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http://dx.doi.org/10.1007/s43188-021-00102-4

Hemorrhagic changes and microglia activation induced by Macrovipera lebetina obtusa venom with the inhibited enzymatic activity in rat brain  

Voskanyan, Armen V. (Orbeli Institute of Physiology, National Academy of Sciences Armenia)
Darbinyan, Anna A. (Orbeli Institute of Physiology, National Academy of Sciences Armenia)
Parseghyan, Lilya M. (Orbeli Institute of Physiology, National Academy of Sciences Armenia)
Publication Information
Toxicological Research / v.38, no.2, 2022 , pp. 195-204 More about this Journal
Abstract
The metalloproteinases and phospholipase A2 are the main enzymes in the venom of Macrovipera lebetina obtusa that play a decisive role in the destructive and toxic effects on the organism of the prey. Metalloproteinases cause hemorrhagic damage, destroy the basement membrane of the blood vessel and disrupt the connections between endothelial cells. Phospholipase A2 causes hemolysis of erythrocytes, destroy the cell membranes, and inhibits the adhesion of platelets and so on. The state of the capillaries of the rat brain and microglia under the action of the venom with separately inhibited enzymes was investigated and compared to the action of the crude venom. Also, the toxicity LD50 of the venom of Macrovipera lebetina obtusa with the inhibited enzymatic activity was determined. The histochemical study showed that the inhibition of phospholipase A2 enzymatic activity did not significantly change the vasodestructive effect of the venoms. In case of action of a venom with inhibited enzymatic activity of metalloproteinases, low activity of microglia and less damaged capillaries were observed. The toxicity of the venom with inhibited phospholipase A2 and with inhibited metalloproteinases was respectively 1.8 and 3.7 times weaker than that of the crude venom. We can claim that both the toxicity of the venom of Macrovipera lebetina obtusa, the damaged brain vessels and the increased activity of CNS microglia are determined mainly by the action of metalloproteinases.
Keywords
Brain capillaries; Metalloproteinases; Microglial cells; Phospholipase $A_2$; Viper venom; LD50;
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1 Wu WB, Huang TF (2003) Activation of MMP-2, cleavage of matrix proteins, and adherens junctions during a snake venom metalloproteinase-induced endothelial cell apoptosis. Exp Cell Res. https://doi.org/10.1016/S0014-4827(03)00183-6   DOI
2 Marcussi S, SantAna C, Oliveira C, Quintero Rueda A, Menaldo D, Beleboni R, Stabeli R, Giglio J, Fontes M, Soares A (2007) Snake Venom Phospholipase A2 Inhibitors: Medicinal Chemistry and therapeutic Potential. Curr Top Med Chem. https://doi.org/10.2174/156802607780487614   DOI
3 Bazaa A, Pasquier E, Defilles C, Limam I, Kessentini-Zouari R, Kallech-Ziri O, Battari AE, Braguer D, Ayeb ME, Marrakchi N, Luis J (2010) MVL-PLA2, a snake venom phospholipase A2, inhibits angiogenesis through an increase in microtubule dynamics and disorganization of focal adhesions. PLoS ONE. https://doi.org/10.1371/journal.pone.0010124   DOI
4 Evans AT, Formukong E, Evans FJ (1987) Activation of phospholipase A2 by cannabinoids. Lack of correlation with CNS effects. FEBS Lett. https://doi.org/10.1016/0014-5793(87)81420-5   DOI
5 Cotrim CA, De Oliveira SCB, Diz Filho EBS, Fonseca FV, Baldissera L, Antunes E, Ximenes RM, Monteiro HSA, Rabello MM, Hernandes MZ, De Oliveira Toyama D, Toyama MH (2011) Quercetin as an inhibitor of snake venom secretory phospholipase A2. Chem-Biol Interact. https://doi.org/10.1016/j.cbi.2010.10.016   DOI
6 Leon G, Sanchez L, Hernandez A, Villalta M, Herrera M, Segura A, Estrada R, Gutierrez JM (2011) Immune response towards snake venoms. Inflamm Allergy Drug Targets. https://doi.org/10.2174/187152811797200605   DOI
7 Hovhannisyan M, Voskanyan A, Bezuglov V, Vardapetyan H, Koshatashyan H, Darbinyan A, Antonyan M (2015) (274) Phospholipase A2 of Macrovipera lebetina obtusa venom as a main target to relief pain after snake bites. J Pain. https://doi.org/10.1016/j.jpain.2015.01.192   DOI
8 Song J, Xu X, Zhang Y, Guo M, Yan X, Wang S, Gao S (2013) Purification and characterization of AHPM, a novel non-hemorrhagic P-IIIc metalloproteinase with α-fibrinogenolytic and platelet aggregation-inhibition activities, from Agkistrodon halys pallas venom. Biochimie. https://doi.org/10.1016/j.biochi.2012.10.013   DOI
9 Nieuwenhuizen W, Kunze H, De Haas GH (1974) [15] Phospholipase A2 (Phosphatide Acylhydrolase, EC 3.1.1.04) from Porcine Pancreas. Methods Enzymol. https://doi.org/10.1016/0076-6879(74)32018-6   DOI
10 Randhawa MA (2009) Calculation of LD50 values from the method of Miller and Tainter, 1944. J Ayub Med Coll Abbottabad 21:184-185
11 Ouyang Y, Kaminski NE (1999) Phospholipase A2 inhibitors p-bromophenacyl bromide and arachidonyl trifluoromethyl ketone suppressed interleukin-2 (IL-2) expression in murine primary splenocytes. Arch Toxicol. https://doi.org/10.1007/s002040050579   DOI
12 Darbinyan A, Antonyan M, Koshatashyan H, Parsegyan L, Bezuglov V, Voskanyan A (2019) Snake's and arthropod's venominduced pain-like behavior. Toxicon. https://doi.org/10.1016/j.toxicon.2018.11.369   DOI
13 Archundia IG, de Roodt AR, Ramos-Cerrillo B, Chippaux JP, Olguin-Perez L, Alagon A, Stock RP (2011) Neutralization of Vipera and Macrovipera venoms by two experimental polyvalent antisera: A study of paraspecificity. Toxicon. https://doi.org/10.1016/j.toxicon.2011.04.009   DOI
14 Abramoff MD, Magalhaes PJ, Ram SJ (2004) Image processing with imageJ. In: Biophotonics International
15 Jose MG, Teresa E, Alexandra R, Cristina H (2016) Hemorrhage caused by snake venom metalloproteinases: a journey of discovery and understanding. Toxins (Basel) 8:93. https://doi.org/10.3390/toxins8040093   DOI
16 Gyoneva S, Davalos D, Biswas D, Swanger SA, Garnier-Amblard E, Loth F, Akassoglou K, Traynelis SF (2014) Systemic inflammation regulates microglial responses to tissue damage in vivo. Glia. https://doi.org/10.1002/glia.22686   DOI
17 Kondo H, Kondo S, Ikezawa H, Murata R, Ohsaka A (2014) Studies on the quantitative method for determination of hemorrhagic activity of habu snake venom. Jpn J Med Sci Biol. https://doi.org/10.7883/yoken1952.13.43   DOI
18 Hovens I, Nyakas C, Schoemaker R (2014) A novel method for evaluating microglial activation using ionized calcium-binding adaptor protein-1 staining: cell body to cell size ratio. Neuroimmunol Neuroinflamm. https://doi.org/10.4103/ 2347-8659.139719   DOI
19 Chilingaryan A, Chilingaryan AM, Martin GG (2006) The threedimensional detection of microvasculatory bed in the brain of white rat Rattus norvegicus by a CA2+-ATPase method. Brain Res. https://doi.org/10.1016/j.brainres.2005.11.059   DOI
20 Olamide TO, Patty KS, Heloisa SS-A, Dulce HFS (2020) Snake Venom Metalloproteinases (SVMPs): a structure-function update. Toxicon X 7:100052. https://doi.org/10.1016/j.toxcx.2020.100052   DOI
21 Jaya V, Amira AZ, Syed MS, Norliana M, Halijah I, Stephen A (2017) Uncovering a protease in snake venom capable to coagulate milk to curd. Int J Adv Biotechnol Res 8:409-424
22 Wu X, Hart H, Cheng C, Roach P, Tatchell K (2001) Characterization of Gac1p, a regulatory subunit of protein phosphatase type I involved in glycogen accumulation in Saccharomyces cerevisiae. Mol Genet Genomics. https://doi.org/10.1007/s004380100455   DOI
23 Darbinyan AA, Antonyan MV, Koshatashyan HR, Gevorgyan SS, Arestakesyan HV, Karabekian ZI, Ayvazyan NM, Voskanyan AV (2018) Changes in microglia activity of rat brain induced by Macrovipera lebetina obtusa venom. Neuroimmunol Neuroinflamm. https://doi.org/10.20517/2347-8659.2018.33   DOI
24 Siigur J, Aaspollu A, Siigur E (2019) Biochemistry and pharmacology of proteins and peptides purified from the venoms of the snakes Macrovipera lebetina subspecies. Toxicon. https://doi.org/10.1016/j.toxicon.2018.11.294   DOI
25 Calvete JJ, Sanz L, Angulo Y, Lomonte B, Gutierrez JM (2009) Venoms, venomics, antivenomics. FEBS Lett. https://doi.org/10.1016/j.febslet.2009.03.029   DOI
26 Page-McCaw A, Ewald AJ, Werb Z (2007) Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol. https://doi.org/10.1038/nrm2125   DOI
27 Lindsey ML, Iyer RP, Jung M, DeLeon-Pennell KY, Ma Y (2016) Matrix metalloproteinases as input and output signals for post-myocardial infarction remodeling. J Mol Cell Cardiol. https://doi.org/10.1016/j.yjmcc.2015.12.018   DOI
28 Sanz L, Ayvazyan N, Calvete JJ (2008) Snake venomics of the Armenian mountain vipers Macrovipera lebetina obtusa and Vipera raddei. J Proteomics. https://doi.org/10.1016/j.jprot.2008.05.003   DOI
29 Kettenmann H, Verkhratsky A (2011) Neuroglia-living nerve glue. Fortschritte Der Neurologie Psychiatrie. https://doi.org/10.1055/s-0031-12817 04   DOI
30 Ayvazyan NM, Zaqaryan NA, Ghazaryan NA (2012) Molecular events associated with Macrovipera lebetina obtusa and Montivipera raddei venom intoxication and condition of biomembranes. Biochim Biophys Acta Biomembranes. https://doi.org/10.1016/j.bbamem.2012.02.001   DOI
31 Samel M, Vija H, Kurvet I, Kunnis-Beres K, Trummal K, Subbi J, Kahru A, Siigur J (2013) Interactions of PLA2-s from Vipera lebetina, Vipera berus berus and Naja naja oxiana venom with platelets, bacterial and cancer cells. Toxins. https://doi.org/10.3390/toxins5020203   DOI