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Toxins 2019, 11(1), 39; https://doi.org/10.3390/toxins11010039

Intradermal Application of Crotamine Induces Inflammatory and Immunological Changes In Vivo

1
School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, s/n, CEP 14040-903 Ribeirão Preto, SP, Brazil
2
Graduate Program in Biomedical Sciences Hermínio Ometto University Center, FHO-UNIARARAS, Av. Dr. Maximiliano Baruto, 500, CEP 13607-339 Araras, SP, Brazil
*
Author to whom correspondence should be addressed.
Received: 24 November 2018 / Revised: 9 January 2019 / Accepted: 9 January 2019 / Published: 14 January 2019
(This article belongs to the Special Issue Toxins and Immunology)
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Abstract

Crotamine is a single-chain polypeptide with cell-penetrating properties, which is considered a promising molecule for clinical use. Nevertheless, its biosafety data are still scarce. Herein, we assessed the in vivo proinflammatory properties of crotamine, including its local effect and systemic serum parameters. Sixty male Wistar rats were intradermically injected with 200, 400 and 800 µg crotamine and analyzed after 1, 3 and 7 days. Local effect of crotamine was assessed by determination of MPO and NAG activities, NO levels and angiogenesis. Systemic inflammatory response was assessed by determination of IL-10, TNF-α, CRP, NO, TBARS and SH groups. Crotamine induced macrophages and neutrophils chemotaxis as evidenced by the upregulation of both NAG (0.5–0.6 OD/mg) and MPO (0.1–0.2 OD/mg) activities, on the first and third day of analysis, respectively. High levels of NO were observed for all concentrations and time-points. Moreover, 800 μg crotamine resulted in serum NO (64.7 μM) and local tissue NO (58.5 μM) levels higher or equivalent to those recorded for their respective histamine controls (55.7 μM and 59.0 μM). Crotamine also induced a significant angiogenic response compared to histamine. Systemically, crotamine induced a progressive increase in serum CRP levels up to the third day of analysis (22.4–45.8 mg/mL), which was significantly greater than control values. Crotamine (400 μg) also caused an increase in serum TNF-α, in the first day of analysis (1095.4 pg/mL), however a significant increase in IL-10 (122.2 pg/mL) was also recorded for the same time-point, suggesting the induction of an anti-inflammatory effect. Finally, crotamine changed the systemic redox state by inducing gradual increase in serum levels of TBARS (1.0–1.8 μM/mL) and decrease in SH levels (124.7–19.5 μM/mL) throughout the experimental period of analysis. In summary, rats intradermally injected with crotamine presented local and systemic acute inflammatory responses similarly to histamine, which limits crotamine therapeutic use on its original form. View Full-Text
Keywords: Crotalus durissus terrificus; crotamine; cell-penetrating peptide; inflammation Crotalus durissus terrificus; crotamine; cell-penetrating peptide; inflammation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Silvestrini, A.V.P.; de Macedo, L.H.; de Andrade, T.A.M.; Mendes, M.F.; Pigoso, A.A.; Mazzi, M.V. Intradermal Application of Crotamine Induces Inflammatory and Immunological Changes In Vivo. Toxins 2019, 11, 39.

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