1,721,158 research outputs found
The binding of botulinum neurotoxins to different peripheral neurons
Full text linkBotulinum neurotoxins are the most potent toxins known. The double receptor binding modality represents one of the most significant properties of botulinum neurotoxins and largely accounts for their incredible potency and lethality. Despite the high affinity and the very specific binding, botulinum neurotoxins are versatile and multi-tasking toxins. Indeed they are able to act both at the somatic and at the autonomic nervous system. In spite of the preference for cholinergic nerve terminals botulinum neurotoxins have been shown to inhibit to some extent also the noradrenergic postganglionic sympathetic nerve terminals and the afferent nerve terminals of the sensory neurons inhibiting the release of neuropeptides and glutamate, which are responsible of nociception. Therefore, there is increasing evidence that the therapeutic effect in both motor and autonomic disorders is based on a complex mode of botulinum neurotoxin action modulating the activity of efferent as well as afferent nerve fibres
Vesicle-associated membrane protein (VAMP)/synaptobrevin-2 is associated with dense-core secretory granules in PC12 neuroendocrine cells
No full textThe presence and intracellular distribution of vesicle-associated membrane protein-1 (VAMP-1) and VAMP-2 were investigated in the PC12 neuroendocrine cell line using isotype-specific polyclonal antibodies. VAMP-2 was detected in the total membrane fraction, while VAMP-1 was undetectable. Subcellular fractionation demonstrates that a substantial amount of the VAMP-2 (24-36%) is associated with dense core, catecholamine-containing granules (DCGs). This was confirmed by immunofluorescence microscopy. The L chain of tetanus neurotoxin, known to inhibit granule mediated secretion in permeabilized PC12 cells, as well as botulinum neurotoxins F and G, effectively cleaved DCG-associated VAMP-2. These data demonstrate that VAMP-2 is present on the secretory granules of PC12 cells
The role of the single interchains disulfide bond in tetanus and botulinum neurotoxins and the development of antitetanus and antibotulism drugs
Full text linkA large number of bacterial toxins consist of active and cell binding protomers linked by an interchain disulfide bridge. The largest family of such disulfide-bridged exotoxins is that of the clostridial neurotoxins that consist of two chains and comprise the tetanus neurotoxins causing tetanus and the botulinum neurotoxins causing botulism. Reduction of the interchain disulfide abolishes toxicity, and we discuss the experiments that revealed the role of this structural element in neuronal intoxication. The redox couple thioredoxin reductase-thioredoxin (TrxR-Trx) was identified as the responsible for reduction of this disulfide occurring on the cytosolic surface of synaptic vesicles. We then discuss the very relevant finding that drugs that inhibit TrxR-Trx also prevent botulism. On this basis, we propose that ebselen and PX-12, two TrxR-Trx specific drugs previously used in clinical trials in humans, satisfy all the requirements for clinical tests aiming at evaluating their capacity to effectively counteract human and animal botulism arising from intestinal toxaemias such as infant botulism
Tetanus and tetanus neurotoxin: From peripheral uptake to central nervous tissue targets
Full text linkTetanus 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. (Figure presented.)
Biochemical and electrophysiological characterization of Tetanus neurotoxin-induced epilepsy in mouse visual cortex in vivo
No full textEntrapping of impermeant probes of different size into nonpermeabilized synaptosomes as a method to study presynaptic mechanisms
No full textTetanus toxin-sensitive VAMP-related proteins are present in murine macrophages
No full textThe light chain of tetanus neurotoxin (TeTx) is a zinc endopeptidase specific for VAMP/synaptobrevin (VAMP), a 120-amino-acid integral protein previously described in the small synaptic vesicles of neuronal cells. TeTx has been shown to be active also on nonneuronal cells. By SDS-PAGE and quantitative immunoblotting on proteins derived from murine macrophages (M phi) exposed to TeTx, we have shown that: (1) VAMP-related proteins are also present in M phi and (2) such proteins are sensitive to TeTx proteolytic cleavage. The demonstration that TeTx acts on VAMP-related proteins also in M phi offers a new and useful tool for molecular studies on M phi exocytosis
Long-distance retrograde effects of botulinum neurotoxin A
Full text linkBotulinum neurotoxins (designated BoNT/A-BoNT/G) are bacterial enzymes that block neurotransmitter release by cleaving essential components of the vesicle fusion machinery. BoNT/A, which cleaves SNAP-25 (synaptosomal-associated protein of 25 kDa), is extensively exploited in clinical medicine to treat neuromuscular pathologies, facial wrinkles, and various types of pain. It is widely assumed that BoNT/A remains at the synaptic terminal and its effects are confined to the injection site. Here we demonstrate that catalytically active BoNT/A is retrogradely transported by central neurons and motoneurons and is then transcytosed to afferent synapses, in which it cleaves SNAP-25. SNAP-25 cleavage by BoNT/A was observed in the contralateral hemisphere after unilateral BoNT/A delivery to the hippocampus. Appearance of cleaved SNAP-25 resulted in blockade of hippocampal activity in the untreated hemisphere. Injections of BoNT/A into the optic tectum led to the appearance of BoNT/A-truncated SN..
Clinical duration of action of different botulinum toxin types in humans
Full text linkThe Botulinum NeuroToxin (BoNT) comprises several serotypes with distinct properties, mechanisms of action, sensitivity and duration of effect in different species. The serotype A (BoNT/A) is the prevalent neurotoxin applied in human's disease. In this paper we present an overview of the current knowledge regarding the duration of effect and the neuromuscular sprouting of different BoNT serotypes in humans. Then, we report the original results of a study in healthy subjects treated with BoNT/A, B, C and F using different neurophysiological techniques. Twelve healthy volunteers (7 men, 5 women) are treated with BoNT/A, B, C and F or placebo in Abductor digiti minimi (ADM) muscle of the hand. Before and after injections, an extensive neurophysiological study is performed with the CMAP amplitude variation, Multi-Motor Unit Action Potentials (MUAPs) analysis, the Turns/Amplitude ratio of interference pattern (IP) and determination of jitter and Fiber Density (FD) at single-fiber electromyography (SFEMG), at week 2 (w2), 4 (w4), 6 (w6) and 8 (w8). A maximal neuromuscular block is obtained at w2 for all the serotypes. Afterwards, the CMAP trend appear similar for BoNT/A, B, and C while, BoNT/F shows a faster recover. Multi-MUAPs analysis and IP detect mild changes at w2 for all serotypes, except for BoNT/F that shows a greater change since w4. SFEMG have minimal changes in FD while, Jitter increase at w2 with a slower decrease over the time for all BoNTs. In conclusion, BoNT/F has earlier sprouting and complete recovery at w8. Other serotypes present a slower and similar profile. The EMG appear useful to study the functional recovery in humans, and these results should provide new evidence for assessing different serotypes. These findings improve our knowledge regarding the methods to evaluate duration of effects and dose equivalents in different serotypes, that in the future could change the clinicians strategy for disease-tailored BoNT therapies
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