An agonist of the CXCR4 receptor accelerates the recovery from the peripheral neuroparalysis induced by Taipan snake envenomation

Abstract

Envenomation by snakes is a major neglected human disease. Hospitalization and use of animal-derived antivenom are the primary therapeutic supports currently available. There is consensus that additional, not expensive, treatments that can be delivered even long after the snake bite are needed. We recently showed that the drug dubbed NUCC-390 shortens the time of recovery from the neuroparalysis caused by traumatic or toxic degeneration of peripheral motor neurons. These syndromes are characterized by the activation of a proregenerative molecular axis, consisting of the CXCR4 receptor expressed at the damaged site in neuronal axons and by the release of its ligand CXCL12α, produced by surrounding Schwann cells. This intercellular signaling axis promotes axonal growth and functional recovery from paralysis. NUCC-390 is an agonist of CXCR4 acting similarly to CXCL12α. Here, we have tested its efficacy in a murine model of neuroparalytic envenoming by a Papuan Taipan (Oxyuranus scutellatus) where a degeneration of the motor axon terminals caused by the presynaptic PLA2 toxin Taipoxin, contained in the venom, occurs. Using imaging of the neuromuscular junction and electrophysiological analysis, we found that NUCC-390 administration after injection of either the purified neuroparalytic Taipoxin or the whole Taipan venom, significantly accelerates the recovery from paralysis. These results indicate that NUCC-390, which is non-toxic in mice, should be considered for trials in humans to test its efficacy in accelerating the recovery from the peripheral neuroparalysis induced by Taipans. NUCC-390 should be tested as well in the envenomation by other snakes that cause neuroparalytic syndromes in humans. NUCC-390 could become an additional treatment, common to many snake envenomings, that can be delivered after the bite to reduce death by respiratory deficits and to shorten and improve functional recovery.

Models and methods to study Schwann cells

“…In this model, a sub‐lethal amount of α‐Latrotoxin (a pore‐forming neurotoxin from the black widow spider) or SPANs (Snake PLA 2 neurotoxins) locally injected in the mouse hind limb induces a rapid Ca ++ ‐mediated degeneration of motor axon terminals. Strikingly, nerve terminal degeneration is fully reversible, and motor axon terminals completely recover both structurally and functionally in a few days (Duregotti et al, 2015b , 2015c ; Negro et al, 2017 ; Stazi et al, 2020 ). By this toxin‐based experimental model, one can monitor the time course of morphological changes of PSCs, the activation of specific intracellular signaling pathways, and the effects of their manipulation on the recovery of motor function.…”

“…This transcriptome revealed that PSCs express the chemokine CXCL12α in response to injury, which, by engaging the CXCR4 receptor on the motor nerve stump, promotes axonal re‐growth and neurotransmission rescue. Of note, a chemical agonist of CXCR4 stimulates nerve regeneration in several conditions, recapitulating CXCL12α action (Negro et al, 2019 , Zanetti et al, 2019 ; Stazi et al, 2020 ).…”

“…Strikingly, nerve terminal degeneration is fully reversible, and motor axon terminals completely recover both structurally and functionally in a few days (Duregotti et al, 2015b(Duregotti et al, , 2015cNegro et al, 2017;Stazi et al, 2020). By this toxin-based experimental model, one can monitor the time course of morphological changes of PSCs, the activation of specific intracellular signaling pathways, and the effects of their manipulation on the recovery of motor function.…”

The Search for Natural and Synthetic Inhibitors That Would Complement Antivenoms as Therapeutics for Snakebite Envenoming

“…Furthermore, therapeutic interventions may be directed towards improving the regenerative capacity of affected tissues and cells. This is the case of NUCC-390, an agonist of CXCR 4 receptor, which promotes the regeneration of nerve terminals affected by neurotoxic PLA 2 s that act presynaptically [ 115 ], or possible therapies to improve skeletal muscle regeneration after venom-induced myonecrosis [ 116 , 117 ]. Hence, the in depth understanding of venom composition, the mechanisms of action of the most relevant toxins, and the pathophysiology of envenomings will provide valuable information not only for the design of specific toxin inhibitors, but also for other interventions aimed at controlling endogenous pathways playing a role in envenoming.…”

Latrotoxin-Induced Neuromuscular Junction Degeneration Reveals Urocortin 2 as a Critical Contributor to Motor Axon Terminal Regeneration

“…Then, isolation of the NMJs and sequencing of their RNA provided a time-resolved mRNA profiling of the NMJ during the entire process of degeneration and regeneration [15]. By this approach, we found that the molecular axis composed by the chemokine CXCL12α and its receptor CXCR4 acts as a potent driver of MAT regeneration [15], and that the small molecule compound NUCC-390, an agonist of CXCR4 [16], is a strong promoter of nerve regeneration in several models of PNS damage, spanning from neurotoxic venoms to traumas [17][18][19].…”