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

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...

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Bibliographic Details
Published in:	PloS one Vol. 8; no. 7; p. e70020
Main Authors:	Pinto, Alipio, Jacobsen, Mariana, Geoghegan, Patricia A, Cangelosi, Adriana, Cejudo, María Laura, Tironi-Farinati, Carla, Goldstein, Jorge
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 23-07-2013 Public Library of Science (PLoS)
Subjects:	Abnormalities Analysis Animal models Animals Anti-Inflammatory Agents - pharmacology Antibiotics Astrocytes - drug effects Astrocytes - pathology Blood-brain barrier Central nervous system depressants Colitis Cortex (motor) Cytotoxicity Degeneration Dexamethasone Dexamethasone - pharmacology Disease Models, Animal Drug Synergism E coli Encephalopathy Escherichia coli Female Gene expression Hemolytic uremic syndrome Hemorrhage Inflammation Kinases Lethal dose Lipopolysaccharides Lipopolysaccharides - toxicity Mice Microvasculature Microvessels - drug effects Mitogens Mortality Motor Cortex - blood supply Motor Cortex - drug effects Motor Cortex - pathology Movement disorders Nervous system diseases Neurodegeneration Neurons Neurons - drug effects Neurons - pathology Neurophysiology Neurotoxicity Syndromes - drug therapy Neurotoxicity Syndromes - etiology Parenchyma Proteins Shiga toxin Shiga toxin 2 Shiga Toxin 2 - isolation & purification Shiga Toxin 2 - toxicity Shiga-Toxigenic Escherichia coli - chemistry Specific Pathogen-Free Organisms Steroids Steroids (Organic compounds) Toxins Argentina
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Summary:	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.
Bibliography:	Competing Interests: The authors have declared that no competing interests exist. Conceived and designed the experiments: AP CTF JG PG AC. Performed the experiments: AP MJ PG AC MC CTF JG. Analyzed the data: AP JG PG AC. Contributed reagents/materials/analysis tools: JG AP PG AC. Wrote the manuscript: AP JG.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0070020