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

Abstract

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.

Botulinum Neurotoxins beyond Neurons: Interplay with Glial Cells

“…They found that BoNT/A significantly inhibited the activation of LPS-activated microglia and reduced the release of TNF-α, IL-6, Il-1β, iNOS, and MIP-1α, without any effect on the astrocytes’ activation. This latter result appears to be in contrast with findings that detect the cl-SNAP25 immunoreaction after treatment with BoNT/A, both in LPS-activated astrocytes [ 56 ] and in spinal astrocytes, either in CCI pain models [ 18 , 62 ] or in spinal cord injury models [ 63 ]. Interestingly, Finocchiaro et al [ 64 ] reported a strong reduction in the activation of spinal astrocytes, a study which also involved CCI mice that were treated with BoNT/B (intraplantar injection of 7.5 pg/mouse of 150 KDa of purified BoNT/B).…”

“…Oligodendrocytes and SCs are the myelin-forming cells within CNS and PNS, respectively. A recent paper on the therapeutic potential of BoNT/A in counteracting paralysis and neuropathic pain, which used a model involving spinal cord injuries (SCI) in mice, analyzed the possible interaction between BoNT/A and oligodendrocytes [ 63 ]. Oligodendrocytes are highly susceptible to spinal cord damage that is induced by traumatic injury, and they easily undergo apoptosis as consequence of SCI [ 72 ].…”

“…Oligodendrocytes are highly susceptible to spinal cord damage that is induced by traumatic injury, and they easily undergo apoptosis as consequence of SCI [ 72 ]. Accordingly, Vacca et al [ 63 ] observed a massive expression of the apoptotic marker Caspase 3, which is partially co-localized with oligodendrocytes, at the epicenter of the spinal impact. An intrathecal injection of BoNT/A (15 pg/mouse of 150 KDa purified BoNT/A in spinal cord) significantly reduced Caspase 3 expression, thus indicating protection against apoptotic processes.…”

Botulinum Neurotoxins in Central Nervous System: An Overview from Animal Models to Human Therapy

“…Recently, the effect of BoNT/A (15 pg/mouse, laboratory prepared toxin) on spinal regeneration and functional recovery after spinal traumas has been analyzed in two model of SCI contusion model [127]. A long-lasting paralysis and pain insensitivity was induced in a severe trauma model useful to evaluate the effects of BoNT/A on motor and sensitivity recovery, axonal regeneration, and neuroprotection.…”

“…treatment with BoNT/A during the acute phase of SCI reduced tissue damage and promoted motoneurons survival and spinal cord regeneration. Although the comprehension of all molecular events responsible for the spinal regeneration induced by BoNT/A needs to be deeply elucidated, study of Vacca et al [127] opens a new scenario in therapy of spinal lesions and, as pharmacology, safety, and toxicity of BoNT/A are well documented, strongly encourage the clinical translation.…”