Allopurinol attenuates acute kidney injury following Bothrops jararaca envenomation

PLoS Negl Trop Dis. 2017 Nov 20;11(11):e0006024. doi: 10.1371/journal.pntd.0006024. eCollection 2017 Nov.

Abstract

Snakebites have been recognized as a neglected public health problem in several tropical and subtropical countries. Bothrops snakebites frequently complicate with acute kidney injury (AKI) with relevant morbidity and mortality. To date, the only treatment available for Bothrops envenomation is the intravenous administration of antivenom despite its several limitations. Therefore, the study of novel therapies in Bothrops envenomation is compelling. The aim of this study was to evaluate the protective effect of Allopurinol (Allo) in an experimental model of Bothrops jararaca venom (BJ)-associated AKI. Five groups of Wistar rats were studied: Sham, Allo, BJ, BJ+Allo, BJ+ipAllo. BJ (0.25 mg/kg) was intravenously injected during 40'. Saline at same dose and infusion rate was administered to Sham and Allo groups. Allo and BJ+Allo groups received Allo (300 mg/L) in the drinking water 7 days prior to Saline or BJ infusion respectively. BJ+ipAllo rats received intraperitoneal Allo (25 mg/Kg) 40' after BJ infusion. BJ rats showed markedly reduced glomerular filtration rate (GFR, inulin clearance) associated with intense renal vasoconstriction, hemolysis, hemoglobinuria, reduced glutathione and increased systemic and renal markers of nitro-oxidative stress (Nitrotyrosine). Allo ameliorated GFR, renal blood flow (RBF), renal vascular resistance and arterial lactate levels. In addition, Allo was associated with increased serum glutathione as well as reduced levels of plasma and renal Nitrotyrosine. Our data show that Allo attenuated BJ-associated AKI, reduced oxidative stress, improved renal hemodynamics and organ perfusion. It might represent a novel adjuvant approach for Bothrops envenomation, a new use for an old and widely available drug.

MeSH terms

  • Acute Kidney Injury / chemically induced
  • Acute Kidney Injury / drug therapy*
  • Acute Kidney Injury / physiopathology
  • Allopurinol / pharmacology*
  • Allopurinol / therapeutic use
  • Animals
  • Antioxidants / pharmacology*
  • Antioxidants / therapeutic use
  • Bothrops*
  • Crotalid Venoms / toxicity*
  • Glomerular Filtration Rate / drug effects
  • Glutathione / blood
  • Hemolysis
  • Kidney / blood supply
  • Kidney / physiopathology
  • Lactic Acid / blood
  • Male
  • Oxidative Stress / drug effects
  • Rats, Wistar
  • Tyrosine / analogs & derivatives
  • Tyrosine / blood

Substances

  • Antioxidants
  • Crotalid Venoms
  • Lactic Acid
  • 3-nitrotyrosine
  • Tyrosine
  • Allopurinol
  • Glutathione

Grants and funding

This work was supported by National Council for Scientific and Technological Development (CNPq, Grant number 306148/2013-7, http://cnpq.br/) and São Paulo Research Foundation (FAPESP, grant number 2015/11933-3, http://www.fapesp.br/en/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.