Abstract
The phospholipase A2 (PLA2) inhibitor Varespladib (LY315920) and its orally bioavailable prodrug, methyl-Varespladib (LY333013) inhibit PLA2 activity of a wide variety of snake venoms. In this study, the ability of these two forms of Varespladib to halt or delay lethality of potent neurotoxic snake venoms was tested in a mouse model. The venoms of Notechis scutatus, Crotalus durissus terrificus, Bungarus multicinctus, and Oxyuranus scutellatus, all of which have potent presynaptically acting neurotoxic PLA2s of variable quaternary structure, were used to evaluate simple dosing regimens. A supralethal dose of each venom was injected subcutaneously in mice, followed by the bolus intravenous (LY315920) or oral (LY333013) administration of the inhibitors, immediately and at various time intervals after envenoming. Control mice receiving venom alone died within 3 h of envenoming. Mice injected with O. scutellatus venom and treated with LY315920 or LY333013 survived the 24 h observation period, whereas those receiving C. d. terrificus and B. multicinctus venoms survived at 3 h or 6 h with a single dose of either form of Varespladib, but not at 24 h. In contrast, mice receiving N. scutatus venom and then the inhibitors died within 3 h, similarly to the control animals injected with venom alone. LY315920 was able to reverse the severe paralytic manifestations in mice injected with venoms of O. scutellatus, B. multicinctus, and C. d. terrificus. Overall, results suggest that the two forms of Varespladib are effective in abrogating, or delaying, neurotoxic manifestations induced by some venoms whose neurotoxicity is mainly dependent on presynaptically acting PLA2s. LY315920 is able to reverse paralytic manifestations in severely envenomed mice, but further work is needed to understand the significance of species-specific differences in animal models as they compare to clinical syndromes in human and for potential use in veterinary medicine.
Highlights
Snakebite envenoming is a neglected tropical disease that kills or maims hundreds of thousands of people every year, especially in impoverished rural communities of sub-Saharan Africa, Asia, LatinAmerica, and parts of Oceania [1]
Such is the case of the phospholipase A2 (PLA2) inhibitor Varespladib (LY315920) and its orally available derivative methyl-Varespladib (LY333013), which were developed for the therapy of several unrelated conditions [11,12]
Recent studies have shown the ability of these drugs to inhibit enzymatic PLA2 activity of a large number of venoms in vitro [7], and to abrogate, in animal models, lethality induced by two neurotoxic elapid venoms whose toxicity is based on the presynaptic action of neurotoxic PLA2 s [18,19]
Summary
Snakebite envenoming is a neglected tropical disease that kills or maims hundreds of thousands of people every year, especially in impoverished rural communities of sub-Saharan Africa, Asia, LatinAmerica, and parts of Oceania [1]. An unmet need is for the development of novel therapies that could be administered in the field rapidly after the onset of envenoming [4], as well as to augment antivenom performance where specific toxins have become inaccessible to antivenom upon distribution into the tissues, but might be amenable to inhibition or dislodgement by smaller molecules. Promising developments in this area have emerged, including natural and synthetic inhibitors of snake venom metalloproteinases (SVMPs) [5,6], phospholipases A2 (PLA2 s) [7], cytotoxins of the three finger toxin family [8,9], and α-neurotoxins [10], among others
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