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 pro-regenerative 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.
Highlights
Snakebite envenoming is a neglected disease that the World Health Organization has estimated to affect 1.8–2.7 million people each year, causing as many as 81000–138000 deaths and 400 000 cases of permanent disability, mainly in tropical and sub-tropical areas of the world [1]
We have taken here a different angle in the search for novel treatments of snake envenomings by focusing of the phase of recovery from the peripheral neuroparalysis caused by neurotoxic snakes
We have found a drug, dubbed NUCC-390, which accelerates the functional recovery from peripheral neuroparalysis caused by the Taipan venom in mice, by acting on the CXCR4 receptor
Summary
Snakebite envenoming is a neglected disease that the World Health Organization has estimated to affect 1.8–2.7 million people each year, causing as many as 81000–138000 deaths and 400 000 cases of permanent disability, mainly in tropical and sub-tropical areas of the world [1]. Many envenomed patients develop permanent physical and psychological sequelae, affecting their quality of life with associated increase in social costs [1, 2, 3, 4, 5]. Australo-Papuan Taipans cause an acute neuromuscular paralysis and impairment of the autonomic peripheral nervous system This envenomation induces a wide range of symptoms, from respiratory and locomotor paralysis to sensory effects, that closely resemble those of botulism and of the GuillainBarrè autoimmune syndrome. A rapid reduction of the compound muscle action potential upon electrical stimulation of motor neurons was observed in bitten patients to reach values as low as 10% of the normal figure within 30–40 hours from bite; this is usually followed by a slow recovery to 2/3 of original value within 500–700 hours [24, 25]
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