Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology.
01 Apr 2017-Pharmacological Reviews (American Society for Pharmacology and Experimental Therapeutics)-Vol. 69, Iss: 2, pp 200-235
TL;DR: 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, and suggest novel uses in therapeutics with increasing disease/symptom specifity.
Abstract: 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.
Citations
More filters
TL;DR: The impact of environmental stressors in contributing to muscle pathophysiology including atrophy, hypertrophy, and fibrosis is emphasized.
Abstract: Decades of research in skeletal muscle physiology have provided multiscale insights into the structural and functional complexity of this important anatomical tissue, designed to accomplish the task of generating contraction, force and movement. Skeletal muscle can be viewed as a biomechanical device with various interacting components including the autonomic nerves for impulse transmission, vasculature for efficient oxygenation, and embedded regulatory and metabolic machinery for maintaining cellular homeostasis. The "omics" revolution has propelled a new era in muscle research, allowing us to discern minute details of molecular cross-talk required for effective coordination between the myriad interacting components for efficient muscle function. The objective of this review is to provide a systems-level, comprehensive mapping the molecular mechanisms underlying skeletal muscle structure and function, in health and disease. We begin this review with a focus on molecular mechanisms underlying muscle tissue development (myogenesis), with an emphasis on satellite cells and muscle regeneration. We next review the molecular structure and mechanisms underlying the many structural components of the muscle: neuromuscular junction, sarcomere, cytoskeleton, extracellular matrix, and vasculature surrounding muscle. We highlight aberrant molecular mechanisms and their possible clinical or pathophysiological relevance. We particularly emphasize the impact of environmental stressors (inflammation and oxidative stress) in contributing to muscle pathophysiology including atrophy, hypertrophy, and fibrosis. This article is categorized under: Physiology > Mammalian Physiology in Health and Disease Developmental Biology > Developmental Processes in Health and Disease Models of Systems Properties and Processes > Cellular Models.
225 citations
TL;DR: The use of botulinun neurotoxin has been expanding during the past 3 decades to include the treatment of a variety of ophthalmologic, gastrointestinal, urologic, orthopedic, dermatologic, dental, secretory, painful, cosmetic, and other conditions.
Abstract: Botulinun neurotoxin (BoNT) has emerged as one of the most multipurpose therapeutic agents in modern medicine with more clinical applications than any other drug currently on the market. Initially developed in the treatment of strabismus and neurologic movement disorders, the use of botulinun neurotoxin has been expanding during the past 3 decades to include the treatment of a variety of ophthalmologic, gastrointestinal, urologic, orthopedic, dermatologic, dental, secretory, painful, cosmetic, and other conditions. In addition to onabotulinumtoxinA (Botox), abobotulinumtoxinA (Dysport), incobotulinumtoxinA (Xeomin), and RimabotulinumtoxinB (Myobloc or NeuroBloc) there are other novel botulinun neurotoxin products currently in development. With a better understanding of the cellular mechanisms of botulinun neurotoxin and advances in biotechnology, future botulinun neurotoxin products will likely be even more effective and customized to the specific indication and tailored to the needs of the patients. © 2017 International Parkinson and Movement Disorder Society.
132 citations
Cites background from "Botulinum Neurotoxins: Biology, Pha..."
...The regulation of fusion of the synaptic vesicle with the plasma membrane involved a complex of proteins collectively referred to as SNAREs (soluble N-ethylmaleimide sensitive factor attachment protein receptor) or SNAP receptors.(11,12) The 2013 Nobel Prize in physiology or medicine was awarded to James E....
[...]
...BoNTs are large proteins ( 150 kDa) that are produced by nonaerobic Clostridia bacteria.(11,12) Recently, non-Clostridial bacteria, Weissella oryzae, was found to also produce BoNT....
[...]
TL;DR: This review summarizes the progress on the understanding of BoNTs and TeNT, focusing on the PTC, receptor recognition, new BoNT-like toxins, and therapeutic toxin engineering.
Abstract: Botulinum neurotoxins (BoNTs) and tetanus neurotoxin (TeNT) are the most potent toxins known and cause botulism and tetanus, respectively. BoNTs are also widely utilized as therapeutic toxins. They contain three functional domains responsible for receptor-binding, membrane translocation, and proteolytic cleavage of host proteins required for synaptic vesicle exocytosis. These toxins also have distinct features: BoNTs exist within a progenitor toxin complex (PTC), which protects the toxin and facilitates its absorption in the gastrointestinal tract, whereas TeNT is uniquely transported retrogradely within motor neurons. Our increasing knowledge of these toxins has allowed the development of engineered toxins for medical uses. The discovery of new BoNTs and BoNT-like proteins provides additional tools to understand the evolution of the toxins and to engineer toxin-based therapeutics. This review summarizes the progress on our understanding of BoNTs and TeNT, focusing on the PTC, receptor recognition, new BoNT-like toxins, and therapeutic toxin engineering.
114 citations
TL;DR: The effects contributing to these advantageous properties of BoNT/A in pain therapy, specific actions along the nociceptive pathway, consequences of its central activities, the molecular mechanisms of actions in neurons, and general pharmacokinetic parameters are summarized.
Abstract: Already a well-established treatment for different autonomic and movement disorders, the use of botulinum toxin type A (BoNT/A) in pain conditions is now continuously expanding. Currently, the only approved use of BoNT/A in relation to pain is the treatment of chronic migraines. However, controlled clinical studies show promising results in neuropathic and other chronic pain disorders. In comparison with other conventional and non-conventional analgesic drugs, the greatest advantages of BoNT/A use are its sustained effect after a single application and its safety. Its efficacy in certain therapy-resistant pain conditions is of special importance. Novel results in recent years has led to a better understanding of its actions, although further experimental and clinical research is warranted. Here, we summarize the effects contributing to these advantageous properties of BoNT/A in pain therapy, specific actions along the nociceptive pathway, consequences of its central activities, the molecular mechanisms of actions in neurons, and general pharmacokinetic parameters.
108 citations
Cites background from "Botulinum Neurotoxins: Biology, Pha..."
...After local injections in tissues like the muscle, dermis, or subcutis, BoNT/A binds to the neuronal membrane and enters the neurons, while the unbound fraction is probably diluted in the lymphatic circulation and washed away from the injection sites, thus being unable to affect more distant neuronal endings because of too low concentration [33]....
[...]
...The 150 kDa neurotoxin is a typical bacterial AB-structured toxin, consisting of heavy chain with membrane acceptor–binding and translocation domains, and a smaller 50 kDa light chain, a catalytic domain that mediates the intracytosolic proteolytic activity of the neurotoxin [33]....
[...]
...[33,55,56], which might depend on the level of expression of high-affinity protein acceptors in the neuronal membrane....
[...]
...The toxin light chain is released into the cytosol by energy- and pH-dependent pore-forming process involving thioredoxin thioreductase [33]....
[...]
TL;DR: Methods to increase the productivity and yield/titer scan by controlling metabolic flux through individual or combinatorial use of CRISPR/Cas andCRISPRi systems with introduction of synthetic pathway in industrially common bacteria including Escherichia coli are focused on.
Abstract: The clustered regularly interspaced short palindromic repeats/CRISPR-associated (CRISPR/Cas) adaptive immune system has been extensively used for gene editing, including gene deletion, insertion, and replacement in bacterial and eukaryotic cells owing to its simple, rapid, and efficient activities in unprecedented resolution. Furthermore, the CRISPR interference (CRISPRi) system including deactivated Cas9 (dCas9) with inactivated endonuclease activity has been further investigated for regulation of the target gene transiently or constitutively, avoiding cell death by disruption of genome. This review discusses the applications of CRISPR/Cas for genome editing in various bacterial systems and their applications. In particular, CRISPR technology has been used for the production of metabolites of high industrial significance, including biochemical, biofuel, and pharmaceutical products/precursors in bacteria. Here, we focus on methods to increase the productivity and yield/titer scan by controlling metabolic flux through individual or combinatorial use of CRISPR/Cas and CRISPRi systems with introduction of synthetic pathway in industrially common bacteria including Escherichia coli. Further, we discuss additional useful applications of the CRISPR/Cas system, including its use in functional genomics.
105 citations
Cites background from "Botulinum Neurotoxins: Biology, Pha..."
...botulinum is the most potent biological fetal poison which paralyzes muscles; however, this toxin is currently widely used for cosmetic surgery and numerous therapeutic purposes including the management of different muscle disorders and headache [97]....
[...]
References
More filters
TL;DR: It is now becoming clear that lipid micro-environments on the cell surface — known as lipid rafts — also take part in this process of signalling transduction, where protein–protein interactions result in the activation of signalling cascades.
Abstract: Signal transduction is initiated by complex protein-protein interactions between ligands, receptors and kinases, to name only a few. It is now becoming clear that lipid micro-environments on the cell surface -- known as lipid rafts -- also take part in this process. Lipid rafts containing a given set of proteins can change their size and composition in response to intra- or extracellular stimuli. This favours specific protein-protein interactions, resulting in the activation of signalling cascades.
6,080 citations
"Botulinum Neurotoxins: Biology, Pha..." refers background in this paper
...proteins, PSG form anionic microdomains in the plasma membrane (Simons and Toomre, 2000; Sonnino et al., 2007; Prinetti et al., 2009)....
[...]
...Together with sphingomyelin, cholesterol, and some proteins, PSG form anionic microdomains in the plasma membrane (Simons and Toomre, 2000; Sonnino et al., 2007; Prinetti et al., 2009)....
[...]
TL;DR: The acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial are described and compared.
Abstract: Objective: This report describes the participants and compares the acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Method: A broadly representative adult outpatient sample with nonpsychotic major depressive disorder received one (N=3,671) to four (N=123) successive acute treatment steps. Those not achieving remission with or unable to tolerate a treatment step were encouraged to move to the next step. Those with an acceptable benefit, preferably symptom remission, from any particular step could enter a 12-month naturalistic follow-up phase. A score of ≤5 on the Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR 16 ) (equivalent to ≤7 on the 17-item Hamilton Rating Scale for Depression [HRSD 17 ]) defined remission; a QIDS-SR 16 total score of ≥11 (HRSD 17 ≥14) defined relapse. Results: The QIDS-SR 16 remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, t...
3,768 citations
TL;DR: PHluorins are developed pH-sensitive mutants of green fluorescent protein by structure-directed combinatorial mutagenesis, with the aim of exploiting the acidic pH inside secretory vesicles, to monitor vesicle exocytosis and recycling.
Abstract: In neural systems, information is often carried by ensembles of cells rather than by individual units. Optical indicators provide a powerful means to reveal such distributed activity, particularly when protein-based and encodable in DNA: encodable probes can be introduced into cells, tissues, or transgenic organisms by genetic manipulation, selectively expressed in anatomically or functionally defined groups of cells, and, ideally, recorded in situ, without a requirement for exogenous cofactors. Here we describe sensors for secretion and neurotransmission that fulfil these criteria. We have developed pH-sensitive mutants of green fluorescent protein ('pHluorins') by structure-directed combinatorial mutagenesis, with the aim of exploiting the acidic pH inside secretory vesicles to monitor vesicle exocytosis and recycling. When linked to a vesicle membrane protein, pHluorins were sorted to secretory and synaptic vesicles and reported transmission at individual synaptic boutons, as well as secretion and fusion pore 'flicker' of single secretory granules.
2,472 citations
"Botulinum Neurotoxins: Biology, Pha..." refers methods in this paper
...By using fluorescent synaptophluorins, the luminal pH of SV was estimated to be ;5.8 pH units (Miesenbock et al., 1998)....
[...]
TL;DR: A fascinating picture of these robust nanomachines is emerging, which seems to be conserved and adaptable for fusion reactions as diverse as those involved in cell growth, membrane repair, cytokinesis and synaptic transmission.
Abstract: Since the discovery of SNARE proteins in the late 1980s, SNAREs have been recognized as key components of protein complexes that drive membrane fusion. Despite considerable sequence divergence among SNARE proteins, their mechanism seems to be conserved and is adaptable for fusion reactions as diverse as those involved in cell growth, membrane repair, cytokinesis and synaptic transmission. A fascinating picture of these robust nanomachines is emerging.
2,424 citations
"Botulinum Neurotoxins: Biology, Pha..." refers background in this paper
...Specific isoforms of SNARE proteins selectively interact and form heterotrimeric coiled-coil complexes (SNARE complexes), which mediate most intracellular events of vesicle–target membrane fusion (Jahn and Scheller, 2006)....
[...]
TL;DR: All mammalian thioredoxin reduct enzyme isozymes are homologous to glutathione reductase and contain a conserved C-terminal elongation with a cysteine-selenocysteine sequence forming a redox-active selenenylsulfide/selenolthiol active site and are inhibited by goldthioglucose and other clinically used drugs.
Abstract: Thioredoxin, thioredoxin reductase and NADPH, the thioredoxin system, is ubiquitous from Archea to man. Thioredoxins, with a dithiol/disulfide active site (CGPC) are the major cellular protein disulfide reductases; they therefore also serve as electron donors for enzymes such as ribonucleotide reductases, thioredoxin peroxidases (peroxiredoxins) and methionine sulfoxide reductases. Glutaredoxins catalyze glutathione-disulfide oxidoreductions overlapping the functions of thioredoxins and using electrons from NADPH via glutathione reductase. Thioredoxin isoforms are present in most organisms and mitochondria have a separate thioredoxin system. Plants have chloroplast thioredoxins, which via ferredoxin-thioredoxin reductase regulates photosynthetic enzymes by light. Thioredoxins are critical for redox regulation of protein function and signaling via thiol redox control. A growing number of transcription factors including NF-kappaB or the Ref-1-dependent AP1 require thioredoxin reduction for DNA binding. The cytosolic mammalian thioredoxin, lack of which is embryonically lethal, has numerous functions in defense against oxidative stress, control of growth and apoptosis, but is also secreted and has co-cytokine and chemokine activities. Thioredoxin reductase is a specific dimeric 70-kDa flavoprotein in bacteria, fungi and plants with a redox active site disulfide/dithiol. In contrast, thioredoxin reductases of higher eukaryotes are larger (112-130 kDa), selenium-dependent dimeric flavoproteins with a broad substrate specificity that also reduce nondisulfide substrates such as hydroperoxides, vitamin C or selenite. All mammalian thioredoxin reductase isozymes are homologous to glutathione reductase and contain a conserved C-terminal elongation with a cysteine-selenocysteine sequence forming a redox-active selenenylsulfide/selenolthiol active site and are inhibited by goldthioglucose (aurothioglucose) and other clinically used drugs.
2,383 citations