Intracellular targets and metalloprotease activity of tetanus and botulism neurotoxins.
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The active forms of tetanus and botulinum neurotoxins, released from the precursor molecule by specific proteolysis and reduction, block the release of neurotransmitters via a Zn(2+)-dependent protease activity. VAMP/synaptobrevin, an integral membrane protein of the synaptic vesicles, is cleaved at a single site by tetanus and botulinum B, D and F neurotoxins. The unique sequence, mechanism of activation and site of activity of clostridial neurotoxins mark them out as an independent group of Zn(2+)-endopeptidases.
Botulinum toxins (A and B) are neurotoxins derived from Clostridium botulinum. Clostridium are anaerobic bacteria. C. botulinum produces exotoxins (A to G) with distinct antigenicities. The neurotoxins inhibit the release of the neurotransmitter acetylcholine from the axon terminals of motor neurons. Botulinum toxin is officially used in clinic for the treatment of muscular hyperactivity (strabismus, blepharospam, cervical dystonia). Botulinum toxins are also used in non recognized clinical applications: neurogenic incontinence, palmar and axillary hyperhidrosis, chronic anal fissure. The respective formulations of Botox, Dysport and Neurobloc are described. Special considerations for administration are introduced.
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Neurotoxins produced by strains of Clostridium sp. are belonging to the most toxic biological substances. In the study phenotypes and genotypes of C. botulinum strains in animal studies in vivo and on the DNA level were evaluated, respectively. Additionally, the presence of genes encoding BoNT toxins of A, B, and E types among strains of Clostridium sp. were identified. In case of C. botulinum DNA was isolated from vegetative bacterial cells and from spores. Two different genes encoding two different neurotoxins harboured by three strains of Ae biotype/ae genotype, and by two strains of B biotype/be genotype were detected. Additionally, above E type C. botulinum strains, the presence of gene encoding E type neurotoxin, was found in genome of two C. baratii, two C. butyricum, and C. bifidobacterium, and C. oedematicum strains. C. bifidobacterium and C. oedematicum strains positive for presence of gene encoding E type neurotoxin, were found negative for E neurotoxin production in vivo in TN test. The study indicates that genes encoding BoNT/E neurotoxins are very common among Clostridium species. Phenotype and genotype analysis indicated co-presence of B phenotype together with be genotype and A phenotype together with ae genotype among C. botulinum strains.
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Reinnervation by botulinus toxin impaired motor nerve implantation was investigated in rat experiments with a purpose of elucidating conditions for regeneration of nerve fibers in the area of botulinic paralysis. Administration of the sublethal dose of toxin into the limb accelerated synaptogenesis of the nerve implanted. The latter exerts a normalizing effect on the muscular tissue and polarization level of its fibers.
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