Double-Binding Botulinum Molecule with Reduced Muscle Paralysis: Evaluation in In Vitro and In Vivo Models of Migraine.
Analgesics
/ administration & dosage
Animals
Botulinum Toxins
/ administration & dosage
Cell Line, Tumor
/ drug effects
Disease Models, Animal
Electromyography
Humans
Male
Migraine Disorders
/ drug therapy
Muscle, Skeletal
/ drug effects
Nitroglycerin
/ pharmacology
Rats
Rats, Sprague-Dawley
Trigeminal Ganglion
/ drug effects
Migraine
botulinum
glyceryl trinitrate model
multivalent
neuronal delivery
trigeminal
trigeminovascular
Journal
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
ISSN: 1878-7479
Titre abrégé: Neurotherapeutics
Pays: United States
ID NLM: 101290381
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
accepted:
04
11
2020
pubmed:
19
11
2020
medline:
15
12
2021
entrez:
18
11
2020
Statut:
ppublish
Résumé
With a prevalence of 15%, migraine is the most common neurological disorder and among the most disabling diseases, taking into account years lived with disability. Current oral medications for migraine show variable effects and are frequently associated with intolerable side effects, leading to the dissatisfaction of both patients and doctors. Injectable therapeutics, which include calcitonin gene-related peptide-targeting monoclonal antibodies and botulinum neurotoxin A (BoNT/A), provide a new paradigm for treatment of chronic migraine but are effective only in approximately 50% of subjects. Here, we investigated a novel engineered botulinum molecule with markedly reduced muscle paralyzing properties which could be beneficial for the treatment of migraine. This stapled botulinum molecule with duplicated binding domain-binary toxin-AA (BiTox/AA)-cleaves synaptosomal-associated protein 25 with a similar efficacy to BoNT/A in neurons; however, the paralyzing effect of BiTox/AA was 100 times less when compared to native BoNT/A following muscle injection. The performance of BiTox/AA was evaluated in cellular and animal models of migraine. BiTox/AA inhibited electrical nerve fiber activity in rat meningeal preparations while, in the trigeminovascular model, BiTox/AA raised electrical and mechanical stimulation thresholds in Aδ- and C-fiber nociceptors. In the rat glyceryl trinitrate (GTN) model, BiTox/AA proved effective in inhibiting GTN-induced hyperalgesia in the orofacial formalin test. We conclude that the engineered botulinum molecule provides a useful prototype for designing advanced future therapeutics for an improved efficacy in the treatment of migraine.
Identifiants
pubmed: 33205382
doi: 10.1007/s13311-020-00967-7
pii: 10.1007/s13311-020-00967-7
pmc: PMC8116399
doi:
Substances chimiques
Analgesics
0
Botulinum Toxins
EC 3.4.24.69
Nitroglycerin
G59M7S0WS3
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
556-568Subventions
Organisme : National Centre for the Replacement, Refinement and Reduction of Animals in Research
ID : NC/S000925/1
Pays : United Kingdom
Organisme : Kazan Federal University
ID : 0671-2020-0059
Organisme : Finnish Academy
ID : 325392
Organisme : Medical Research Council
ID : MR/K022539/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_16058
Pays : United Kingdom
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