Neurotoxin botulinum

Botulinum neurotoxins (A-G), tetanus toxin Synaptic peptides a) Synapto-brevin b) Syntaxin c) SNAP25 Zinc dependent endoprotease Cleavage of synaptic peptides Inhibition of transmitter release (tetanus, botulism)... 

Botulinum neurotoxins are widely used as therapeutic agents to cause reduction or paralysis of skeletal muscle contraction. They are used to treat cervical dystonia, which causes regional involuntary muscle spasms often associated with pain. Moreover, they are used in strabism, blepharospasm, hemifacial spasm, and... 

The most ingenious exocytosis toxins, however, come from the anaerobic bacteria Clostridium botulinum and Clostridium tetani. The former produces the seven botulinum neurotoxins (BoNTs) A-G the latter produces tetanus neurotoxin (TeNT). All eight toxins consist of a heavy (H) chain and a light (L) chain that are associated by an interchain S-S bond. The L-chains enter the cytosol of axon terminals. Importantly, BoNT L-chains mainly enter peripheral cholinergic terminals, whereas the TeNT L-chain mainly enters cerebral and spinal cord GABAergic and glycinergic terminals. The L-chains are the active domains of the toxins. They are zinc-endopeptidases and specifically split the three core proteins of exocytosis, i.e. the SNAREs (Fig. 1 inset). Each ofthe eight toxins splits a... 

Bullens, R. W., O Hanlon, G. M., Wagner, E. etal. Complex gangliosides at the neuromuscular junction are membrane receptors for autoantibodies and botulinum neurotoxin but redundant for normal synaptic function. /. Neurosci. 22 6876-6884, 2002. 

G. Schiavo, F. Benfenati, B. Poulain, O. Rossetto, P. Polverino de Laureto, B. R. Das-Gupta, C. Montecucco, Tetanus and Botulinum-B Neurotoxins Block Neurotransmitter Release by Proteolytic Cleavage of Synaptobrevin , Nature 1992a, 359, 832-835 G. Schiavo, O. Rossetto, A. Santucci, B. R. DasGupta, C. Montecucco, Botulinum Neurotoxins are Zinc Proteins , J. Biol. Chem. 1992b, 267, 23479-23483. 

The role of C2 toxin in disease is not clear because all C. botulinum strains that produce C2 toxin also synthesize extremely potent neurotoxins, the effector molecules of botulism. When Simpson compared the pharmacological properties of C. botulinum neurotoxin type Cl with C2 toxin in detail, it became obvious that C2 toxin does not cause the flaccid paralysis symptoms attributed to classic botulism. However, isolated C2 toxin is a potent enterotoxin that proves lethal in various animals 2 pmol of C2 toxin readily kill mice, rats, guinea pigs, and chickens within 1 h after application. For mice, the LD50 (i.v.) of C2 toxin is less than 50 ftnol. Ohishi and Odagiri also reported that C2 toxin causes necrotic, hemorrhagic lesions in the intestinal wall, whereas Simpson reported that C2 toxin elicits hypotension as well as fluid accumulation in the lungs. ... 

Bakry, N., Kamata, Y. and Simpson, L.L., Lectins from Triticum vulgaris and Umax flavus are universal antagonists of botulinum neurotoxin and tetanus toxin, J. Pharmacol. Exp. Ther., 258, 830-836, 1991. 

Black, J.D. and Dolly, J.O., Interaction of 125, I-labelled botulinum neurotoxins with nerve terminals. I. Ultrastructural autoradiographic localization and quantitation of distinct membrane acceptors for types A and B on motor nerves, J. Cell Biol, 103, 521-534, 1986. 

Chaddock, J.A., Purkiss, J.R., Friis, L.M., Broadbridge, J.D., Duggan, M.J. Fooks, S.J., Shone, C.C., Quinn, C.P. and Foster, K.A., Inhibition of vesicular secretion in both neuronal and nonneuronal cells by a retargeted endopeptidase derivate of Clostridium botulinum neurotoxin type A, Infect. Immun., 68, 2587-2593, 2000. 

DasGupta, B.R., Structure and biological activity of botulinum neurotoxin, J. Physiol., 84, 220-228, 1990. 

Dolly, J.O., Black, J., Williams, R.S. and Melling, J., Acceptors for botulinum neurotoxin reside on motor nerve terminals and mediate its internalization. Nature, 307, 457 60, 1984. 

East, A.K., Stacey, I.M. and Collins, M.D., Cloning and sequencing of hemagglutinin component of the botulinum neurotoxin complex encoded by Clostridium botulinum types A and B, Syst. Appl. Microbiol., 17, 306-312, 1994. 

Eklund, M.W., Poysky, F.T. and Habig, W.H., Bacteriophages and plasmids in Clostridium botulinum and Clostridium tetani and their relationship to production of toxins, in Simpson, L.L., ed., Botulinum Neurotoxin and Tetanus Toxin, Academic Press, New York, pp. 25-51, 1989. 

Evans, D., Williams, R.S., Shone, C.C., Hambleton, P., Melling, J. and Dolly, J.O., Botulinum neurotoxin type B. Its purification, radioiodination and interaction with rat-brain synaptosomal membranes, Eur. I. Biochem., 154, 409-416, 1986. 

Hatheway, C.L., Clostridium botulinum and other Clostridia that produce botulinum neurotoxin, in Hauschild, A.H.W. and Dodds, K.L,. eds., Clostridium botulinum Ecology and Control in Foods, Marcel Dekker, New York, pp. 3-20, 1993. 

Krieglstein, K.G., DasGupta, B.R. and Henschen, A.H., Covalent structure of botulinum neurotoxin type-A-location of sulfhydryl groups, and disulfide... 

Montecucco, C. and Schiavo, G., Mechanism of action of tetanus and botulinum neurotoxins. Mol. Microbiol., 13, 1-8, 1994. 

Poulain, B., Mochida, S., Weller, U., Hogy, B., Habermann, E., Wadsworth, J. D., Shone, C.C., Dolly, J.O. and Tauc, L., Heterologous combinations of heavy and light chains from botulinum neurotoxin A and tetanus toxin inhibit neurotransmitter release in Aplysia, J. Biol. Chem., 266, 9580-9585, 1991. 

Prabakaran, S., Tepp, W. and DasGupta, B.R., Botulinum neurotoxin types B and E purification, limited proteolysis by endoproteinase Glu-C and pepsin, and comparison of their identified cleaved sites relative to the three-dimensional structure of t q)e A neurotoxin, Toxicon, 39, 1515-1531, 2001. 

Schiavo, G., Shone, C.C., Rossetto, O., Alexander, F.C. and Montecucco, C., Botulinum neurotoxin serotype 1 is a zinc endopeptidase specific for VAMP/ synaptobrevin, J. Biol. Chern., 268, 11516-11519, 1993. 

Schiavo, G., Rossetto, O., Benfenati, F., Poulain, B. and Montecucco, C., Tetanus and botulinum neurotoxins are zinc proteases specific for components of the neuroexcytosis apparatus, Ann. N. Y. Acad. Sci., 710, 65-75, 1994. 

The effect of administering different botulinum neurotoxin serotypes at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin. Aminoglycosides Cautiously perform coadministration of botulinum toxin type A and aminoglycosides or other agents interfering with neuromuscular transmission (eg, curare-like nondepolarizing blockers, lincosamides, polymyxins, quinidine, magnesium sulfate, anticholinesterases, succinylcholine chloride) because the effect of the toxin may be potentiated. 

Botulinum neurotoxin is produced by me anaerobic bacterium Clostridium botulinum. It is me... 

Clostridium botulinum neurotoxin, the most effective toxin known to date, with a mice lethal dose of about 50 pg/mL (330 fmol/mL) was the target antigen in IPCR assays developed by Wu et al. [48] and Chao et al. [88]. In these assays, detection limits of 5 fg (33 amol) and 50 fg (330 amol), respectively, were found. 

Wu HC, Huang YL, Lai SC, Huang YY, Shaio MF. Detection of Clostridium botulinum neurotoxin type A using immuno-PCR. Lett Appl Microbiol 2001 32(5) 321—325. 

Chao HY, Wang YC, Tang SS, Liu HW. A highly sensitive immuno-polymerase chain reaction assay for Clostridium botulinum neurotoxin type A. Toxicon 2004 43(1) 27—34. 

Remarkably, SV2 also appears to be the cellular receptor for botulinum neurotoxin A (Dong et al., 2006). In particular, a segment of the large lumenal loop binds to the toxin, and all of the SV2 isoforms appear capable of serving as receptors. Thus, levetiracetam, even if it is bound to the same site as the toxin, seems unlikely to protect against poisoning since it interacts only with SV2A. 

The botulinum neurotoxins and the snake presynaptic PLA2 neurotoxins share three levels of interest (1) they are pathogenic to humans and animals, (2) they contribute to the understanding of the molecular steps of neurotransmission, and (3) their present and future clinical applications. In this chapter, these neurotoxins are considered in terms of mode of action and in relation to their potential use in cell biology and neuroscience research as well as therapeutics in some human neurodisorders. 

Tetanus and botulinum neurotoxins are the most potent toxins known, as few nanograms/Kg are sufficient to kill most mammals. When injected peripherally the mouse LD50 s of TeNT and BoNTs are between 0.4 ng and 1 ng of toxin per Kg of body weight (Gill 1982). When BoNTA and BoNT/B are injected into the brain the LD50 s are comparable with those determined by intraperitoneal injection in mice (Luvisetto et al. 2003). 

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