Dexamethasone rescues neurovascular unit integrity from cell damage caused by systemic administration of shiga toxin 2 and lipopolysaccharide in mice motor cortex.

Alipio Pinto,María Laura Cejudo,Carla Tironi-Farinati,Jorge Goldstein,Patricia A Geoghegan,Mariana Jacobsen,Adriana Cangelosi

doi:10.1371/journal.pone.0070020

Abstract

Shiga toxin 2 (Stx2)-producing Escherichia coli (STEC) causes hemorrhagic colitis and hemolytic uremic syndrome (HUS) that can lead to fatal encephalopathies. Neurological abnormalities may occur before or after the onset of systemic pathological symptoms and motor disorders are frequently observed in affected patients and in studies with animal models. As Stx2 succeeds in crossing the blood-brain barrier (BBB) and invading the brain parenchyma, it is highly probable that the observed neurological alterations are based on the possibility that the toxin may trigger the impairment of the neurovascular unit and/or cell damage in the parenchyma. Also, lipopolysaccharide (LPS) produced and secreted by enterohemorrhagic Escherichia coli (EHEC) may aggravate the deleterious effects of Stx2 in the brain. Therefore, this study aimed to determine (i) whether Stx2 affects the neurovascular unit and parenchymal cells, (ii) whether the contribution of LPS aggravates these effects, and (iii) whether an inflammatory event underlies the pathophysiological mechanisms that lead to the observed injury. The administration of a sub-lethal dose of Stx2 was employed to study in detail the motor cortex obtained from a translational murine model of encephalopathy. In the present paper we report that Stx2 damaged microvasculature, caused astrocyte reaction and neuronal degeneration, and that this was aggravated by LPS. Dexamethasone, an anti-inflammatory, reversed the pathologic effects and proved to be an important drug in the treatment of acute encephalopathies.

Highlights

Shiga toxin (Stx)-producing Escherichia coli (STEC) causes hemorrhagic colitis and Hemolytic Uremic Syndrome (HUS) [1], the triad of thrombocytopenia, microangiopathic hemolytic anemia and acute renal failure [2], and it is the main cause of acute renal failure and the second cause of chronic renal failure and renal transplantation in children in Argentina [3]
A maximal and significant decrease in density of microvessels (p
Various authors have reported that systemic infection with Stx2 or STEC causes brain damage in different animal models [39,40,41]

Summary

Introduction

Shiga toxin (Stx)-producing Escherichia coli (STEC) causes hemorrhagic colitis and Hemolytic Uremic Syndrome (HUS) [1], the triad of thrombocytopenia, microangiopathic hemolytic anemia and acute renal failure [2], and it is the main cause of acute renal failure and the second cause of chronic renal failure and renal transplantation in children in Argentina [3]. Central nervous system (CNS) alterations caused by STEC are a leading cause of mortality among children during the period of acute illness [4,5,6]. In North America and Europe, 0.72 to 1.44 cases of HUS per 100,000 population are reported each year [7]. May and July 2011 and began in northern Germany. The death toll in Germany was 53 [8,9]. Argentina has the highest occurrence of HUS worldwide, with approximately 420 cases reported annually and an incidence of 17/100,000 in children under 5 years of age [10]. It has been reported that the mortality rate derived from HUS ranges between 0–5% of the cases, and 7-40% when the CNS is involved [11,12,13]

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