Revealing the Therapeutic Potential of Botulinum Neurotoxin Type A in Counteracting Paralysis and Neuropathic Pain in Spinally Injured Mice

• Published in: Toxins 2020-07, Vol.12 (8), p.491
• Main Authors: Vacca, Valentina, Madaro, Luca, De Angelis, Federica, Proietti, Daisy, Cobianchi, Stefano, Orsini, Tiziana, Puri, Pier Lorenzo, Luvisetto, Siro, Pavone, Flaminia, Marinelli, Sara
• Format: Article
• Language: English
• Subjects: Analgesics - therapeutic use; Animal models; Animals; Apoptosis; Blocking; botulinum neurotoxin type A; Botulinum toxin; Botulinum Toxins, Type A - therapeutic use; Cell death; Cell Proliferation - drug effects; Chemical compounds; Cicatrix - prevention & control; Complex formation; Contusions; Dimensional analysis; Drug dosages; Female; Glia; glial scar; Hyperreactivity; Hypersensitivity; Inflammation; Ischemia; Mice; Muscles; Muscular Atrophy - drug therapy; Neuralgia; Neuralgia - drug therapy; neurodegeneration; Neuroglia; Neuroglia - drug effects; Neurological diseases; Neuromuscular Agents - therapeutic use; Neurons - drug effects; neuropathic pain; Neuroprotective Agents - therapeutic use; Neurotoxins; Pain; Pain perception; Paralysis; Paralysis - drug therapy; Pharmacology; Proteolysis; Restoration; Scars; SNAP receptors; SNAP-25 protein; Spinal cord; Spinal cord injuries; Spinal Cord Injuries - drug therapy; spinal cord injury; Toxicity; Toxins; Trauma
• ISSN: 2072-6651; 2072-6651
• DOI: 10.3390/toxins12080491

Botulinum neurotoxin type A (BoNT/A) is a major therapeutic agent that has been proven to be a successful treatment for different neurological disorders, with emerging novel therapeutic indications each year. BoNT/A exerts its action by blocking SNARE complex formation and vesicle release through the specific cleavage of SNAP-25 protein; the toxin is able to block the release of pro-inflammatory molecules for months after its administration. Here we demonstrate the extraordinary capacity of BoNT/A to neutralize the complete paralysis and pain insensitivity induced in a murine model of severe spinal cord injury (SCI). We show that the toxin, spinally administered within one hour from spinal trauma, exerts a long-lasting proteolytic action, up to 60 days after its administration, and induces a complete recovery of muscle and motor function. BoNT/A modulates SCI-induced neuroglia hyperreactivity, facilitating axonal restoration, and preventing secondary cells death and damage. Moreover, we demonstrate that BoNT/A affects SCI-induced neuropathic pain after moderate spinal contusion, confirming its anti-nociceptive action in this kind of pain, as well. Our results provide the intriguing and real possibility to identify in BoNT/A a therapeutic tool in counteracting SCI-induced detrimental effects. Because of the well-documented BoNT/A pharmacology, safety, and toxicity, these findings strongly encourage clinical translation.