Different time courses of recovery after poisoning with botulinum neurotoxin serotypes A and E in humans

Eleopra, Roberto; Tugnoli, V.; Rossetto, Ornella; Grandis, D. De; Montecucco, Cesare

doi:10.1016/s0304-3940(98)00775-7

Cited by 179 publications

(134 citation statements)

References 15 publications

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“…42,43 Alternatively, the intraneuronal localization may affect the duration of inhibition. 39 BTX-A has the longest duration of activity when it is used for the treatment of dystonias, inducing clinical effects on neuromuscular activity for longer than 4 months, compared with about 2 months for BTX-B and less than 4 weeks for BTX-E. 44,45 Cell-culture studies that calculated the inhibitory half-life of BTX-A provided further evidence for a prolonged effect of BTX-A; the inhibitory half-life of BTX-A was more than 31 days, compared with 10 days for BTX-B, 2 days for BTX-F, and 19-20 h for BTX-E. 42 Recovery of cholinergic neurotransmission is dependent on removal of the BTX protease and restoration of intact SNARE proteins. 19,42,46 …”

Section: Exocytosis Inhibitionmentioning

confidence: 99%

Drug Insight: biological effects of botulinum toxin A in the lower urinary tract

et al. 2008

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SUMMARYBotulinum toxins can effectively and selectively disrupt and modulate neurotransmission in striated muscle. Recently, urologists have become interested in the use of these toxins in patients with detrusor overactivity and other urological disorders. In both striated and smooth muscle, botulinum toxin A (BTX-A) is internalized by presynaptic neurons after binding to an extracellular receptor (ganglioside and presumably synaptic vesicle protein 2C). In the neuronal cytosol, BTX-A disrupts fusion of the acetylcholine-containing vesicle with the neuronal wall by cleaving the SNAP-25 protein in the synaptic fusion complex. The net effect is selective paralysis of the low-grade contractions of the unstable detrusor, while still allowing high-grade contraction that initiates micturition. Additionally, BTX-A seems to have effects on afferent nerve activity by modulating the release of ATP in the urothelium, blocking the release of substance P, calcitonin gene-related peptide and glutamate from afferent nerves, and reducing levels of nerve growth factor. These effects on sensory feedback loops might not only help to explain the mechanism of BTX-A in relieving symptoms of overactive bladder, but also suggest a potential role for BTX-A in the relief of hyperalgesia associated with lower urinary tract disorders.

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Section: Exocytosis Inhibitionmentioning

confidence: 99%

Drug Insight: biological effects of botulinum toxin A in the lower urinary tract

et al. 2008

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“…Among the seven known serotypes (going from A to E), BoNT-A represents the most investigated in clinical studies. Besides, BoNT-A displays the most sustained action [10]. Major effects can be observed 5 or 6 weeks after the intramuscular injection.…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

Long-term benefits of botulinum toxin type A (BOTOX) in chronic daily headache: a five-year long experience

et al. 2006

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“…Moreover, the blockade of transmitter release by BoNT/E is relatively unaffected by treatments that elevate cytosolic [Ca 2ϩ ] and antagonize inhibition by BoNT/A (20 -24). All these properties would be highly desirable for incorporation into new and improved therapeutic versions of BoNT, although BoNT/E produces transient muscle weakness compared with the long duration of action of BoNT/A (25). Thus, the feasibility of such an approach was assessed.…”

mentioning

confidence: 99%

Novel Chimeras of Botulinum Neurotoxins A and E Unveil Contributions from the Binding, Translocation, and Protease Domains to Their Functional Characteristics

Wang

Meng

Lawrence

et al. 2008

Journal of Biological Chemistry

107

131

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Hyperexcitability disorders of cholinergically innervated muscles are treatable with botulinum neurotoxin (BoNT) A. The seven serotypes (A-G) potently block neurotransmission by binding to presynaptic receptors, undergoing endocytosis, transferring to the cytosol, and inactivating proteins essential for vesicle fusion. Although BoNT/A and BoNT/E cleave SNAP-25, albeit at distinct sites, BoNT/E blocks neurotransmission faster and more potently. To identify the domains responsible for these characteristics, the C-terminal heavy chain portions of BoNT/A and BoNT/E were exchanged to create chimeras AE and EA. After high yield expression in Escherichia coli, these single chain chimeras were purified by two-step chromatography and activated by conversion to disulfide-linked dichains. In vitro, each entered neurons, cleaved SNAP-25, and blocked neuromuscular transmission while causing flaccid paralysis in vivo. Acidification-dependent translocation of the light chain to the cytosol occurred more rapidly for BoNT/E and EA than for BoNT/A and AE because the latter pair remained susceptible for longer to inhibitors of the vesicular proton pump, and BoNT/A proved less sensitive. The receptor-binding and protease domains do not seem to be responsible for the speeds of intoxication; rather the N-terminal halves of their heavy chains are implicated, with dissimilar rates of cytosolic transfer of the light chains being due to differences in pH sensitivity. AE produced the most persistent muscle weakening and therefore has therapeutic potential. Thus, proof of principle is provided for tailoring the pharmacological properties of these toxins by protein engineering.

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Different time courses of recovery after poisoning with botulinum neurotoxin serotypes A and E in humans

Cited by 179 publications

References 15 publications

Drug Insight: biological effects of botulinum toxin A in the lower urinary tract

Drug Insight: biological effects of botulinum toxin A in the lower urinary tract

Long-term benefits of botulinum toxin type A (BOTOX) in chronic daily headache: a five-year long experience

Novel Chimeras of Botulinum Neurotoxins A and E Unveil Contributions from the Binding, Translocation, and Protease Domains to Their Functional Characteristics

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