Tetanus, botulinum and snake presynaptic neurotoxins

Rossetto, Ornella; Morbiato, Laura; Caccin, Paola; Rigoni, Michela; Carli, Luca; Paoli, Marco; Cintra-Francischelli, Mariana; Montecucco, Cesare

doi:10.1007/s12210-008-0010-z

Cited by 3 publications

(1 citation statement)

References 77 publications

(80 reference statements)

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“…Lawrence and colleagues used rat sympathetic neurons culture to show that cleaved SNAP-25 can be detected in cell somas after administration of high (10 4 pM) but not low doses of BoNT-A (10 pM, ∼75 U) to their distal neurites, that on its own the cleaved SNAP-25 does not block the functional electrophysiologically recorded synaptic transmission in the cell somas, and that actual blockade requires doses greater than 10 6 pM ( 31 ). Alternatively, cleaved SNAP-25 has a dominant-negative effect on SNARE complex function ( 32 ), and only a single defective SNARE complex may be necessary to inhibit vesicular fusion ( 33 , 34 ). Consistent with Montecucco’s recent observations, SNAP-25 cleaved in the extracranial neuron could traverse a short distance within the fluid neuronal membrane or the cytosol over several days, entering a nearby collateral meningeal nociceptor and impair SNARE function.…”

Section: Discussionmentioning

confidence: 99%

Extracranial injections of botulinum neurotoxin type A inhibit intracranial meningeal nociceptors’ responses to stimulation of TRPV1 and TRPA1 channels: Are we getting closer to solving this puzzle?

et al. 2016

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BackgroundAdministration of onabotulinumtoxinA (BoNT-A) to peripheral tissues outside the calvaria reduces the number of days chronic migraine patients experience headache. Because the headache phase of a migraine attack, especially those preceded by aura, is thought to involve activation of meningeal nociceptors by endogenous stimuli such as changes in intracranial pressure (i.e. mechanical) or chemical irritants that appear in the meninges as a result of a yet-to-be-discovered sequence of molecular/cellular events triggered by the aura, we sought to determine whether extracranial injections of BoNT-A alter the chemosensitivity of meningeal nociceptors to stimulation of their intracranial receptive fields.Material and methodsUsing electrophysiological techniques, we identified 161 C- and 135 Aδ-meningeal nociceptors in rats and determined their mechanical response threshold and responsiveness to chemical stimulation of their dural receptive fields with TRPV1 and TRPA1 agonists seven days after BoNT-A administration to different extracranial sites. Two paradigms were compared: distribution of 5 U BoNT-A to the lambdoid and sagittal sutures alone, and 1.25 U to the sutures and 3.75 U to the temporalis and trapezius muscles.ResultsSeven days after it was administered to tissues outside the calvaria, BoNT-A inhibited responses of C-type meningeal nociceptors to stimulation of their intracranial dural receptive fields with the TRPV1 agonist capsaicin and the TRPA1 agonist mustard oil. BoNT-A inhibition of responses to capsaicin was more effective when the entire dose was injected along the suture lines than when it was injected into muscles and sutures. As in our previous study, BoNT-A had no effect on non-noxious mechanosensitivity of C-fibers or on responsiveness of Aδ-fibers to mechanical and chemical stimulation.DiscussionThis study demonstrates that extracranial administration of BoNT-A suppresses meningeal nociceptors’ responses to stimulation of their intracranial dural receptive fields with capsaicin and mustard oil. The findings suggest that surface expression of TRPV1 and TRPA1 channels in dural nerve endings of meningeal nociceptors is reduced seven days after extracranial administration of BoNT-A. In the context of chronic migraine, reduced sensitivity to molecules that activate meningeal nociceptors through the TRPV1 and TRPA1 channels can be important for BoNT-A’s ability to act as a prophylactic.

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Section: Discussionmentioning

confidence: 99%

Extracranial injections of botulinum neurotoxin type A inhibit intracranial meningeal nociceptors’ responses to stimulation of TRPV1 and TRPA1 channels: Are we getting closer to solving this puzzle?

et al. 2016

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Protein complexes in snake venom

Doley

Kini

2009

Cell. Mol. Life Sci.

202

125

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Snake venom contains mixture of bioactive proteins and polypeptides. Most of these proteins and polypeptides exist as monomers, but some of them form complexes in the venom. These complexes exhibit much higher levels of pharmacological activity compared to individual components and play an important role in pathophysiological effects during envenomation. They are formed through covalent and/or non-covalent interactions. The subunits of the complexes are either identical (homodimers) or dissimilar (heterodimers; in some cases subunits belong to different families of proteins). The formation of complexes, at times, eliminates the non-specific binding and enhances the binding to the target molecule. On several occasions, it also leads to recognition of new targets as protein-protein interaction in complexes exposes the critical amino acid residues buried in the monomers. Here, we describe the structure and function of various protein complexes of snake venoms and their role in snake venom toxicity.

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