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Journal of Neurochemistry Sep 2021Tetanus is a deadly but preventable disease caused by a protein neurotoxin produced by Clostridium tetani. Spores of C. tetani may contaminate a necrotic wound and... (Review)
Review
Tetanus is a deadly but preventable disease caused by a protein neurotoxin produced by Clostridium tetani. Spores of C. tetani may contaminate a necrotic wound and germinate into a vegetative bacterium that releases a toxin, termed tetanus neurotoxin (TeNT). TeNT enters the general circulation, binds to peripheral motor neurons and sensory neurons, and is transported retroaxonally to the spinal cord. It then enters inhibitory interneurons and blocks the release of glycine or GABA causing a spastic paralysis. This review attempts to correlate the metalloprotease activity of TeNT and its trafficking and localization into the vertebrate body to the nature and sequence of appearance of the symptoms of tetanus.
Topics: Animals; Brain; Humans; Neurotoxins; Peripheral Nerves; Spinal Cord; Tetanus; Tetanus Toxin; Tetanus Toxoid
PubMed: 33629408
DOI: 10.1111/jnc.15330 -
Pharmacological Reviews Apr 2017The study of botulinum neurotoxins (BoNT) is rapidly progressing in many aspects. Novel BoNTs are being discovered owing to next generation sequencing, but their... (Review)
Review
The study of botulinum neurotoxins (BoNT) is rapidly progressing in many aspects. Novel BoNTs are being discovered owing to next generation sequencing, but their biologic and pharmacological properties remain largely unknown. The molecular structure of the large protein complexes that the toxin forms with accessory proteins, which are included in some BoNT type A1 and B1 pharmacological preparations, have been determined. By far the largest effort has been dedicated to the testing and validation of BoNTs as therapeutic agents in an ever increasing number of applications, including pain therapy. BoNT type A1 has been also exploited in a variety of cosmetic treatments, alone or in combination with other agents, and this specific market has reached the size of the one dedicated to the treatment of medical syndromes. The pharmacological properties and mode of action of BoNTs have shed light on general principles of neuronal transport and protein-protein interactions and are stimulating basic science studies. Moreover, the wide array of BoNTs discovered and to be discovered and the production of recombinant BoNTs endowed with specific properties suggest novel uses in therapeutics with increasing disease/symptom specifity. These recent developments are reviewed here to provide an updated picture of the biologic mechanism of action of BoNTs, of their increasing use in pharmacology and in cosmetics, and of their toxicology.
Topics: Animals; Botulinum Toxins; Humans; Neurotoxins
PubMed: 28356439
DOI: 10.1124/pr.116.012658 -
Toxins Mar 2016Botulinum neurotoxin has revolutionized the treatment of spasticity and is now administered worldwide. There are currently three leading botulinum neurotoxin type A... (Review)
Review
Botulinum neurotoxin has revolutionized the treatment of spasticity and is now administered worldwide. There are currently three leading botulinum neurotoxin type A products available in the Western Hemisphere: onabotulinum toxin-A (ONA) Botox(®), abobotulinum toxin-A (ABO), Dysport(®), and incobotulinum toxin A (INCO, Xeomin(®)). Although the efficacies are similar, there is an intense debate regarding the comparability of various preparations. Here we will address the clinical issues of potency and conversion ratios, as well as safety issues such as toxin spread and immunogenicity, to provide guidance for BoNT-A use in clinical practice. INCO was shown to be as effective as ONA with a comparable adverse event profile when a clinical conversion ratio of 1:1 was used. The available clinical and preclinical data suggest that a conversion ratio ABO:ONA of 3:1-or even lower-could be appropriate for treating spasticity, cervical dystonia, and blepharospasm or hemifacial spasm. A higher conversion ratio may lead to an overdosing of ABO. While uncommon, distant spread may occur; however, several factors other than the pharmaceutical preparation are thought to affect spread. Finally, whereas the three products have similar efficacy when properly dosed, ABO has a better cost-efficacy profile.
Topics: Acetylcholine Release Inhibitors; Animals; Botulinum Toxins, Type A; Dystonic Disorders; Humans; Muscle Spasticity; Neuromuscular Agents; Neurotoxins
PubMed: 26959061
DOI: 10.3390/toxins8030065 -
Toxins Dec 2018Botulinum neurotoxin type-A (BoNT-A) blocks the release of acetylcholine from peripheral cholinergic nerve terminals and is an important option for the treatment of... (Comparative Study)
Comparative Study
AbobotulinumtoxinA (Dysport), OnabotulinumtoxinA (Botox), and IncobotulinumtoxinA (Xeomin) Neurotoxin Content and Potential Implications for Duration of Response in Patients.
Botulinum neurotoxin type-A (BoNT-A) blocks the release of acetylcholine from peripheral cholinergic nerve terminals and is an important option for the treatment of disorders characterised by excessive cholinergic neuronal activity. Several BoNT-A products are currently marketed, each with unique manufacturing processes, excipients, formulation, and non-interchangeable potency units. Nevertheless, the effects of all the products are mediated by the 150 kDa BoNT-A neurotoxin. We assessed the quantity and light chain (LC) activity of BoNT-A in three commercial BoNT-A products (Dysport; Botox; Xeomin). We quantified 150 kDa BoNT-A by sandwich ELISA and assessed LC activity by EndoPep assay. In both assays, we assessed the results for the commercial products against recombinant 150 kDa BoNT-A. The mean 150 kDa BoNT-A content per vial measured by ELISA was 2.69 ng/500 U vial Dysport, 0.90 ng/100 U vial Botox, and 0.40 ng/100 U vial Xeomin. To present clinically relevant results, we calculated the 150 kDa BoNT-A/US Food and Drug Administration (FDA)-approved dose in adult upper limb spasticity: 5.38 ng Dysport (1000 U; 2 × 500 U vials), 3.60 ng Botox (400 U; 4 × 100 U vials), and 1.61 ng Xeomin (400 U; 4 × 100 U vials). EndoPep assay showed similar LC activity among BoNT-A products. Thus, greater amounts of active neurotoxin are injected with Dysport, at FDA-approved doses, than with other products. This fact might explain the long duration of action reported across multiple indications, which benefits patients, caregivers, clinicians, and healthcare systems.
Topics: Botulinum Toxins, Type A; Enzyme-Linked Immunosorbent Assay; Humans; Muscle Spasticity; Neuromuscular Agents; Neurotoxins; Treatment Outcome
PubMed: 30551641
DOI: 10.3390/toxins10120535 -
Skin Therapy Letter Jul 2023Botulinum toxin A (BoNTA) is produced by Clostridium botulinum and widely used for aesthetic indications requiring neuromuscular blockade. For dynamic facial lines,... (Review)
Review
Botulinum toxin A (BoNTA) is produced by Clostridium botulinum and widely used for aesthetic indications requiring neuromuscular blockade. For dynamic facial lines, BoNTA is effective and safe, but also temporary, requiring repeat injections approximately every 3-4 months for maintenance of effects. There is a desire by both patients and providers for a longer-lasting neurotoxin to prevent periods of suboptimal correction. Approved by the US Food and Drug Administration (FDA) in September 2022, daxibotulinumtoxinA for injection (DAXI or Daxxify™) is the first long-lasting BoNTA formulated with a 150-kDa BoNTA (RTT150) and proprietary stabilizing excipient peptide (RTP004) in place of human serum albumin. DAXI is approved for treatment of moderate to severe glabellar lines. The median duration of effect was 6 months and results lasted as long as 9 months in some patients. Its unique formulation and prolonged effectiveness positions DAXI as a safe, novel BoNTA for improved durability and patient satisfaction.
Topics: Humans; Botulinum Toxins, Type A; Face; Neurotoxins; Patient Satisfaction; Skin Aging
PubMed: 37440610
DOI: No ID Found -
Translational Stroke Research Oct 2022After a cerebral hemorrhage (intracerebral, subarachnoid, and intraventricular), extravasated blood contributes to both initial brain injury, via physical disruption and... (Review)
Review
After a cerebral hemorrhage (intracerebral, subarachnoid, and intraventricular), extravasated blood contributes to both initial brain injury, via physical disruption and mass effect, and secondary injury, through the release of potentially neurotoxic and pro-inflammatory factors such as hemoglobin, iron, and peroxiredoxin-2. Erythrocytes are a major blood component and are a source of such damaging factors. Erythrolysis after cerebral hemorrhage releases potential neurotoxins, contributing to brain injury and edema. Alternatively, erythrocyte phagocytosis via microglia or macrophages may limit the spill of neurotoxins therefore limiting subsequent brain injury. The aim of this review is to discuss the process of phagocytosis of erythrocytes by microglia or macrophages after cerebral hemorrhage, the effect of erythrolysis on brain injury, novel mechanisms of erythrocyte and phagocyte egress from the brain, and exciting new targets in this pathway to attenuate brain injury. Understanding the fate of erythrocytes after cerebral hemorrhage may uncover additional potential interventions for clinical translational research.
Topics: Brain Injuries; Cerebral Hemorrhage; Erythrocytes; Hemolysis; Humans; Microglia; Neurotoxins
PubMed: 35066815
DOI: 10.1007/s12975-021-00980-8 -
Life Sciences 1993The venom of the Eastern green mamba from Africa, Dendroaspis angusticeps, contains a number of toxins which block the binding of 3H-antagonists to genetically-defined... (Review)
Review
The venom of the Eastern green mamba from Africa, Dendroaspis angusticeps, contains a number of toxins which block the binding of 3H-antagonists to genetically-defined m1 and m4 muscarinic acetylcholine receptors. Most of the anti-muscarinic activity of the venom is due to the presence of a newly-isolated toxin, "m1-toxin", which has 64 amino acids and a molecular mass of 7361 Daltons. At present m1-toxin is the only ligand which is known to be capable of fully blocking m1 receptors without affecting m2-m5 receptors. It binds very rapidly, specifically and pseudoirreversibly to the extracellular face of m1 receptors on cells, in membranes or in solution, whether or not the primary receptor site is occupied by an antagonist. Bound toxin can either prevent the binding and action of agonists or antagonists, or prevent the dissociation of antagonists. The toxin is useful for identifying m1 receptors during anatomical and functional studies, for recognizing and stabilizing receptor complexes, and for occluding m1 receptors so that other receptors are more readily studied.
Topics: Acetylcholine; Animals; CHO Cells; Cricetinae; Elapid Venoms; Ligands; Muscarinic Antagonists; Neurotoxins
PubMed: 8441325
DOI: 10.1016/0024-3205(93)90299-i -
Toxins Oct 2022Two 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... (Review)
Review
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.
Topics: Humans; Botulinum Toxins; Antipruritics; Pruritus; Neurons; Neurotoxins
PubMed: 36287970
DOI: 10.3390/toxins14100701 -
Toxins May 2022and are Gram-positive, spore-forming, and anaerobic bacteria that produce the most potent neurotoxins, botulinum toxin (BoNT) and tetanus toxin (TeNT), responsible for... (Review)
Review
and are Gram-positive, spore-forming, and anaerobic bacteria that produce the most potent neurotoxins, botulinum toxin (BoNT) and tetanus toxin (TeNT), responsible for flaccid and spastic paralysis, respectively. The main habitat of these toxigenic bacteria is the environment (soil, sediments, cadavers, decayed plants, intestinal content of healthy carrier animals). can grow and produce BoNT in food, leading to food-borne botulism, and in some circumstances, can colonize the intestinal tract and induce infant botulism or adult intestinal toxemia botulism. More rarely, colonizes wounds, whereas tetanus is always a result of wound contamination by The synthesis of neurotoxins is strictly regulated by complex regulatory networks. The highest levels of neurotoxins are produced at the end of the exponential growth and in the early stationary growth phase. Both microorganisms, except E, share an alternative sigma factor, BotR and TetR, respectively, the genes of which are located upstream of the neurotoxin genes. These factors are essential for neurotoxin gene expression. and share also a two-component system (TCS) that negatively regulates neurotoxin synthesis, but each microorganism uses additional distinct sets of TCSs. Neurotoxin synthesis is interlocked with the general metabolism, and CodY, a master regulator of metabolism in Gram-positive bacteria, is involved in both clostridial species. The environmental and nutritional factors controlling neurotoxin synthesis are still poorly understood. The transition from amino acid to peptide metabolism seems to be an important factor. Moreover, a small non-coding RNA in , and quorum-sensing systems in and possibly in , also control toxin synthesis. However, both species use also distinct regulatory pathways; this reflects the adaptation of and to different ecological niches.
Topics: Animals; Botulinum Toxins; Botulism; Clostridium botulinum; Clostridium tetani; Humans; Neurotoxins
PubMed: 35737025
DOI: 10.3390/toxins14060364 -
Current Biology : CB Oct 2016In this Quick Guide, Lorentz et al. discuss the function of tetrodotoxin and its distribution in the animal kingdom.
In this Quick Guide, Lorentz et al. discuss the function of tetrodotoxin and its distribution in the animal kingdom.
Topics: Animals; Invertebrates; Neurotoxins; Organ Specificity; Tetrodotoxin; Vertebrates
PubMed: 27728785
DOI: 10.1016/j.cub.2016.05.067