Synergism between baltergin metalloproteinase and Ba SPII RP4 PLA2 from Bothrops alternatus venom on skeletal muscle (C2C12) cells

Bustillo, Soledad; Denegri, Maria Emília Garcia; Ponce-Soto, Luis Alberto; Joffé, Elisa Bal de Kier; Acosta, Ofelia; Leiva, Laura

doi:10.1016/j.toxicon.2011.11.007

Cited by 45 publications

(23 citation statements)

References 28 publications

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“…The PLA 2 family has recently been regarded a promising target for broad spectrum antivenom drug development, due to their wide-distribution, high content, and diverse toxicological effects [ 25 ]. Previous studies revealed that PLA 2 s acts with other toxic components in a synergistic manner, mostly zinc-dependent metalloproteinases, which are responsible for hemorrhage, blistering, and necrosis [ 26 , 27 , 28 ]. The anti-PLA 2 IgGs developed from Ba spII RP4 PLA 2 (a non-toxic PLA 2 from Bothrops alternates venom) could inhibit haemolysis and myotoxicity of the crude venom, and also decreased 50% of mortality of mice dosed with four times the LD 50 .…”

Section: Discussionmentioning

confidence: 99%

Exploration of the Inhibitory Potential of Varespladib for Snakebite Envenomation

Wang

Zhang

et al. 2018

Molecules

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Phospholipase A2s (PLA2) is a major component of snake venom with diverse pathologic toxicities and, therefore, a potential target for antivenom therapy. Varespladib was initially designed as an inhibitor of mammal PLA2s, and was recently repurposed to a broad-spectrum inhibitor of PLA2 in snake venom. To evaluate the protective abilities of varespladib to hemorrhage, myonecrosis, and systemic toxicities that are inflicted by different crude snake venoms, subcutaneous ecchymosis, muscle damage, and biochemical variation in serum enzymes derived from the envenomed mice were determined, respectively. Varespladib treatment showed a significant inhibitory effect to snake venom PLA2, which was estimated by IC50 in vitro and ED50 in vivo. In animal models, the severely hemorrhagic toxicity of D. acutus and A. halys venom was almost fully inhibited after administration of varespladib. Moreover, signs of edema in gastrocnemius muscle were remarkably attenuated by administration of varespladib, with a reduced loss of myonecrosis and desmin. Serum levels of creatine kinase, lactate dehydrogenase isoenzyme 1, aspartate transaminase, and alanine transaminase were down-regulated after treatment with varespladib, which indicated the protection to viscera injury. In conclusion, varespladib may be a potential first-line drug candidate in snakebite envenomation first aid or clinical therapy.

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Section: Discussionmentioning

confidence: 99%

Exploration of the Inhibitory Potential of Varespladib for Snakebite Envenomation

Wang

Zhang

et al. 2018

Molecules

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“…alternatus and B . jararacussu show cytotoxic effect on muscle cells [ 43 , 44 ]. svMPs with cytotoxic effect include the ones isolated from B .…”

Section: Discussionmentioning

confidence: 99%

“…asper [ 45 , 46 ]. The effects observed in Bothrops and Bothropoides venoms are probably due to a synergic and/or additive effect between these and other fractions with cytotoxic effect [ 43 ]. An important aspect of B .…”

Section: Discussionmentioning

confidence: 99%

Involvement of Nitric Oxide on Bothropoides insularis Venom Biological Effects on Murine Macrophages In Vitro

et al. 2016

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Viperidae venom has several local and systemic effects, such as pain, edema, inflammation, kidney failure and coagulopathy. Additionally, bothropic venom and its isolated components directly interfere on cellular metabolism, causing alterations such as cell death and proliferation. Inflammatory cells are particularly involved in pathological envenomation mechanisms due to their capacity of releasing many mediators, such as nitric oxide (NO). NO has many effects on cell viability and it is associated to the development of inflammation and tissue damage caused by Bothrops and Bothropoides venom. Bothropoides insularis is a snake found only in Queimada Grande Island, which has markedly toxic venom. Thus, the aim of this work was to evaluate the biological effects of Bothropoides insularis venom (BiV) on RAW 264.7 cells and assess NO involvement. The venom was submitted to colorimetric assays to identify the presence of some enzymatic components. We observed that BiV induced H2O2 production and showed proteolytic and phospholipasic activities. RAW 264.7 murine macrophages were incubated with different concentrations of BiV and then cell viability was assessed by MTT reduction assay after 2, 6, 12 and 24 hours of incubation. A time- and concentration-dependent effect was observed, with a tendency to cell proliferation at lower BiV concentrations and cell death at higher concentrations. The cytotoxic effect was confirmed after lactate dehydrogenase (LDH) measurement in the supernatant from the experimental groups. Flow cytometry analyses revealed that necrosis is the main cell death pathway caused by BiV. Also, BiV induced NO release. The inhibition of both proliferative and cytotoxic effects with L-NAME were demonstrated, indicating that NO is important for these effects. Finally, BiV induced an increase in iNOS expression. Altogether, these results demonstrate that B. insularis venom have proliferative and cytotoxic effects on macrophages, with necrosis participation. We also suggest that BiV acts by inducing iNOS expression and causing NO release.

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“…The search for in vitro tests that would substitute in vivo assays, such as lethality and determination of hemorrhagic, myotoxic, dermonecrotic, and defibrinogenating activities, has been difficult due to the complex biochemical and toxicological nature of snake venoms, whereby toxicity is often determined by several toxins acting together in synergistic and additive fashions [102,103]. For neurotoxic venoms, the use of ex vivo neuromuscular preparations is useful for assessing neuromuscular blockade and its neutralization [79,104,105].…”

Section: Implementation Of the 3rs In Antivenom Testingmentioning

confidence: 99%

Preclinical Evaluation of the Efficacy of Antivenoms for Snakebite Envenoming: State-of-the-Art and Challenges Ahead

Gutiérrez

Solano

Plá

et al. 2017

Toxins

127

100

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Animal-derived antivenoms constitute the mainstay in the therapy of snakebite envenoming. The efficacy of antivenoms to neutralize toxicity of medically-relevant snake venoms has to be demonstrated through meticulous preclinical testing before their introduction into the clinical setting. The gold standard in the preclinical assessment and quality control of antivenoms is the neutralization of venom-induced lethality. In addition, depending on the pathophysiological profile of snake venoms, the neutralization of other toxic activities has to be evaluated, such as hemorrhagic, myotoxic, edema-forming, dermonecrotic, in vitro coagulant, and defibrinogenating effects. There is a need to develop laboratory assays to evaluate neutralization of other relevant venom activities. The concept of the 3Rs (Replacement, Reduction, and Refinement) in Toxinology is of utmost importance, and some advances have been performed in their implementation. A significant leap forward in the study of the immunological reactivity of antivenoms against venoms has been the development of “antivenomics”, which brings the analytical power of mass spectrometry to the evaluation of antivenoms. International partnerships are required to assess the preclinical efficacy of antivenoms against snake venoms in different regions of the world in order to have a detailed knowledge on the neutralizing profile of these immunotherapeutics.

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Synergism between baltergin metalloproteinase and Ba SPII RP4 PLA2 from Bothrops alternatus venom on skeletal muscle (C2C12) cells

Cited by 45 publications

References 28 publications

Exploration of the Inhibitory Potential of Varespladib for Snakebite Envenomation

Exploration of the Inhibitory Potential of Varespladib for Snakebite Envenomation

Involvement of Nitric Oxide on Bothropoides insularis Venom Biological Effects on Murine Macrophages In Vitro

Preclinical Evaluation of the Efficacy of Antivenoms for Snakebite Envenoming: State-of-the-Art and Challenges Ahead

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