
|
Reddy AG, Dick BP, Natale C, Akula KP, Yousif A, Hellstrom WJG. Application of Botulinum Neurotoxin in Male Sexual Dysfunction: Where Are We Now? Sex Med Rev 2020; 9:320-330. [PMID: 32641225 DOI: 10.1016/j.sxmr.2020.05.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 05/11/2020] [Accepted: 05/21/2020] [Indexed: 11/26/2022]
Abstract
INTRODUCTION Botulinum neurotoxin (BoNT) is a recognized therapeutic agent of modern medical care, routinely used to treat medical conditions affecting a variety of organ systems including the musculoskeletal, integumentary, and urological domains. Ongoing research is exploring BoNT's potential role as a therapeutic agent for a variety of male sexual pathologies. OBJECTIVE To review and analyze the literature regarding BoNT as a treatment option for male sexual dysfunction. METHODS A PubMed search was performed for English-language articles in peer-reviewed journals between 1970 and 2019 (with one article from 1897). Relevant articles referenced within these texts were also included. One article did not have an accompanied English full-text available. The following search terms were used: "Botox", "Botulinum toxin", "Botulinum toxin A", "Onabotulinum A", "Abobutlinum A", "BoNT", "BoNT-A", "Male sexual health", "Male sexual pathology", "Peyronie's disease", "Premature ejaculation", "Scrotal Pain", "Penile Retraction", "Scrotox", "Erectile Dysfunction", and "Botox in Urology". RESULTS There is interest in the potential role of BoNT in the treatment of male sexual pathologies. We identified studies that used BoNT to treat chronic scrotal content pain, premature ejaculation, erectile dysfunction, Peyronie's disease, penile retraction, and more. However, despite preclinical/clinical data indicating some potential efficacy and safety in these settings, a lack of robust clinical trial data has resulted in no current Food and Drug Administration-approved indications for the use of BoNT in the treatment of male sexual pathology. As a result, much of the current use of BoNT by today's providers is "off-label," and ongoing clinical trials aim to further elucidate the potential role of this therapeutic agent. CONCLUSION Current data suggest that BoNT could have a potential role as a treatment option for certain types of male sexual pathologies. However, more randomized controlled trial data regarding its long-term safety and efficacy are necessary before a widespread clinical adoption can take place. Reddy AG, Dick BP, Natale C, et al. Application of Botulinum Neurotoxin in Male Sexual Dysfunction: Where Are We Now?. J Sex Med 2021;9:320-330.
Collapse
Affiliation(s)
- Amit G Reddy
- Department of Urology, Tulane University School of Medicine, New Orleans, USA
| | - Brian P Dick
- Department of Urology, Tulane University School of Medicine, New Orleans, USA
| | - Caleb Natale
- Department of Urology, Tulane University School of Medicine, New Orleans, USA
| | - Kole P Akula
- Department of Urology, Tulane University School of Medicine, New Orleans, USA
| | - Ayad Yousif
- Department of Urology, Tulane University School of Medicine, New Orleans, USA
| | - Wayne J G Hellstrom
- Department of Urology, Tulane University School of Medicine, New Orleans, USA.
| |
Collapse
|
|
46
|
|
|
47
|
Neurons, Glia, Extracellular Matrix and Neurovascular Unit: A Systems Biology Approach to the Complexity of Synaptic Plasticity in Health and Disease. Int J Mol Sci 2020; 21:ijms21041539. [PMID: 32102370 PMCID: PMC7073232 DOI: 10.3390/ijms21041539] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 02/19/2020] [Accepted: 02/20/2020] [Indexed: 02/06/2023] Open
Abstract
The synaptic cleft has been vastly investigated in the last decades, leading to a novel and fascinating model of the functional and structural modifications linked to synaptic transmission and brain processing. The classic neurocentric model encompassing the neuronal pre- and post-synaptic terminals partly explains the fine-tuned plastic modifications under both pathological and physiological circumstances. Recent experimental evidence has incontrovertibly added oligodendrocytes, astrocytes, and microglia as pivotal elements for synapse formation and remodeling (tripartite synapse) in both the developing and adult brain. Moreover, synaptic plasticity and its pathological counterpart (maladaptive plasticity) have shown a deep connection with other molecular elements of the extracellular matrix (ECM), once considered as a mere extracellular structural scaffold altogether with the cellular glue (i.e., glia). The ECM adds another level of complexity to the modern model of the synapse, particularly, for the long-term plasticity and circuit maintenance. This model, called tetrapartite synapse, can be further implemented by including the neurovascular unit (NVU) and the immune system. Although they were considered so far as tightly separated from the central nervous system (CNS) plasticity, at least in physiological conditions, recent evidence endorsed these elements as structural and paramount actors in synaptic plasticity. This scenario is, as far as speculations and evidence have shown, a consistent model for both adaptive and maladaptive plasticity. However, a comprehensive understanding of brain processes and circuitry complexity is still lacking. Here we propose that a better interpretation of the CNS complexity can be granted by a systems biology approach through the construction of predictive molecular models that enable to enlighten the regulatory logic of the complex molecular networks underlying brain function in health and disease, thus opening the way to more effective treatments.
Collapse
|
|
48
|
SNAP-25 Puts SNAREs at Center Stage in Metabolic Disease. Neuroscience 2019; 420:86-96. [DOI: 10.1016/j.neuroscience.2018.07.035] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 07/12/2018] [Accepted: 07/19/2018] [Indexed: 12/20/2022]
|
|
49
|
Traini C, Vannucchi MG. The Botulinum Treatment of Neurogenic Detrusor Overactivity: The Double-Face of the Neurotoxin. Toxins (Basel) 2019; 11:E614. [PMID: 31652991 PMCID: PMC6891665 DOI: 10.3390/toxins11110614] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 10/18/2019] [Accepted: 10/20/2019] [Indexed: 12/13/2022] Open
Abstract
Botulinum neurotoxin (BoNT) can counteract the highly frequent involuntary muscle contractions and the uncontrolled micturition events that characterize the neurogenic detrusor overactivity (NDO) due to supra-sacral spinal cord lesions. The ability of the toxin to block the neurotransmitter vesicular release causes the reduction of contractions and improves the compliance of the muscle and the bladder filling. BoNT is the second-choice treatment for NDO once the anti-muscarinic drugs have lost their effects. However, the toxin shows a time-dependent efficacy reduction up to a complete loss of activity. The cellular mechanisms responsible for BoNT effects exhaustion are not yet completely defined. Similarly, also the sites of its action are still under identification. A growing amount of data suggest that BoNT, beyond the effects on the efferent terminals, would act on the sensory system recently described in the bladder mucosa. The specimens from NDO patients no longer responding to BoNT treatment displayed a significant increase of the afferent terminals, likely excitatory, and signs of a chronic neurogenic inflammation in the mucosa. In summary, beyond the undoubted benefits in ameliorating the NDO symptomatology, BoNT treatment might bring to alterations in the bladder sensory system able to shorten its own effectiveness.
Collapse
Affiliation(s)
- Chiara Traini
- Department of Experimental and Clinical Medicine, Research Unit of Histology and Embryology, University of Florence, 50139 Florence, Italy.
| | - Maria Giuliana Vannucchi
- Department of Experimental and Clinical Medicine, Research Unit of Histology and Embryology, University of Florence, 50139 Florence, Italy.
| |
Collapse
|
|
50
|
Pons L, Vilain C, Volteau M, Picaut P. Safety and pharmacodynamics of a novel recombinant botulinum toxin E (rBoNT-E): Results of a phase 1 study in healthy male subjects compared with abobotulinumtoxinA (Dysport®). J Neurol Sci 2019; 407:116516. [PMID: 31655410 DOI: 10.1016/j.jns.2019.116516] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 08/30/2019] [Accepted: 09/30/2019] [Indexed: 12/26/2022]
Abstract
Naturally occurring botulinum toxin (BoNT) serotypes have different pharmacological features of therapeutic and aesthetic interest. This phase 1, double-blind, placebo-controlled study (EudraCT: 2016-002609-20) assessed safety, tolerability and pharmacodynamics (PD) of the first recombinant BoNT serotype E (rBoNT-E) versus abobotulinumtoxinA (Dysport®), administered to extensor digitorum brevis (EDB) of healthy males. Subjects were randomised 3:1 (n = 28) to single ascending rBoNT-E (0.04-3.6 ng) doses or placebo. A further 24 subjects received abobotulinumtoxinA (20, 40, or 70 U) or placebo. PD were assessed using compound muscle action potential (CMAP) amplitude. Demographics were similar between groups. All rBoNT-E doses were well tolerated (no severe treatment-emergent adverse events [TEAEs], serious adverse events, or treatment-related toxicities). Most TEAEs were mild/moderate and treatment-unrelated. rBoNT-E had a faster onset of action (days 1-2 post-injection), greater peak effect (>90% CMAP inhibition), and shorter duration of effect at highest tested doses versus abobotulinumtoxinA (onset of action ≤7 days post-injection; 70% maximal CMAP inhibition). rBoNT-E duration of effect was 2-7 weeks versus >26 weeks for abobotulinumtoxinA. Dose-dependent effects were observed for magnitude and duration of EDB CMAP inhibition, plateauing at 0.9 and 3.6 ng. rBoNT-E demonstrated a good safety profile and a PD profile that may address unmet therapeutic and aesthetic patient needs.
Collapse
|