Research Article: Trisulfate Disaccharide Decreases Calcium Overload and Protects Liver Injury Secondary to Liver Ischemia/Reperfusion

Date Published: February 22, 2016

Publisher: Public Library of Science

Author(s): Enio Rodrigues Vasques, Jose Eduardo Monteiro Cunha, Ana Maria Mendonca Coelho, Sandra N. Sampietre, Rosely Antunes Patzina, Emilio Elias Abdo, Helena B. Nader, Ivarne L. S. Tersariol, Marcelo Andrade Lima, Carlos M. G. Godoy, Tiago Rodrigues, Eleazar Chaib, Luiz A. C. D’Albuquerque, Jordi Gracia-Sancho.


Ischemia and reperfusion (I/R) causes tissue damage and intracellular calcium levels are a factor of cell death. Sodium calcium exchanger (NCX) regulates calcium extrusion and Trisulfated Disaccharide (TD) acts on NCX decreasing intracellular calcium through the inhibition of the exchange inhibitory peptide (XIP).

The aims of this research are to evaluate TD effects in liver injury secondary to I/R in animals and in vitro action on cytosolic calcium of hepatocytes cultures under calcium overload.

Wistar rats submitted to partial liver ischemia were divided in groups: Control: (n = 10): surgical manipulation with no liver ischemia; Saline: (n = 15): rats receiving IV saline before reperfusion; and TD: (n = 15): rats receiving IV TD before reperfusion. Four hours after reperfusion, serum levels of AST, ALT, TNF-α, IL-6, and IL-10 were measured. Liver tissue samples were collected for mitochondrial function and malondialdehyde (MDA) content. Pulmonary vascular permeability and histologic parameters of liver were determined. TD effect on cytosolic calcium was evaluated in BRL3A hepatic rat cell cultures stimulated by thapsigargin pre and after treatment with TD.

AST, ALT, cytokines, liver MDA, mitochondrial dysfunction and hepatic histologic injury scores were less in TD group when compared to Saline Group (p<0.05) with no differences in pulmonary vascular permeability. In culture cells, TD diminished the intracellular calcium raise and prevented the calcium increase pre and after treatment with thapsigargin, respectively. TD decreases liver cell damage, preserves mitochondrial function and increases hepatic tolerance to I/R injury by calcium extrusion in Ca2+ overload situations.

Partial Text

Ischemia-reperfusion (I/R) injury remains a major problem in various clinical situations, including trauma, shock, hemorrhage, liver resection, and transplantation [1, 2]. Current therapeutic procedures, such as ischemic pre or post conditioning and intermittent vascular occlusion, can minimize but not prevent hepatic I/R injury [3–6]. Up to the present time, although many compounds have been tested, only a few drugs have been shown to ameliorate or diminish liver I/R injury [7–8].

Multiple clinical situations expose the liver to I/R injury. The pathogenesis of I/R damage is multifactorial [30–32]. Altered cellular calcium handling is known to be of vital importance in the I/R injury. Many investigators agree that modulation of cellular calcium homeostasis represents a key strategy for preventing I/R injury [33].