Heparin at low concentration acts as antivenom against Bothrops jararacussu venom and bothropstoxin-I neurotoxic and myotoxic actions

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Abstract

Heparin has been shown to antagonize myotoxic effects of crotaline venoms. Here a very low heparin concentration (LHC) was examined in its ability to antagonize the neurotoxic/myotoxic effects of Bothrops jararacussu venom and its phospholipase A ₂ myotoxin, bothropstoxin-I (BthTX-I), in an in vitroz nerve-muscle preparation and in mice gastrocnemius. Normalization of results was done by assays with commercial antibothropic antivenom (CBA). LHC (1IU/ml) added to the incubation bath reduced by 4- and 4.5-fold ( vs 2.8- and 2.5-fold by CBA) the neuromuscular paralysis, by 5.4 and 4.4-fold ( vs 2.5- and 13.3-fold by CBA) the percentage of fibers damaged and by 6- and 1.7-fold ( vs 30- and 1.6-fold by CBA) the CK activity induced by B. jararacussu and BthTX-I, respectively. Protamine sulphate added 15min after the incubation of the preparation with LHC+venom, avoided the LHC neutralizing effect against venom neurotoxicity. This strongly attests that given the polycationic nature of protamine, it probably complexed with the polyanionic heparin making it unattainable for binding to basic components of venom, reducing toxicity. Since heparin antagonism is generally stronger against venom effects than is myotoxin we discuss that other venom components than the BthTX-I are likely target for the antagonism promoted by the polyanionic heparin.

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The structure of glycosaminoglycans and their interactions with proteins.

Neha Gandhi, Ricardo L. Mancera (2008)

Glycosaminoglycans (GAGs) are important complex carbohydrates that participate in many biological processes through the regulation of their various protein partners. Biochemical, structural biology and molecular modelling approaches have assisted in understanding the molecular basis of such interactions, creating an opportunity to capitalize on the large structural diversity of GAGs in the discovery of new drugs. The complexity of GAG-protein interactions is in part due to the conformational flexibility and underlying sulphation patterns of GAGs, the role of metal ions and the effect of pH on the affinity of binding. Current understanding of the structure of GAGs and their interactions with proteins is here reviewed: the basic structures and functions of GAGs and their proteoglycans, their clinical significance, the three-dimensional features of GAGs, their interactions with proteins and the molecular modelling of heparin binding sites and GAG-protein interactions. This review focuses on some key aspects of GAG structure-function relationships using classical examples that illustrate the specificity of GAG-protein interactions, such as growth factors, anti-thrombin, cytokines and cell adhesion molecules. New approaches to the development of GAG mimetics as possible new glycotherapeutics are also briefly covered.

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Snake venom metalloproteinases: their role in the pathogenesis of local tissue damage.

J Gutiérrez, A Rucavado (2000)

The biochemical characteristics of hemorrhagic metalloproteinases isolated from snake venoms are reviewed, together with their role in the pathogenesis of the local tissue damage characteristic of crotaline and viperine snake envenomations. Venom metalloproteinases differ in their domain structure. Some enzymes comprise only the metalloproteinase domain, others have disintegrin-like and high cysteine domains and others present, besides these domains, an additional lectin-like subunit. All of them are zinc-dependent enzymes with highly similar zinc binding environments. Some metalloproteinases induce hemorrhage by directly affecting mostly capillary blood vessels. It is suggested that hemorrhagic enzymes cleave, in a highly selective fashion, key peptide bonds of basement membrane components, thereby affecting the interaction between basement membrane and endothelial cells. As a consequence, these cells undergo a series of morphological and functional alterations in vivo, probably associated with biophysical hemodynamic factors such as tangential fluid shear stress. Eventually, gaps are formed in endothelial cells through which extravasation occurs. In addition to hemorrhage, venom metalloproteinases induce skeletal muscle damage, myonecrosis, which seems to be secondary to the ischemia that ensues in muscle tissue as a consequence of bleeding and reduced perfusion. Microvessel disruption by metalloproteinases also impairs skeletal muscle regeneration, being therefore responsible of fibrosis and permanent tissue loss after snakebites. Moreover, venom metalloproteinases participate in the degradation of extracellular matrix components and play a relevant role in the prominent local inflammatory response that characterizes snakebite envenomations, since they induce edema, activate endogenous matrix metalloproteinases (MMPs) and are capable of releasing TNF-alpha from its membrane-bound precursor. Owing to their protagonic role in the pathogenesis of local tissue damage, snake venom metalloproteinases constitute relevant targets for natural and synthetic inhibitors which may complement antivenoms in the neutralization of these effects.

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Phospholipase A2 myotoxins from Bothrops snake venoms.

JoséMaría Gutiérrez, Bruno Lomonte (1995)

Several myotoxins have been isolated from Bothrops snake venoms during the last 10 years. All of them are group II basic phospholipases A2, although some lack enzymatic activity (i.e. Lys-49 variants). These myotoxins appear as an antigenically related family of proteins occurring in many, but not all, Bothrops venoms, bearing a close structural and antigenic relationship to toxins found in other crotalid venoms of the genera Agkistrodon and Trimeresurus. Myotoxins are quantitatively important venom components in some Bothrops species. Intramuscular injection of Bothrops myotoxins leads to a rapid series of drastic degenerative events, probably initiated at the plasma membrane level, which culminate in a selective skeletal muscle necrosis. This in vivo specificity contrasts with the ability of myotoxins to lyse many types of cells in culture. Muscle damage, as well as cytolysis and liposome disruption, occur in conditions where phospholipase A2 activity is inhibited, although enzymatic activity might enhance myotoxin actions. A membrane receptor for Bothrops myotoxins has not been identified yet. A working hypothesis on the mechanism of action is proposed. Current evidence suggests that these toxins interact with biological membranes via a molecular region distinct from their known catalytic site. The active region is likely to be formed by a combination of basic and hydrophobic amino acid residues near the C-terminus of the protein, which allow electrostatic interaction and bilayer penetration. These events may lead to membrane destabilization and loss of selective permeability to ions such as calcium, both of which appear to be important mediators in the process of muscle necrosis.

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Author and article information

Journal

Journal ID (nlm-ta): J Venom Res

Journal ID (publisher-id): jvr

Title: Journal of Venom Research

Publisher: Library Publishing Media

ISSN (Electronic): 2044-0324

Publication date Collection: 2010

Publication date (Electronic): 15 October 2010

Volume: 1

Pages: 54-60

Affiliations

[1] ^αDepartamento de Farmacologia, Faculdade de Ciências Médicas, CP 6111, Universidade Estadual de Campinas - UNICAMP, Brasil,

[2] ^βDepartamento de Análises Clínicas, Toxicológica e Bromatológica, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, Ribeirão Preto, SP, Brasil,

[3] ^γDepartamento de Histologia e Embriologia, Instituto de Biologia, C.P. 6109, Universidade Estadual de Campinas - UNICAMP, CEP 13083-970 Campinas, SP, Brasil,

[4] ^δCurso de Farmácia, Universidade de Sorocaba, Sorocaba, SP, Brasil

Author notes

[* ]Correspondence to: Yoko Oshima-Franco, Email: yofranco@terra.com.br, Tel: +55 019 3521 9533, Fax: +55 019 3289 2968

Article

PMC ID: 3086186

PubMed ID: 21544183

SO-VID: fa480749-8656-4dd6-9b12-18a749029d1b

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This is an open access article, published under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.0/uk/). This license permits non-commercial use, distribution and reproduction of the article, provided the original work is appropriately acknowledged with correct citation details.

Heparin at low concentration acts as antivenom against Bothrops jararacussu venom and bothropstoxin-I neurotoxic and myotoxic actions

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Most cited references 42

The structure of glycosaminoglycans and their interactions with proteins.

Snake venom metalloproteinases: their role in the pathogenesis of local tissue damage.

Phospholipase A2 myotoxins from Bothrops snake venoms.

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