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      Blood-brain barrier permeability and physical exercise

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          Abstract

          In this narrative review, a theoretical framework on the crosstalk between physical exercise and blood-brain barrier (BBB) permeability is presented. We discuss the influence of physical activity on the factors affecting BBB permeability such as systemic inflammation, the brain renin-angiotensin and noradrenergic systems, central autonomic function and the kynurenine pathway. The positive role of exercise in multiple sclerosis and Alzheimer’s disease is described. Finally, the potential role of conditioning as well as the effect of exercise on BBB tight junctions is outlined. There is a body of evidence that regular physical exercise diminishes BBB permeability as it reinforces antioxidative capacity, reduces oxidative stress and has anti-inflammatory effects. It improves endothelial function and might increase the density of brain capillaries. Thus, physical training can be emphasised as a component of prevention programs developed for patients to minimise the risk of the onset of neuroinflammatory diseases as well as an augmentation of existing treatment. Unfortunately, despite a sound theoretical background, it remains unclear as to whether exercise training is effective in modulating BBB permeability in several specific diseases. Further research is needed as the impact of exercise is yet to be fully elucidated.

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          Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study.

          A subclinical inflammatory reaction has been shown to precede the onset of type 2 (non-insulin-dependent) diabetes. We therefore examined prospectively the effects of the central inflammatory cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha) on the development of type 2 diabetes. We designed a nested case-control study within the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study including 27,548 individuals. Case subjects were defined to be those who were free of type 2 diabetes at baseline and subsequently developed type 2 diabetes during a 2.3-year follow-up period. A total of 192 cases of incident type 2 diabetes were identified and matched with 384 non-disease-developing control subjects. IL-6 and TNF-alpha levels were found to be elevated in participants with incident type 2 diabetes, whereas IL-1beta plasma levels did not differ between the groups. Analysis of single cytokines revealed IL-6 as an independent predictor of type 2 diabetes after adjustment for age, sex, BMI, waist-to-hip ratio (WHR), sports, smoking status, educational attainment, alcohol consumption, and HbA(1c) (4th vs. the 1st quartile: odds ratio [OR] 2.6, 95% CI 1.2-5.5). The association between TNF-alpha and future type 2 diabetes was no longer significant after adjustment for BMI or WHR. Interestingly, combined analysis of the cytokines revealed a significant interaction between IL-1beta and IL-6. In the fully adjusted model, participants with detectable levels of IL-1beta and elevated levels of IL-6 had an independently increased risk to develop type 2 diabetes (3.3, 1.7-6.8), whereas individuals with increased concentrations of IL-6 but undetectable levels of IL-1beta had no significantly increased risk, both compared with the low-level reference group. These results were confirmed in an analysis including only individuals with HbA(1c) <5.8% at baseline. Our data suggest that the pattern of circulating inflammatory cytokines modifies the risk for type 2 diabetes. In particular, a combined elevation of IL-1beta and IL-6, rather than the isolated elevation of IL-6 alone, independently increases the risk of type 2 diabetes. These data strongly support the hypothesis that a subclinical inflammatory reaction has a role in the pathogenesis of type 2 diabetes.
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            Claudin-1 and -2: Novel Integral Membrane Proteins Localizing at Tight Junctions with No Sequence Similarity to Occludin

            Occludin is the only known integral membrane protein localizing at tight junctions (TJ), but recent targeted disruption analysis of the occludin gene indicated the existence of as yet unidentified integral membrane proteins in TJ. We therefore re-examined the isolated junction fraction from chicken liver, from which occludin was first identified. Among numerous components of this fraction, only a broad silver-stained band ∼22 kD was detected with the occludin band through 4 M guanidine-HCl extraction as well as sonication followed by stepwise sucrose density gradient centrifugation. Two distinct peptide sequences were obtained from the lower and upper halves of the broad band, and similarity searches of databases allowed us to isolate two full-length cDNAs encoding related mouse 22-kD proteins consisting of 211 and 230 amino acids, respectively. Hydrophilicity analysis suggested that both bore four transmembrane domains, although they did not show any sequence similarity to occludin. Immunofluorescence and immunoelectron microscopy revealed that both proteins tagged with FLAG or GFP were targeted to and incorporated into the TJ strand itself. We designated them as “claudin-1” and “claudin-2”, respectively. Although the precise structure/function relationship of the claudins to TJ still remains elusive, these findings indicated that multiple integral membrane proteins with four putative transmembrane domains, occludin and claudins, constitute TJ strands.
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              Central nervous system pericytes in health and disease.

              Pericytes are uniquely positioned within the neurovascular unit to serve as vital integrators, coordinators and effectors of many neurovascular functions, including angiogenesis, blood-brain barrier (BBB) formation and maintenance, vascular stability and angioarchitecture, regulation of capillary blood flow and clearance of toxic cellular byproducts necessary for proper CNS homeostasis and neuronal function. New studies have revealed that pericyte deficiency in the CNS leads to BBB breakdown and brain hypoperfusion resulting in secondary neurodegenerative changes. Here we review recent progress in understanding the biology of CNS pericytes and their role in health and disease.
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                Author and article information

                Contributors
                marta.malkiewicz1@wp.pl
                arkadiusz.szarmach@gumed.edu.pl
                agnieszka.sabisz@gumed.edu.pl
                wieslaw.cubala@gumed.edu.pl
                edyta.szurowska@gumed.edu.pl
                +48 58 3491515 , pawelwinklewski@wp.pl
                Journal
                J Neuroinflammation
                J Neuroinflammation
                Journal of Neuroinflammation
                BioMed Central (London )
                1742-2094
                24 January 2019
                24 January 2019
                2019
                : 16
                : 15
                Affiliations
                [1 ]ISNI 0000 0001 0531 3426, GRID grid.11451.30, Department of Human Physiology, Faculty of Health Sciences, , Medical University of Gdansk, ; Tuwima Str. 15, 80-210 Gdansk, Poland
                [2 ]ISNI 0000 0001 0531 3426, GRID grid.11451.30, Department of Psychiatry, Faculty of Medicine, , Medical University of Gdansk, ; Gdansk, Poland
                [3 ]ISNI 0000 0001 0531 3426, GRID grid.11451.30, 2-nd Department of Radiology, Faculty of Health Sciences, , Medical University of Gdansk, ; Gdansk, Poland
                [4 ]GRID grid.440638.d, Department of Clinical Anatomy and Physiology, Faculty of Health Sciences, , Pomeranian University of Slupsk, ; Slupsk, Poland
                Author information
                http://orcid.org/0000-0002-1671-2163
                Article
                1403
                10.1186/s12974-019-1403-x
                6345022
                30678702
                c097d8ae-c4c0-4646-a44a-3f045d463193
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 4 October 2018
                : 9 January 2019
                Categories
                Review
                Custom metadata
                © The Author(s) 2019

                Neurosciences
                blood-brain barrier permeability,physical exercise,inflammation,brain renin-angiotensin system,central autonomic function,kynurenine pathway

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