Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.69 (botulinum neurotoxin)
 1,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Botulinum toxin A (BoNT-A) develops its muscle-relaxing effect by the inhibition of acetylcholine (ACh) release. This toxin is also known to relieve muscular pain in different disorders. Conspicuously, pain in some patients responds earlier and sometimes even better than muscle tension, indicating that the effect of BoNT-A on pain is not only due to inhibition of ACh release. A questionnaire was distributed to 88 patients suffering from cervical dystonia (CD). Thirty-five completed questionnaires could be used for data analysis. After intramuscular injections of BoNT-A, patients with CD experience significant reductions in pain which sometimes occur significantly earlier than the improvements in head posture. In the iris sphincter muscle of the rabbit and in dorsal root ganglion cells (DRG) of the rat, inhibition of the release of substance P by BoNT-A has been shown experimentally, and BoNT-C has been proven to develop endopeptidase activity toward substance P (SP) in vitro. Findings in the current literature and our observations allow the conclusion that alleviation of muscle pain by BoNT-A may also be due to an effect on the release of nociceptive neuropeptides, among which SP seems to have a key function.
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PMID:[Reduction of pain and muscle spasms by botulinum toxin A]. 1132 Aug 66

Botulinum toxin (BTX) injections are a well-recognised therapeutic modality for the treatment of regional involuntary muscle disorders and recently BTX has been used for treatment of pain and inflammatory disorders. The primary purpose of this review is to discuss the mechanism of action of therapeutic BTX in light of both the traditional understanding of BTX pharmacological effects as well as new observations. The review will deal with clinical observations and relevant animal experimentation. The data and hypotheses presented are not only relevant to botulinum toxin technology but will certainly prove important in the basic mechanisms of some of the diseases where botulinum toxin has been successfully applied. BTX used clinically comprises botulinum neurotoxin (BoNT) complexed with non-toxic proteins. The non-toxic components of the BTX complexes stabilise the labile BoNT during purification and formulation as a therapeutic. The complex proteins may also have unrecognised clinical significance such as slowing diffusion in tissues or imparting stability. The mechanisms of BTX formulations acting on SNARE proteins are briefly reviewed providing a basis for BTX clinical applications. The potential for design of improved botulinum toxins and formulations is addressed.
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PMID:Botulinum toxin therapy for pain and inflammatory disorders: mechanisms and therapeutic effects. 1177 68

Clostridial neurotoxins potently and specifically inhibit neurotransmitter release in defined cell types. Here we report that a catalytically active derivative (termed LH(N)/A) of the type A neurotoxin from Clostridium botulinum has been coupled to a lectin obtained from Erythrina cristagalli to form a novel conjugate. This conjugate exhibits an in vitro selectivity for nociceptive afferents compared with the anatomically adjacent spinal neurons, as assessed using in vitro primary neuronal culture systems to measure inhibition of release of neurotransmitters. Chemical conjugates prepared between E. cristagalli lectin and either natively sourced LH(N)/A or recombinant LH(N)/A purified from Escherichia coli are assessed, and equivalence of the recombinant material are demonstrated. Furthermore, the dependence of inhibition of neurotransmitter release on the cleavage of SNAP-25 is demonstrated through the use of an endopeptidase-deficient LH(N)/A conjugate variant. The duration of action of inhibition of neurotransmitter released by the conjugate in vitro is assessed and is comparable with that observed with Clostridium botulinum neurotoxin. Finally, in vivo electrophysiology shows that these in vitro actions have biological relevance in that sensory transmission from nociceptive afferents through the spinal cord is significantly attenuated. These data demonstrate that the potent endopeptidase activity of clostridial neurotoxins can be selectively retargeted to cells of interest and that inhibition of release of neurotransmitters from a neuronal population of therapeutic relevance to the treatment of pain can be achieved.
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PMID:Inhibition of release of neurotransmitters from rat dorsal root ganglia by a novel conjugate of a Clostridium botulinum toxin A endopeptidase fragment and Erythrina cristagalli lectin. 1210 93

The seven botulinum neurotoxin serotypes share less than 50% sequence homology and are immunologically distinct. The neurotoxins inhibit release of the neurotransmitter acetylcholine from the axon terminals of motor neurons, preganglionic sympathetic and parasympathetic neurons, and postganglionic parasympathetic nerves by a multi-step mechanism that differs slightly, but significantly, for each serotype. The inhibition is long lasting but temporary. The resulting muscle paralysis has provided the basis for therapeutic use of botulinum toxin types A and B in a variety of focal dystonias. The safety of the botulinum toxins, when administered focally, has permitted their widespread use in a number of other painful conditions.
Clin J Pain
PMID:Therapeutic use of botulinum toxins: background and history. 1256 58

Clinical experience thus far has shown BoNT-A to be a safe and efficacious method in the short to medium term management of spasticity of the upper limb in cerebral palsy. The relaxation of hypertonic musculature allows for improvement in function and posture, reduction of pain, and in some patients, improvement in cosmesis. It is also a valuable tool in predicting response to and guiding contemplated muscle-tendon surgery. Careful patient selection, detailed clinical assessment of deformity and disability, and a clear outline of treatment goals are essential to good outcomes. Further work needs to be done to determine optimum doses of BoNT-A for individual muscles and to evaluate the long-term outcome of repeated injections.
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PMID:Botulinum toxin A in the management of upper limb spasticity in cerebral palsy. 1459 51

Botulinum toxin type A (BoNT-A) produced by the bacterium Clostridium botulinum is a potent inhibitor of acetylcholine release in the neuromuscular junction and has been used to treat many disorders related to excessive muscle contraction. However, BoNT-A has recently been used in pain therapy to treat myofascial pain, low back pain and various types of headaches, including migraine. The purpose of this study is to investigate the antinociceptive effect of BoNT-A and its underlying mechanism in the rat formalin inflammatory pain model. BoNT-A (3.5, 7, 15 and 30 U/kg) or vehicle was administered to the plantar surface of the right hindpaw of male Sprague-Dawley rats. BoNT-A dose-dependently (P<0.05) inhibited formalin-induced nociceptive behavior during phase 2 but not during phase 1 when administered 5 h to 12 days before formalin challenge. The onset of the antinociceptive effect started at 5 h after pre-treatment and this effect lasted for at least 12 days. BoNT-A (7 U/kg) also reduced edema. Consistent with the lack of effect in the formalin phase 1, BoNT-A, at 15 U/kg, had no effect on acute thermal nociception; no local muscle weakness was observed at this dose. Pre-treatment of rats with BoNT-A (3.5, 7 or 15 U/kg) all significantly reduced formalin-evoked glutamate (Glu) release. These results demonstrate that local peripheral injection of BoNT-A significantly reduces formalin-induced nociceptive behaviors with the absence of obvious muscle weakness. Such an antinociceptive effect of BoNT-A is associated with the inhibition of formalin-induced release of Glu (and/or neuropeptides) from primary afferent terminals.
Pain 2004 Jan
PMID:Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. 1471 98

Myofascial pain syndrome is defined as subacute or chronic pain with sensory, motor and autonomic symptoms referred from active trigger points with associated painful dysfunctions. Authors present the usefulness of botulinum toxin A or B (BoNT/A or BoNT/B) injected into target muscles since the toxin is capable of controlling not only the muscular spasm but mostly the pain by alternative mechanisms of action, which are discussed. Posology of BoNT, technical aspects and results are presented. BoNT represents an interesting and useful tool for an adequate management of patients with myofascial pain.
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PMID:Botulinum toxin (BoNT) and back pain. 1499 38

Clostridial neurotoxins potently and specifically inhibit neurotransmitter release in defined cell types. Previously reported data have demonstrated that the catalytically active LH(N) endopeptidase fragment of botulinum neurotoxin type A (termed LH(N)/A) can be retargeted to a range of cell types in vitro to lead to inhibition of secretion of a range of transmitters. Here, we report the synthesis of endopeptidase conjugates with in vitro selectivity for nociceptive afferents compared to spinal neurons. Chemical conjugates prepared between Erythrina cristagalli lectin and LH(N)/A are assessed in vitro and in in vivo models of pain. Chemical conjugates prepared between E. cristagalli lectin and either natively sourced LH(N)/A, or recombinant LH(N)/A purified from Escherichia coli are assessed, and equivalence of the recombinant material is demonstrated. The duration of action of inhibition of neurotransmitter release by the conjugate in vitro is also assessed and is comparable to that observed with Clostridium botulinum neurotoxin. Selectivity of targeting and therapeutic potential have been confirmed by in vivo electrophysiology studies. Furthermore, the analgesic properties of the conjugate have been assessed in in vivo models of pain and extended duration effects observed. These data provide proof of principle for the concept of retargeted clostridial endopeptidases as novel analgesics.
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PMID:Retargeted clostridial endopeptidases: inhibition of nociceptive neurotransmitter release in vitro, and antinociceptive activity in in vivo models of pain. 1502 53

The vanilloid receptor-1 (TRPV1) plays a key role in the perception of peripheral thermal and inflammatory pain. TRPV1 expression and channel activity are notably up-regulated by proalgesic agents. The transduction pathways involved in TRPV1 sensitization are still elusive. We have used a yeast two-hybrid screen to identify proteins that associate with the N terminus of TRPV1. We report that two vesicular proteins, Snapin and synaptotagmin IX (Syt IX), strongly interact in vitro and in vivo with the TRPV1 N-terminal domain. In primary dorsal root ganglion neurons, TRPV1 co-distributes in vesicles with Syt IX and the vesicular protein synaptobrevin. Neither Snapin nor Syt IX affected channel function, but they notably inhibited protein kinase C (PKC)-induced potentiation of TRPV1 channel activity with a potency that rivaled the blockade evoked by botulinum neurotoxin A, a potent blocker of neuronal exocytosis. Noteworthily, we found that PKC activation induced a rapid delivery of functional TRPV1 channels to the plasma membrane. Botulinum neurotoxin A blocked the TRPV1 membrane translocation induced by PKC that was activated with a phorbol ester or the metabotropic glutamate receptor mGluR5. Therefore, our results indicate that PKC signaling promotes at least in part the SNARE-dependent exocytosis of TRPV1 to the cell surface. Taken together, these findings imply that activity-dependent delivery of channels to the neuronal surface may contribute to the buildup and maintenance of thermal inflammatory hyperalgesia in peripheral nociceptor terminals.
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PMID:Regulated exocytosis contributes to protein kinase C potentiation of vanilloid receptor activity. 1506 94

Clinical data and experience to date have demonstrated that BoNT-A is an effective and well-tolerated therapy for the prevention of migraine and other headache disorders. It has a long duration of action that may last over 4 months with no systemic or serious AEs. Several issues remain to be defined, however, including dosing, location, and number of injections; optimal dilution of BoNT-A; specific headache types that respond best to BoNT-A; and long-term efficacy and safety. Data from ongoing well-designed trials that include a larger patient population investigating these issues may confirm a role for BoNT-A as a first-line agent for migraine prevention. Neurotoxin therapy is part of a broader headache management approach. Because the injection techniques for headache are unique and vary depending on the primary headache disorder being treated and the location and pattern of pain referral, the use of BoNT-A for headache is not simply an extension of its use for cosmesis. The use of BoNT-A in the overall management of primary headache disorders should be reserved for medical practitioners who not only have experience with BoNT-A injections, but possess the expertise in the diagnosis and management of complex headache disorders. Educating patients and addressing headache triggers and optimizing acute treatment improve the outcome of any preventive program.
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PMID:Botulinum neurotoxin for the treatment of migraine and other primary headache disorders. 1522 77


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