Evaluation of anti-inflammatory potential of crotoxin, a phospholipase A2 isolated from Crotalus durissus terrificus venom, in a disseminated intravascular coagulation model induced by endotoxemia

• Grant number: 15/06290-6
• Support Opportunities: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): June 01, 2015
• Effective date (End): January 31, 2019
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Suely Vilela
• Grantee: Marco Aurélio Sartim
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 11/23236-4 - Native and recombinant animal toxins: functional, structural and molecular analysis, AP.TEM

Abstract

The disseminated intravascular coagulation (DIC) is a syndrome characterized by coagulation disturbs, occurring in a wide varied of inflammatory pathological conditions such as sepsis. The therapeutical strategies involve the treatment with anticoagulat agents as well as anti-inflammatory/immune suppressors drugs capable to inhibit the process that initiates the inflammation-induced coagulation activation. The venom from the sanke Crotalus durissus terrificus is known to exhibit an immunomodulator behavior, attributed to the main component within the venom: the crotoxin (CTX). Studies have shown that this neurotoxin, composed by an enzymatically active basic phospholipase A2 and an acidic enzymatically inactive subunit (crotapotin), is responsible to induce an anti-inflammatory/immune suppressor propriety in experimental models in vitro and in vivo. Considering these evidences, the aim of the present project is to evaluate the potential immunomodulator activity of CTX on DIC using the endotoxemia model. The present study also intent to evaluate the CTX mechanistic response by investigating the involvement of (I) lipid mediators and (II) the neuroimmune axis on the CTX anti-inflammatory behavior. The DIC will be induced by the administration of lipopolysaccharide (LPS) in mice. The CTX will be administrated in different time and doses, previously and after LPS administration, and the response will be assessed by the analysis of hemostatic, hematological and inflammatory parameters. In order to understand the mechanism of CTX, the involvement of neuroimmune axis will be evaluated by: (A) involvement of autonomic nervous system thru the participation of cholinergic and adrenergic pathways; and (B) by the stimulation of neuroendocrine axis hypothalamic-pituitary-adrenal (HPA) thru corticosterone participation. The involvement of lipid mediators will be evaluated by the stimulation of eicosanoids production by CTX and identify the mechanism of these mediators on the resolution of the DIC. Therefore, the present project intents to evaluate the capacity of CTX in resolve the process of inflammation-induced coagulation activation, where the results obtained will contribute in order to the better understand the immunomodulator mechanism of this neurotoxin, and a possible therapeutical application on inflammatory disturbs.

Scientific publications

(5)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SARTIM, MARCO A.; CEZARETTE, GABRIEL N.; JACOB-FERREIRA, ANNA L.; FRANTZ, FABIANI G.; FACCIOLI, LUCIA H.; SAMPAIO, SUELY V.. Disseminated intravascular coagulation caused by moojenactivase, a procoagulant snake venom metalloprotease. International Journal of Biological Macromolecules, v. 103, p. 1077-1086, OCT 2017. (15/06290-6, 11/23236-4)

SARTIM, MARCO AURELIO; SOUZA, CAMILA O. S.; DINIZ, CASSIANO RICARDO A. F.; DA FONSECA, VANESSA M. B.; SOUSA, LUCAS O.; PETI, ANA PAULA F.; COSTA, TASSIA RAFAELLA; LOURENCO, ALAN G.; BORGES, MARCOS C.; SORGI, CARLOS A.; et al. Crotoxin-Induced Mice Lung Impairment: Role of Nicotinic Acetylcholine Receptors and COX-Derived Prostanoids. BIOMOLECULES, v. 10, n. 5, MAY 2020. (15/06290-6, 11/23236-4)

BRUNA TERADA GIMENEZ; GABRIEL NEVES CEZARETTE; ALINE DE SOUSA BOMFIM; WUELTON MARCELO MONTEIRO; ELISA MARIA DE SOUSA RUSSO; FABIANI GAI FRANTZ; SUELY VILELA SAMPAIO; MARCO AURELIO SARTIM. Role of crotoxin in coagulation: novel insights into anticoagulant mechanisms and impairment of inflammation-induced coagulation. Journal of Venomous Animals and Toxins including Tropical Diseases, v. 26, 2020-11-27. (11/23236-4, 16/04079-9, 15/06290-6)

SARTIM, MARCO AURELIO; MENALDO, DANILO LUCCAS; SAMPAIO, SUELY VILELA. Immunotherapeutic potential of Crotoxin: anti-inflammatory and immunosuppressive properties. Journal of Venomous Animals and Toxins including Tropical Diseases, v. 24, DEC 17 2018. (15/06290-6, 11/23236-4)

CEZARETTE, G. N.; SARTIM, M. A.; SAMPAIO, S. V.. Inflammation and coagulation crosstalk induced by BJcuL, a galactose-binding lectin isolated from Bothrops jararacussu snake venom. International Journal of Biological Macromolecules, v. 144, p. 296-304, FEB 1 2020. (11/23236-4, 15/06290-6, 16/04079-9)