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Toxins
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Snake Venom: Toxicology and Associated Countermeasures
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Snake Venom: Toxicology and Associated Countermeasures

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Animal Venoms".

Deadline for manuscript submissions: closed (30 September 2024) | Viewed by 15184

Special Issue Editor

Dr. Nicholas Youngman

E-Mail Website
Guest Editor
Reptile Department, Billabong Sanctuary, Nome, QLD 4816, Australia
Interests: animal–human conflict; anticoagulants; antivenom; coagulopathy; australian elapids; prothrombinase complex; venom phospholipase A2

Special Issue Information

Dear Colleagues,

I am pleased to invite you to contribute to this Special Issue of Toxins which will focus on all aspects of the toxicology of snakebite envenoming with respect to accompanying countermeasures. Snakebite remains one of the world’s most neglected tropical diseases, with antivenom being administered as the only current specific treatment option utilized for the neutralization of toxin activity. Antivenom continues to be limited in its effectiveness, however, with multiple limiting factors affecting its availability and implementation in reducing the morbidity and mortality associated with snakebite envenoming. Animal–human conflict is projected to continually increase as human populations and densities continue to increase. Conflict with snakes is most certainly no exception, reinforcing the dire need for additional research and effective countermeasures.           

This Special Issue aims to give further insight into cases and research that details the toxicological effects of snakebite envenoming around the world and evaluated the continued efficacy of current countermeasures alongside novel treatments. Additionally, papers on the functional activities of toxins and clinical syndromes from medically relevant species or previously under or entirely uninvestigated species are welcome.

Original studies or reviews detailing snakebite envenoming cases, including toxicological effects, treatment, and outcomes, are welcome, as well as original research articles and reviews which investigate all aspects of snake venom toxicological activities and potential countermeasures to neutralize toxin activity. Research which focuses on novel treatment options such as small molecule therapeutics is also of particular interest.

Dr. Nicholas Youngman
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a double-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • antivenom
  • animal–human conflict
  • envenomation
  • pathophysiology
  • small-molecule therapeutics
  • snakebite

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Published Papers (7 papers)

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Research

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17 pages, 1223 KiB  
Article
Physical and Sensory Long-Term Disabilities from Bothrops Snakebite Envenomings in Manaus, Western Brazilian Amazon
by Eduardo M. G. Fernández, Débora N. Oliveira, Alexandre V. Silva-Neto, Rafaela N. Dávila, Ligia Lengler, Marco A. Sartim, Altair S. Farias, Luiz C. L. Ferreira, Érica da Silva Carvalho, Fan H. Wen, Felipe Murta, Fernando Almeida-Val, Manuela B. Pucca, Jacqueline A. G. Sachett and Wuelton M. Monteiro
Toxins 2025, 17(1), 22; https://doi.org/10.3390/toxins17010022 - 3 Jan 2025
Viewed by 1202
Abstract
Snakebites caused by Bothrops snakes are the most prevalent in the Amazon region, causing local and systemic complications. Local complications are mostly represented by necrosis, secondary bacterial infection and compartment syndrome. There are reports of long-term disabilities, but their burden is poorly investigated. [...] Read more.
Snakebites caused by Bothrops snakes are the most prevalent in the Amazon region, causing local and systemic complications. Local complications are mostly represented by necrosis, secondary bacterial infection and compartment syndrome. There are reports of long-term disabilities, but their burden is poorly investigated. This study aims to describe and estimate the frequency of physical and sensory long-term disabilities from Bothrops snakebites in the Manaus Region, in the western Brazilian Amazon region. Participants were >18-years individuals that accepted to return to the hospital 3–12 months (average follow-up time of 195 days) after the discharge for neuromusculoskeletal, chronic pain and sensory assessments. Assessment of disability was also performed using the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). Factors associated with summary disability using WHODAS 2.0 were identified. Fifty participants were enrolled. A frequency of 20% of the participants reported difficulty in moving the affected limb (20%), and 23.7% reported difficulty in walking. Limitations of daily activities were reported by 26% of the patients. Decreased strength of the affected limb was observed in 22% of the patients. Decreased range of joint motion was seen in 20% of the patients. Chronic pain was reported in 48% of the patients. Tactile sensibility was decreased in 30%, thermal sensibility in 14%, painful sensibility (hypoalgesia) in 12%, kinetic-postural sensibility (hypokinesthesia) in 4% and vibratory sensibility was decreased or abolished in 16% of the participants. Cognition and mobility domains were those with the highest frequencies of participants with any degree of disability, each with 57%. The summary WHODAS 2.0 disability rate was 59%. Age > 59 years (p = 0.02)] was associated with protection against disability. Difficulty in moving the limb (p = 0.05), pain at the affected limb (p < 0.01), limitations of daily activities (p < 0.01) and decreased thermal sensibility (p = 0.05) were significantly associated with disability. The present study consists of the first follow-up investigation involving Bothrops snakebite patients related to long-term disabilities. These findings represent important data on Bothrops snakebites causing clinically significant long-term neuromusculoskeletal and sensory disabilities, resulting in reduced quality of life of the patients. Full article
(This article belongs to the Special Issue Snake Venom: Toxicology and Associated Countermeasures)
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20 pages, 3697 KiB  
Article
Isolation and Pharmacological Characterisation of Pre-Synaptic Neurotoxins from Thai and Javanese Russell’s Viper (Daboia siamensis) Venoms
by Mimi Lay and Wayne C. Hodgson
Toxins 2024, 16(9), 405; https://doi.org/10.3390/toxins16090405 - 19 Sep 2024
Cited by 1 | Viewed by 1518
Abstract
The widespread geographical distribution of Russell’s vipers (Daboia spp.) is associated with marked variations in the clinical outcomes of envenoming by species from different countries. This is likely to be due to differences in the quantity and potency of key toxins and, [...] Read more.
The widespread geographical distribution of Russell’s vipers (Daboia spp.) is associated with marked variations in the clinical outcomes of envenoming by species from different countries. This is likely to be due to differences in the quantity and potency of key toxins and, potentially, the presence or absence of some toxins in venoms across the geographical spectrum. In this study, we aimed to isolate and pharmacologically characterise the major neurotoxic components of D. siamensis venoms from Thailand and Java (Indonesia) and explore the efficacy of antivenom and a PLA2 inhibitor, Varespladib, against the neuromuscular activity. These data will provide insights into the link between venom components and likely clinical outcomes, as well as potential treatment strategies. Venoms were fractionated using RP-HPLC and the in vitro activity of isolated toxins assessed using the chick biventer cervicis nerve-muscle preparation. Two major PLA2 fractions (i.e., fractions 8 and 10) were isolated from each venom. Fraction 8 from both venoms produced pre-synaptic neurotoxicity and myotoxicity, whereas fraction 10 from both venoms was weakly neurotoxic. The removal of the two fractions from each venom abolished the in vitro neurotoxicity, and partially abolished myotoxicity, of the whole venom. A combination of the two fractions from each venom produced neurotoxic activity that was equivalent to the respective whole venom (10 µg/mL), but the myotoxic effects were not additive. The in vitro neurotoxicity of fraction 8 (100 nM) from each venom was prevented by the pre-administration of Thai Russell’s viper monovalent antivenom (2× recommended concentration) or preincubation with Varespladib (100 nM). Additionally, the neurotoxicity produced by a combination of the two fractions was partially reversed by the addition of Varespladib (100–300 nM) 60 min after the fractions. The present study demonstrates that the in vitro skeletal muscle effects of Thai and Javanese D. siamensis venoms are primarily due to key PLA2 toxins in each venom. Full article
(This article belongs to the Special Issue Snake Venom: Toxicology and Associated Countermeasures)
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15 pages, 1683 KiB  
Article
Tiny but Mighty: Vipera ammodytes meridionalis (Eastern Long-Nosed Viper) Ontogenetic Venom Variations in Procoagulant Potency and the Impact on Antivenom Efficacies
by Zichen Qiao, Lee Jones, Lachlan A. Bourke, Lorenzo Seneci, Abhinandan Chowdhury, Aude Violette, Rudy Fourmy, Raul Soria, Matt Aldridge and Bryan G. Fry
Toxins 2024, 16(9), 396; https://doi.org/10.3390/toxins16090396 - 14 Sep 2024
Cited by 3 | Viewed by 2095
Abstract
The Eastern Long-Nosed Viper (Vipera ammodytes meridionalis) is considered one of the most venomous snakes in Europe. However, it is unknown whether ontogenetic variation in venom effects occurs in this subspecies and how this may impact antivenom efficacy. In this study, [...] Read more.
The Eastern Long-Nosed Viper (Vipera ammodytes meridionalis) is considered one of the most venomous snakes in Europe. However, it is unknown whether ontogenetic variation in venom effects occurs in this subspecies and how this may impact antivenom efficacy. In this study, we compared the procoagulant activities of V. a. meridionalis venom on human plasma between neonate and adult venom phenotypes. We also examined the efficacy of three antivenoms—Viperfav, ViperaTAb, and Inoserp Europe—across our neonate and adult venom samples. While both neonate and adult V. a. meridionalis venoms produced procoagulant effects, the effects produced by neonate venom were more potent. Consistent with this, neonate venom was a stronger activator of blood-clotting zymogens, converting them into their active forms, with a rank order of Factor X >> Factor VII > Factor XII. Conversely, the less potent adult venom had a rank order of FXII marginally more activated than Factor VII, and both much more so than Factor X. This adds to the growing body of evidence that activation of factors besides FII (prothrombin) and FX are significant variables in reptile venom-induced coagulopathy. Although all three examined antivenoms displayed effective neutralization of both neonate and adult V. a. meridionalis venoms, they generally showed higher efficacy on adult venom than on neonate venom. The ranking of antivenom efficacy against neonate venom, from the most effective to the least effective, were Viperfav, Inoserp Europe, ViperaTAb; for adult venom, the ranking was Inoserp Europe, Viperfav, ViperaTAb. Our data reveal ontogenetic variation in V. a meridionalis, but this difference may not be of clinical concern as antivenom was effective at neutralizing both adult and neonate venom phenotypes. Regardless, our results highlight a previously undocumented ontogenetic shift, likely driven by the documented difference in prey preference observed for this species across age classes Full article
(This article belongs to the Special Issue Snake Venom: Toxicology and Associated Countermeasures)
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12 pages, 976 KiB  
Article
Effect of Seaweed-Derived Fucoidans from Undaria pinnatifida and Fucus vesiculosus on Coagulant, Proteolytic, and Phospholipase A2 Activities of Snake Bothrops jararaca, B. jararacussu, and B. neuwiedi Venom
by Camila Castro-Pinheiro, Luiz Carlos Simas Pereira Junior, Eladio Flores Sanchez, Ana Cláudia Rodrigues da Silva, Corinna A. Dwan, Samuel S. Karpiniec, Alan Trevor Critchley and Andre Lopes Fuly
Toxins 2024, 16(4), 188; https://doi.org/10.3390/toxins16040188 - 12 Apr 2024
Cited by 2 | Viewed by 1766
Abstract
Background: Snakebite envenomation (SBE) causes diverse toxic effects in humans, including disability and death. Current antivenom therapies effectively prevent death but fail to block local tissue damage, leading to an increase in the severity of envenomation; thus, seeking alternative treatments is crucial. Methods: [...] Read more.
Background: Snakebite envenomation (SBE) causes diverse toxic effects in humans, including disability and death. Current antivenom therapies effectively prevent death but fail to block local tissue damage, leading to an increase in the severity of envenomation; thus, seeking alternative treatments is crucial. Methods: This study analyzed the potential of two fucoidan sulfated polysaccharides extracted from brown seaweeds Fucus vesiculosus (FVF) and Undaria pinnatifida (UPF) against the fibrinogen or plasma coagulation, proteolytic, and phospholipase A2 (PLA2) activities of Bothrops jararaca, B. jararacussu, and B. neuwiedi venom. The toxicity of FVF and UPF was assessed by the hemocompatibility test. Results: FVF and UPF did not lyse human red blood cells. FVF and UPF inhibited the proteolytic activity of Bothrops jararaca, B. jararacussu, and B. neuwiedi venom by approximately 25%, 50%, and 75%, respectively, while all venoms led to a 20% inhibition of PLA2 activity. UPF and FVF delayed plasma coagulation caused by the venoms of B. jararaca and B. neuwiedi but did not affect the activity of B. jararacussu venom. FVF and UPF blocked the coagulation of fibrinogen induced by all these Bothropic venoms. Conclusion: FVF and UPF may be of importance as adjuvants for SBE caused by species of Bothrops, which are the most medically relevant snakebite incidents in South America, especially Brazil. Full article
(This article belongs to the Special Issue Snake Venom: Toxicology and Associated Countermeasures)
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12 pages, 2418 KiB  
Article
One-Step Affinity Purification of Leucine-Rich α2-Glycoproteins from Snake Sera and Characterization of Their Phospholipase A2-Inhibitory Activities as β-Type Phospholipase A2 Inhibitors
by Ryoichi Shirai, Kana Shibata, Shinobu Fujii, Rikiro Fukunaga and Seiji Inoue
Toxins 2024, 16(3), 126; https://doi.org/10.3390/toxins16030126 - 1 Mar 2024
Viewed by 1873
Abstract
Snakes contain three types of phospholipase A2 (PLA2)-inhibitory proteins in their blood, PLIα, β, and γ, which protect them from their own venom, PLA2. PLIβ is the snake ortholog of leucine-rich α2 glycoprotein (LRG). Since autologous cytochrome [...] Read more.
Snakes contain three types of phospholipase A2 (PLA2)-inhibitory proteins in their blood, PLIα, β, and γ, which protect them from their own venom, PLA2. PLIβ is the snake ortholog of leucine-rich α2 glycoprotein (LRG). Since autologous cytochrome c (Cyt c) serves as an endogenous ligand for LRG, in this study, we purified snake LRGs from various snake serum samples using Cyt c affinity chromatography. All purified snake LRGs were found to be dimers linked by disulfide bonds. Laticauda semifasciata and Naja kaouthia LRGs showed no inhibitory activity against L. semifasciata PLA2 and weak inhibitory activity against Gloydius brevicauda basic PLA2. Elaphe climacophora PLIβ had weaker inhibitory activity against G. brevicauda basic PLA2 than G. brevicauda and Elaphe quadrivirgata PLIs, which are abundant in blood and known to neutralize G. brevicauda basic PLA2. Protobothrops flavoviridis LRG showed no inhibitory activity against basic venom PLA2, PL-X, or G. brevicauda basic PLA2. Binding analysis of P. flavoviridis LRG using surface plasmon resonance showed very strong binding to snake Cyt c, followed by that to horse Cyt c, weak binding to yeast Cyt c, and no binding to P. flavoviridis PL-X or BPI/II. We also deduced the amino acid sequences of L. semifasciata and P. flavoviridis LRG by means of cDNA sequencing and compared them with those of other known sequences of PLIs and LRGs. This study concluded that snake LRG can potentially inhibit basic PLA2, but, whether it actually functions as a PLA2-inhibitory protein, PLIβ, depends on the snake. Full article
(This article belongs to the Special Issue Snake Venom: Toxicology and Associated Countermeasures)
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13 pages, 1864 KiB  
Article
Immunological Cross-Reactivity and Preclinical Assessment of a Colombian Anticoral Antivenom against the Venoms of Three Micrurus Species
by Ariadna Rodríguez-Vargas, Adrián Marcelo Franco-Vásquez, Miguel Triana-Cerón, Shaha Noor Alam-Rojas, Derly C. Escobar-Wilches, Gerardo Corzo, Fernando Lazcano-Pérez, Roberto Arreguín-Espinosa and Francisco Ruiz-Gómez
Toxins 2024, 16(2), 104; https://doi.org/10.3390/toxins16020104 - 15 Feb 2024
Cited by 1 | Viewed by 2926
Abstract
Snakebite accident treatment requires the administration of antivenoms that provide efficacy and effectiveness against several snake venoms of the same genus or family. The low number of immunogenic components in venom mixtures that allow the production of antivenoms consequently gives them partial neutralization [...] Read more.
Snakebite accident treatment requires the administration of antivenoms that provide efficacy and effectiveness against several snake venoms of the same genus or family. The low number of immunogenic components in venom mixtures that allow the production of antivenoms consequently gives them partial neutralization and a suboptimal pharmacological response. This study evaluates the immunorecognition and neutralizing efficacy of the polyvalent anticoral antivenom from the Instituto Nacional de Salud (INS) of Colombia against the heterologous endemic venoms of Micrurus medemi, and M. sangilensis, and M. helleri by assessing immunoreactivity through affinity chromatography, ELISA, Western blot, and neutralization capability. Immunorecognition towards the venoms of M. medemi and M. sangilensis showed values of 62% and 68% of the protein composition according to the immunoaffinity matrix, respectively. The analysis by Western blot depicted the highest recognition patterns for M. medemi, followed by M. sangilensis, and finally by M. helleri. These findings suggest that the venom compositions are closely related and exhibit similar recognition by the antivenom. According to enzyme immunoassays, M. helleri requires a higher amount of antivenom to achieve recognition than the others. Besides reinforcing the evaluation of INS antivenom capability, this work recommends the use of M. helleri in the production of Colombian antisera. Full article
(This article belongs to the Special Issue Snake Venom: Toxicology and Associated Countermeasures)
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Review

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30 pages, 2355 KiB  
Review
The Role of Snake Venom Proteins in Inducing Inflammation Post-Envenomation: An Overview on Mechanistic Insights and Treatment Strategies
by Sudharshan Rao, Nisha Reghu, Bipin Gopalakrishnan Nair and Muralidharan Vanuopadath
Toxins 2024, 16(12), 519; https://doi.org/10.3390/toxins16120519 - 2 Dec 2024
Viewed by 2765
Abstract
The intricate combination of organic and inorganic compounds found in snake venom includes proteins, peptides, lipids, carbohydrates, nucleotides, and metal ions. These components work together to immobilise and consume prey through processes such as paralysis and hypotension. Proteins, both enzymatic and non-enzymatic, form [...] Read more.
The intricate combination of organic and inorganic compounds found in snake venom includes proteins, peptides, lipids, carbohydrates, nucleotides, and metal ions. These components work together to immobilise and consume prey through processes such as paralysis and hypotension. Proteins, both enzymatic and non-enzymatic, form the primary components of the venom. Based on the effects they produce, venom can be classified as neurotoxic, hemotoxic, and cytotoxic. Studies have shown that, after envenomation, proteins in snake venom also contribute significantly to the induction of inflammatory responses which can either have systemic or localized consequences. This review delves into the mechanisms by which snake venom proteins trigger inflammatory responses, focusing on key families such as phospholipase A2, metalloproteinases, serine proteases, C-type lectins, cysteine-rich secretory proteins, and L-amino acid oxidase. In addition, the role of venom proteins in activating various inflammatory pathways, including the complement system, inflammasomes, and sterile inflammation are also summarized. The available therapeutic options are examined, with a focus on antivenom therapy and its side effects. In general, this review offers a comprehensive understanding of the inflammatory mechanisms that are triggered by snake venom proteins and the side effects of antivenom treatment. All these emphasize the need for effective strategies to mitigate these detrimental effects. Full article
(This article belongs to the Special Issue Snake Venom: Toxicology and Associated Countermeasures)
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