PLA2 Inhibitor Varespladib as an Alternative to the Antivenom Treatment for Bites from Nikolsky's Viper Vipera berus nikolskii

Oleksandr Zinenko, Igor Tovstukha, Yevgen Korniyenko, Oleksandr Zinenko, Igor Tovstukha, Yevgen Korniyenko

Abstract

Although envenoming by a small East European species of viper is rarely severe, and only exceptionally fatal, lack of specific antivenom stocks in a few areas within this region and possible severe side effects of antivenom application leave most bites to be treated only with antihistamines and supportive therapy. Varespladib is an effective inhibitor of snake phospholipase, and, as such, it could be considered as first-line therapy. The Nikolsky's viper venom contains an extremely high concentration of phospholipase A2 (PLA2), responsible for the toxic effects of the venom, as well as minor amounts of other toxins. If Varespladib can successfully inhibit PLA2 activity, the Nikolsky's viper could be one of the first venomous snakes having an antitoxin-specific treatment regimen. To assess that, Varespladib was administered alone subcutaneously to adult male CD-1 mice (8 mg/kg) and compared to mice exposed to Vipera berus nikolskii crude venom (8 mg/kg = 10 LD50) or a combination of Varespladib and the same amount of the venom. Experimental animals were monitored for the presence of envenoming symptoms and mortality for 48 h after injection. Eighty percent of mice receiving both Varespladib and venom survived, while 100% of the control group receiving venom alone died within 4 h. Experimental results are consistent with Varespladib acting as an effective antitoxin in the mouse model against Nikolsky's viper venom. Further studies are needed under experimental conditions that more closely resemble natural envenoming (i.e., delayed administration).

Keywords: PLA2; Varespladib; Viperidae; inhibitor; mouse; snakebite; therapy.

Conflict of interest statement

Authors declare to have no competing interests.

Figures

Figure 1
Figure 1
In vivo protection with Varespladib LY315920 in CD-1 mice envenomed with V. b. nikolskii venom. The treatment groups were divided into venom alone (blue line), treatment alone (yellow line), and venom exposure plus treatment with Varespladib (orange line).

References

    1. Gutiérrez J.M., Calvete J.J., Habib A.G., Harrison R.A., Williams D.J., Warrell D.A. Snakebite envenoming. Nat. Rev. Dis. Primers. 2017;3:17063. doi: 10.1038/nrdp.2017.63.
    1. WHO (World Health Organization) Guidelines for the Production, Control and Regulation of Snake Antivenom Immunoglobulins. [(accessed on 19 March 2019)]; Available online: .
    1. Theakston R.D.G., Warrell D.A. Crisis in snake antivenom supply for Africa. Lancet. 2000;356:2104. doi: 10.1016/S0140-6736(05)74319-1.
    1. Laustsen A., Engmark M., Milbo C., Johannesen J., Lomonte B., Gutiérrez J.M., Lohse B. From fangs to pharmacology: The future of snakebite envenoming therapy. Curr. Pharm. Des. 2016;22:5270–5293. doi: 10.2174/1381612822666160623073438.
    1. Lewin M., Samuel S., Merkel J., Bickler P. Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation. Toxins. 2016;8:248. doi: 10.3390/toxins8090248.
    1. Lewin M.R., Gutiérrez J.M., Samuel S.P., Herrera M., Bryan-Quirós W., Lomonte B., Bickler P.E., Bulfone T.C., Williams D.J. Delayed Oral LY333013 Rescues Mice from Highly Neurotoxic, Lethal Doses of Papuan Taipan (Oxyuranus scutellatus) Venom. Toxins. 2018;10:380. doi: 10.3390/toxins10100380.
    1. Lewin M.R., Gilliam L.L., Gilliam J., Samuel S.P., Bulfone T.C., Bickler P.E., Gutiérrez J.M. Delayed LY333013 (Oral) and LY315920 (Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs from Lethal Doses of Micrurus fulvius (Eastern Coral Snake) Venom. Toxins. 2018;10:479.
    1. Wang Y., Zhang J., Zhang D., Xiao H., Xiong S., Huang C. Exploration of the inhibitory potential of Varespladib for snakebite envenomation. Molecules. 2018;23:391. doi: 10.3390/molecules23020391.
    1. Bittenbinder M.A., Zdenek C.N., Op den Brouw B., Youngman N.J., Dobson J.S., Naude A., Vonk F.J., Fry B.G. Coagulotoxic cobras: Clinical implications of strong anticoagulant actions of african spitting Naja venoms that are not neutralised by antivenom but are by LY315920 (Varespladib) Toxins. 2018;10:516. doi: 10.3390/toxins10120516.
    1. Morris G.M., Lim-Wilby M. Molecular docking. Methods Mol. Biol. 2008;443:365–382.
    1. Milto K.D., Zinenko O.I. Distribution and morphological variance of Vipera berus in Eastern Europe. In: Ananjeva N., Tsinenko O., editors. Herpetologia Petropolitana, Proceedings of the 12th Ordinary General Meeting of the Societas Europaea Herpetologica, Saint Peterburg, Russia, 12–16 August 2003. SEH; Saint Peterburg, Russia: 2005. pp. 64–73.
    1. Zinenko O., Ţurcanu V., Strugariu A. Distribution and morphological variation of Vipera berus nikolskii Vedmederja, Grubant et Rudaeva, 1986 in Western Ukraine, The Republic of Moldova and Romania. Amphib.-Reptil. 2010;31:51–67. doi: 10.1163/156853810790457885.
    1. Zinenko O.I., Kotenko T.I. Nikolsky’s viper, forest-steppe viper. Vipera nikolskii Vedmederja, Grubant et Rudaeva, 1986. In: Akimov I.A., editor. The Red Data Book of Ukraine. Animals. Global Consulting; Kyiv, Ukraine: 2009. p. 396.
    1. Danilov-Danilyan V.I., editor. The Red Data Book of Russian Federation. Animals. AST, Astrel; Moscow, Russia: 2001. p. 862.
    1. Kovalchuk S.I., Ziganshin R.H., Starkov V.G., Tsetlin V.I., Utkin Y.N. Quantitative proteomic analysis of venoms from Russian vipers of Pelias group: Phospholipases A2 are the main venom components. Toxins. 2016;8:105. doi: 10.3390/toxins8040105.
    1. Gao W., Starkov V.G., Tsetlin V.I., Utkin Y.N., Lin Z., Bi R. Isolation and preliminary crystallographic studies of two new phospholipases A 2 from Vipera nikolskii venom. Acta Cryst. 2005;61:189–192.
    1. Ramazanova A.S., Zavada L.L., Starkov V.G., Kovyazina I.V., Subbotina T.F., Kostyukhina E.E., Dementieva I.N., Ovchinnikova T.V., Utkin Y.U. Heterodimeric neurotoxic phospholipases A2—The first proteins from venom of recently established species Vipera nikolskii: Implication of venom composition in viper systematics. Toxicon. 2008;51:524–537. doi: 10.1016/j.toxicon.2007.11.001.
    1. Dyachenko I.A., Murashev A.N., Andreeva T.V., Tsetlin V.I., Utkin Y.N. Analysis of nociceptive effects of neurotoxic phospholipase A2 from Vipera nikolskii venom in mice. J. Venom Res. 2013;4:1–4.
    1. Malina T. Ph.D. Thesis. Debrecen University; Debrecen, Hungary: 2015. Venom Variation and Their Clinical Significance in Case of an Isolated Population of the Common Adder (Vipera berus) in Eastern Hungary.
    1. Tasoulis T., Isbister G.K. A Review and Database of Snake Venom Proteomes. Toxins. 2017;9:290. doi: 10.3390/toxins9090290.
    1. Calderon L., Lomonte B., Gutierrez J.M., Tarkowski A., Hanson L.A. Biological and biochemical activities of Vipera berus (European viper) venom. Toxicon. 1993;31:743–753. doi: 10.1016/0041-0101(93)90380-2.
    1. Bocian A., Urbanik M., Hus K., Łyskowski A., Petrilla V., Andrejčáková Z., Petrillová M., Legath J. Proteome and Peptidome of Vipera berus berus Venom. Molecules. 2016;21:1398. doi: 10.3390/molecules21101398.
    1. Adis R&D profile “Varespladib”. Am. J. Cardiovasc. Drugs. 2011;11:137–143.
    1. Krasovsky G.N., Rakmanin Y.A., Egorova N.A. Extrapolation of Toxicological Data from Animals to Man. Meditsina Publishers; Moscow, Russia: 2009. p. 208.

Source: PubMed

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