Scorpion envenomation and inflammation: Beyond neurotoxic effects

Reis, Mouzarllem Barros; Zoccal, Karina Furlani; Gardinassi, Luiz Gustavo; Faccioli, Lúcia Helena

doi:10.1016/j.toxicon.2019.06.219

Cited by 37 publications

(42 citation statements)

References 56 publications

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“…In addition, our study demonstrated that both R. crassicauda venom and Rc1 can also activate the NF-kB signaling pathway. This result was consistent with previously reported results for T. serrulatus venom and toxins (5, 53-57), thus we supposed that activation of the NF-kB signaling pathway could be one important mechanism of enhancing the immune responses from several scorpion envenomings (53).…”

Section: Discussionsupporting

confidence: 94%

Pioneering Study on Rhopalurus crassicauda Scorpion Venom: Isolation and Characterization of the Major Toxin and Hyaluronidase

et al. 2020

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Scorpionism is responsible for most accidents involving venomous animals in Brazil, which leads to severe symptoms that can evolve to death. Scorpion venoms consist of complexes cocktails, including peptides, proteins, and non-protein compounds, making separation and purification procedures extremely difficult and time-consuming. Scorpion toxins target different biological systems and can be used in basic science, for clinical, and biotechnological applications. This study is the first to explore the venom content of the unexplored scorpion species Rhopalurus crassicauda, which inhabits exclusively the northernmost state of Brazil, named Roraima, and southern region of Guyana. Here, we pioneer the fractionation of the R. crassicauda venom and isolated and characterized a novel scorpion beta-neurotoxin, designated Rc1, and a monomeric hyaluronidase. R. crassicauda venom and Rc1 (6,882 Da) demonstrated pro-inflammatory activities in vitro and a nociceptive response in vivo. Moreover, Rc1 toxin showed specificity for activating Na v 1.4, Na v 1.6, and BgNa v 1 voltage-gated ion channels. This study also represents a new perspective for the treatment of envenomings in Roraima, since the Brazilian scorpion and arachnid antivenoms were not able to recognize R. crassicauda venom and its fractions (with exception of hyaluronidase). Our work provides useful insights for the first understanding of the painful sting and pro-inflammatory effects associated with R. crassicauda envenomings.

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Section: Discussionsupporting

confidence: 94%

Pioneering Study on Rhopalurus crassicauda Scorpion Venom: Isolation and Characterization of the Major Toxin and Hyaluronidase

et al. 2020

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“…In addition, the observation that Tf2[S14R], which lost excitatory activity in DRG neurons, still caused swelling in vivo suggests that Tf2-induced inflammation is mediated by an additional non-neuronal target. Scorpion venomor toxin-induced inflammatory responses have been described previously and have been linked to the activation of innate immune cells via interaction with pattern recognition receptors [37]. The use of global and sensory neuron-specific Na V 1.3 knockout mice would be required to tease out what contribution, if any, Na V 1.3 has to Tf2-induced pain and inflammation.…”

Section: Discussionmentioning

confidence: 97%

Characterization of Synthetic Tf2 as a NaV1.3 Selective Pharmacological Probe

et al. 2020

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NaV1.3 is a subtype of the voltage-gated sodium channel family. It has been implicated in the pathogenesis of neuropathic pain, although the contribution of this channel to neuronal excitability is not well understood. Tf2, a β-scorpion toxin previously identified from the venom of Tityus fasciolatus, has been reported to selectively activate NaV1.3. Here, we describe the activity of synthetic Tf2 and assess its suitability as a pharmacological probe for NaV1.3. As described for the native toxin, synthetic Tf2 (1 µM) caused early channel opening, decreased the peak current, and shifted the voltage dependence of NaV1.3 activation in the hyperpolarizing direction by −11.3 mV, with no activity at NaV1.1, NaV1.2, and NaV1.4-NaV1.8. Additional activity was found at NaV1.9, tested using the hNav1.9_C4 chimera, where Tf2 (1 µM) shifted the voltage dependence of activation by −6.3 mV. In an attempt to convert Tf2 into an NaV1.3 inhibitor, we synthetized the analogue Tf2[S14R], a mutation previously described to remove the excitatory activity of related β-scorpion toxins. Indeed, Tf2[S14R](10 µM) had reduced excitatory activity at NaV1.3, although it still caused a small −5.8 mV shift in the voltage dependence of activation. Intraplantar injection of Tf2 (1 µM) in mice caused spontaneous flinching and swelling, which was not reduced by the NaV1.1/1.3 inhibitor ICA-121431 nor in NaV1.9-/- mice, suggesting off-target activity. In addition, despite a loss of excitatory activity, intraplantar injection of Tf2[S14R](10 µM) still caused swelling, providing strong evidence that Tf2 has additional off-target activity at one or more non-neuronal targets. Therefore, due to activity at NaV1.9 and other yet to be identified target(s), the use of Tf2 as a selective pharmacological probe may be limited.

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“…The inflammatory response has an important role in promoting the clinical manifestations observed during envenomation [12]. TsV toxins are recognized by PRRs and are able to induce a massive increase in cytokines and lipid mediators systemically in pulmonary and peritoneal macrophages [9].…”

Section: Discussionmentioning

confidence: 99%

“…The antagonism or absence of the IL-1R receptor improved survival and clinical symptoms in poisoning in a murine model [11]. As TsV induces an exacerbated inflammatory response in different organs, and inflammation is an important facet during scorpionism, it was hypothesized that the immune response also played a role in pancreatic dysfunction, since this organ is exposed to high concentrations of venom in the first 24 h after the accident [12].…”

Section: Discussionmentioning

confidence: 99%

“…These interactions activate transcriptional factors such as activator protein 1 (AP-1), nucelar factor kappa-light-chain-enhancer of activated B cells (NF-κB), and peroxisome proliferator-activated receptor gamma (PPAR-γ), which induce the formation of lipid bodies, as well as the production of eicosanoids and cytokines. These inflammatory cascades are directly correlated to the severity of envenomation and caused death in experimental mouse models of envenomation [11,12]. Diabetes is caused by a range of immunological mechanisms [13].…”

Section: Introductionmentioning

confidence: 99%

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Interleukin-1 Receptor-Induced Nitric Oxide Production in the Pancreas Controls Hyperglycemia Caused by Scorpion Envenomation

Reis

Elias-Oliveira

Pastore

et al. 2020

Toxins

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Tityus serrulatus causes numerous scorpion envenomation accidents and deaths worldwide. The symptoms vary from local to systemic manifestations, culminating in pulmonary edema and cardiogenic shock. Among these events, transitory hyperglycemia is a severe manifestation that influences pulmonary edema, hemodynamic alterations, and cardiac disturbances. However, the molecular mechanism that leads to increased glucose levels after T. serrulatus envenomation remains unknown. This study aimed to investigate our hypothesis that hyperglycemia due to scorpion envenomation involves inflammatory signaling in the pancreas. The present study showed that T. serrulatus venom induces the production of IL-1α and IL-1β in the pancreas, which signal via IL-1R and provoke nitric oxide (NO) production as well as edema in β-cells in islets. Il1r1−/− mice were protected from transitory hyperglycemia and did not present disturbances in insulin levels in the serum. These results suggest that the pathway driven by IL-1α/IL-1β-IL-1R-NO inhibits insulin release by β-cells, which increases systemic glucose concentration during severe scorpion envenomation. A supportive therapy that inhibits NO production, combined with antiserum, may help to prevent fatal outcomes of scorpion envenomation. Our findings provide novel insights into the design of supportive therapy with NO inhibitors combined with antiscorpion venom serum to overcome fatal outcomes of scorpion envenomation.

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Scorpion envenomation and inflammation: Beyond neurotoxic effects

Cited by 37 publications

References 56 publications

Pioneering Study on Rhopalurus crassicauda Scorpion Venom: Isolation and Characterization of the Major Toxin and Hyaluronidase

Pioneering Study on Rhopalurus crassicauda Scorpion Venom: Isolation and Characterization of the Major Toxin and Hyaluronidase

Characterization of Synthetic Tf2 as a NaV1.3 Selective Pharmacological Probe

Interleukin-1 Receptor-Induced Nitric Oxide Production in the Pancreas Controls Hyperglycemia Caused by Scorpion Envenomation

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