Excess salt exacerbates blood-brain barrier disruption via a p38/MAPK/SGK1-dependent pathway in permanent cerebral ischemia

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Abstract

High salt diet (HSD) is one of the most important risk factors that contribute to many vascular diseases including ischemic stroke. One proposed mechanism underlying the disruption of blood-brain barrier (BBB) mediated by HSD is indirectly through enhancing blood pressure. The direct role of HSD on BBB integrity is unclear. Our purpose is to determine whether and how HSD might be involved in BBB breakdown during ischemia. To test that, we induced model of cerebral ischemia by permanent middle cerebral artery ligation (pMCAL) in either normal diet or HSD fed mice. We observed that HSD significantly enhanced ischemic brain damage which was associated with enhanced BBB disruption, increased leukocytes infiltration and loss of tight junction (TJ) proteins expression without apparently altering blood pressure. Our in vitro experiment also revealed that sodium chloride (NaCl) treatment down-regulated TJ protein expression by endothelial cells and substantially increased BBB permeability during starvation. Inhibition of p38/MAPK/SGK1 pathway eliminated the effect of NaCl on BBB permeability in vitro. In addition, we noticed a positive correlation between urinary sodium levels and ischemic lesion size in stroke patients. Together, our study demonstrates a hypertension-independent role of HSD during ischemia and provides rationale for post cerebral ischemic attack management.

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Neutrophil recruitment to the brain in mouse and human ischemic stroke.

Isabel Perez-de-Puig, Francesc Miró-Mur, Maura Ferrer-Ferrer … (2015)

Neutrophils are rapidly recruited in response to local tissue infection or inflammation. Stroke triggers a strong inflammatory reaction but the relevance of neutrophils in the ischemic brain is not fully understood, particularly in the absence of reperfusion. We investigated brain neutrophil recruitment in two murine models of permanent ischemia induced by either cauterization of the distal portion of the middle cerebral artery (c-MCAo) or intraluminal MCA occlusion (il-MCAo), and three fatal cases of human ischemic stroke. Flow cytometry analyses revealed progressive neutrophil recruitment after c-MCAo, lesser neutrophil recruitment following il-MCAo, and absence of neutrophils after sham operation. Confocal microscopy identified neutrophils in the leptomeninges from 6 h after the occlusion, in the cortical basal lamina and cortical Virchow-Robin spaces from 15 h, and also in the cortical brain parenchyma at 24 h. Neutrophils showed signs of activation including histone-3 citrullination, chromatin decondensation, and extracellular projection of DNA and histones suggestive of extracellular trap formation. Perivascular neutrophils were identified within the entire cortical infarction following c-MCAo. After il-MCAo, neutrophils prevailed in the margins but not the center of the cortical infarct, and were intraluminal and less abundant in the striatum. The lack of collaterals to the striatum and a collapsed pial anastomotic network due to brain edema in large hemispheric infarctions could impair neutrophil trafficking in this model. Neutrophil extravasation at the leptomeninges was also detected in the human tissue. We concluded that neutrophils extravasate from the leptomeningeal vessels and can eventually reach the brain in experimental animal models and humans with prolonged arterial occlusion.

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Tight junctions of the blood-brain barrier: development, composition and regulation.

Hartwig Wolburg, Andrea Lippoldt (2002)

1. The blood-brain barrier is essential for the maintenance and regulation of the neural microenvironment. The main characteristic features of blood-brain barrier endothelial cells are an extremely low rate of transcytotic vesicles and a restrictive paracellular diffusion barrier. 2. Endothelial blood-brain barrier tight junctions differ from epithelial tight junctions, not only by distinct morphological and molecular properties, but also by the fact that endothelial tight junctions are more sensitive to microenvironmental than epithelial factors. 3. Many ubiquitous molecular tight junction components have been identified and characterized including claudins, occludin, ZO-1, ZO-2, ZO-3, cingulin and 7H6. Signaling pathways involved in tight junction regulation include G-proteins, serine-, threonine- and tyrosine-kinases, extra and intracellular calcium levels, cAMP levels, proteases and cytokines. Common to most of these pathways is the modulation of cytoskeletal elements and the connection of tight junction transmembrane molecules to the cytoskeleton. Additionally, crosstalk between components of the tight junction- and the cadherin-catenin system of the adherens junction suggests a close functional interdependence of the two cell-cell contact systems. 4. Important new molecular aspects of tight junction regulation were recently elucidated. This review provides an integration of these new results.

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Sodium intake and hypertension.

Heikki Karppanen, Eero Mervaala (2015)

In current diets, the level of sodium is very high, whereas that of potassium, calcium, and magnesium is low compared with the level in diets composed of unprocessed, natural foods. We present the biologic rationale and scientific evidence that show that the current salt intake levels largely explain the high prevalence of hypertension. Comprehensive reduction of salt intake, both alone and particularly in combination with increases in intakes of potassium, calcium, and magnesium, is able to lower average blood pressure levels substantially. During the past 30 years, the one-third decrease in the average salt intake has been accompanied by a more than 10-mm Hg fall in the population average of both systolic and diastolic blood pressure, and a 75% to 80% decrease in both stroke and coronary heart disease mortality in Finland. There is no evidence of any harmful effects of salt reduction. Salt-reduction recommendations alone have a very small, if any, population impact. In the United States, for example, the per capita use of salt increased by approximately 55% from the mid-1980s to the late 1990s. We deal with factors that contribute toward increasing salt intakes and present examples of the methods that have contributed to the successful salt reduction in Finland.

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Author and article information

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group

ISSN (Electronic): 2045-2322

Publication date (Electronic): 09 November 2015

Publication date Collection: 2015

Volume: 5

Electronic Location Identifier: 16548

Affiliations

[1 ]Department of Neurobiology, Harbin Medical University , Harbin, China 150081

[2 ]The Key Laboratory of Myocardial Ischemia, The Second Affiliated Hospital of Harbin Medical University , Harbin, China 150081

[3 ]Department of Neurology, The First Affiliated Hospital of Harbin Medical University , Harbin, China 150081

[4 ]Department of Epidemiology and Biostatistics, Harbin Medical University , Harbin, China 150081

Author notes

[a ] wangddhmu@ 123456gmail.com

[b ] lihulun@ 123456aliyun.com

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Publisher Item ID: srep16548

DOI: 10.1038/srep16548

PMC ID: 4637879

PubMed ID: 26549644

SO-VID: 0ee654ce-2542-444d-85d0-55beb8df668e

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Excess salt exacerbates blood-brain barrier disruption via a p38/MAPK/SGK1-dependent pathway in permanent cerebral ischemia

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Most cited references 23

Neutrophil recruitment to the brain in mouse and human ischemic stroke.

Tight junctions of the blood-brain barrier: development, composition and regulation.

Sodium intake and hypertension.

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