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      Metformin attenuates blood-brain barrier disruption in mice following middle cerebral artery occlusion

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          Abstract

          Background

          Metformin, a widely used hypoglycemic drug, reduces stroke incidence and alleviates chronic inflammation in clinical trials. However, the effect of metformin in ischemic stroke is unclear. Here, we investigated the effect of metformin on ischemic stroke in mice and further explored the possible underlying mechanisms.

          Methods

          Ninety-eight adult male CD-1 mice underwent 90-minute transient middle cerebral artery occlusion (tMCAO). Metformin (200 mg/kg) was administrated for up to 14 days. Neurobehavioral outcomes, brain infarct volume, inflammatory factors, blood-brain barrier (BBB) permeability and AMPK signaling pathways were evaluated following tMCAO. Oxygen glucose deprivation was performed on bEND.3 cells to explore the mechanisms of metformin in inhibiting inflammatory signaling pathways.

          Results

          Infarct volume was reduced in metformin-treated mice compared to the control group following tMCAO ( P < 0.05). Neurobehavioral outcomes were greatly improved in metformin-treated mice ( P < 0.05). MPO + cells, Gr1 + cells, MPO activity and BBB permeability were decreased after metformin administration ( P < 0.05). In addition, metformin activated AMPK phosphorylation, inhibited NF-κB activation, down-regulated cytokine (IL-1β, IL-6, TNF-α) and ICAM-1 expression following tMCAO ( P < 0.05). Furthermore, metformin activated AMPK signaling pathway and alleviated oxygen-glucose deprivation-induced ICAM-1 expression in bEND.3 cells ( P < 0.05). Compound C, a selective AMPK inhibitor, eliminated this promotional effect.

          Conclusions

          Metformin down-regulated ICAM-1 in an AMPK-dependent manner, which could effectively prevent ischemia-induced brain injury by alleviating neutrophil infiltration, suggesting that metformin is a promising therapeutic agent in stroke therapy.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12974-014-0177-4) contains supplementary material, which is available to authorized users.

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          Most cited references26

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          AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network.

          Antero Salminen, Kai Kaarniranta (2012)
          Efficient control of energy metabolic homeostasis, enhanced stress resistance, and qualified cellular housekeeping are the hallmarks of improved healthspan and extended lifespan. AMPK signaling is involved in the regulation of all these characteristics via an integrated signaling network. Many studies with lower organisms have revealed that increased AMPK activity can extend the lifespan. Experiments in mammals have demonstrated that AMPK controls autophagy through mTOR and ULK1 signaling which augment the quality of cellular housekeeping. Moreover, AMPK-induced stimulation of FoxO/DAF-16, Nrf2/SKN-1, and SIRT1 signaling pathways improves cellular stress resistance. Furthermore, inhibition of NF-κB signaling by AMPK suppresses inflammatory responses. Emerging studies indicate that the responsiveness of AMPK signaling clearly declines with aging. The loss of sensitivity of AMPK activation to cellular stress impairs metabolic regulation, increases oxidative stress and reduces autophagic clearance. These age-related changes activate innate immunity defence, triggering a low-grade inflammation and metabolic disorders. We will review in detail the signaling pathways of this integrated network through which AMPK controls energy metabolism, autophagic degradation and stress resistance and ultimately the aging process. Copyright © 2011 Elsevier B.V. All rights reserved.
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            Resveratrol stimulates AMP kinase activity in neurons.

            Biplab Dasgupta, Jeffrey Milbrandt (2007)
            Resveratrol is a polyphenol produced by plants that has multiple beneficial activities similar to those associated with caloric restriction (CR), such as increased life span and delay in the onset of diseases associated with aging. CR improves neuronal health, and the global beneficial effects of CR have been postulated to be mediated by the nervous system. One key enzyme thought to be activated during CR is the AMP-activated kinase (AMPK), a sensor of cellular energy levels. AMPK is activated by increases in the cellular AMP:ATP ratio, whereupon it functions to help preserve cellular energy. In this regard, the regulation of dietary food intake by hypothalamic neurons is mediated by AMPK. The suppression of nonessential energy expenditure by activated AMPK along with the CR mimetic and neuroprotective properties of resveratrol led us to hypothesize that neuronal activation of AMPK could be an important component of resveratrol activity. Here, we show that resveratrol activated AMPK in Neuro2a cells and primary neurons in vitro as well as in the brain. Resveratrol and the AMPK-activating compound 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) promoted robust neurite outgrowth in Neuro2a cells, which was blocked by genetic and pharmacologic inhibition of AMPK. Resveratrol also stimulated mitochondrial biogenesis in an AMPK-dependent manner. Resveratrol-stimulated AMPK activity in neurons depended on LKB1 activity but did not require the NAD-dependent protein deacetylase SIRT1 during this time frame. These findings suggest that neuronal activation of AMPK by resveratrol could affect neuronal energy homeostasis and contribute to the neuroprotective effects of resveratrol.
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              Global and regional causes of death.

              Colin D Mathers, Ties Boerma, Doris Ma Fat (2009)
              Assessing the causes of death across all regions of the world requires a framework for integrating, and analysing, the fragmentary information that is available on numbers of deaths and their cause distributions. This paper provides an overview of the met and methods used by the World Health Organization to develop global-, regional- and country-level estimates of mortality for a comprehensive set of causes, and provides an overview of global and regional levels and patterns of causes of death for the year 2004. The paper also examines some of the data gaps, uncertainties and limitations in the resulting mortality estimates. Deaths for 136 disease and injury causes were estimated from available death registration data (111 countries), sample death registration data (India and China), and for the remaining countries from census and survey information, and cause-of-death models. Population-based epidemiological studies and notifications systems also contributed to estimating mortality for 21 of these causes (representing 28% of deaths globally, 58% in Africa). Ischaemic heart disease and cerebrovascular disease are the leading causes of death, followed by lower respiratory infections, chronic obstructive pulmonary disease and diarrhoeal diseases. AIDS and TB are the sixth and seventh most common causes of death, respectively, lower than in previous estimates. One-half of all child deaths are from four preventable and treatable communicable diseases. Globally, around 6 in 10 deaths are from non-communicable diseases, 3 from communicable diseases and 1 from injuries. Injury mortality is highest in South-East Asia, Latin America and the Eastern Mediterranean region. These results illustrate continuing huge disparities in risks and causes of death across the world. Global mortality analyses of the type reported here have been criticized for making estimates of mortality for regions with limited, incomplete and uncertain data. Estimates presented here use a range of techniques depending on the type and quality of evidence. Better evidence on levels of adult mortality is needed for African countries. Considerable gaps and deficiencies remain in the information available on causes of death. Nine of 10 deaths in 2004 occurred in low- and middle-income countries, reinforcing the fundamental importance of improving mortality statistics as a measure of health status in the developing world. Acknowledging the controversies around use of incomplete and uncertain data, systematic assessments and synthesis of the available evidence will continue to provide important inputs for global health planning. Innovative methods involving sample registration, and the use of verbal autopsy questionnaires in surveys, are needed to address these gaps. Research on strategies to improve comparability of cause-of-death certification and coding practices across countries is also a high priority.
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                Author and article information

                Contributors
                Yanqun Liu: liuyanqun588@sina.com
                Guanghui Tang: shtangguanghui@163.com
                Yaning Li: yaning.lee67@gmail.com
                Yang Wang: wangyangshennei@163.com
                Xiaoyan Chen: binsbao@gmail.com
                Xiang Gu: Hallelujahgu@gmail.com
                Zhijun Zhang: zhangzhij@gmail.com
                Yongting Wang: yongting.wang@gmail.com
                Guo-Yuan Yang: gyyang0626@gmail.com
                Journal
                Journal ID (nlm-ta): J Neuroinflammation
                Journal ID (iso-abbrev): J Neuroinflammation
                Title: Journal of Neuroinflammation
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1742-2094
                Publication date (Electronic): 15 October 2014
                Publication date PMC-release: 15 October 2014
                Publication date Collection: 2014
                Volume: 11
                Issue: 1
                Electronic Location Identifier: 177
                Affiliations
                [ ]Department of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025 China
                [ ]Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030 China
                [ ]Department of Neurology, Med-X Research Institute and School of BME, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 1954 Hua-shan Road, Shanghai, 200030 China
                Article
                Publisher ID: 177
                DOI: 10.1186/s12974-014-0177-4
                PMC ID: 4201919
                PubMed ID: 25315906
                SO-VID: bd02033c-a303-44f4-aabf-2869383e75d7
                Copyright © © Liu et al.; licensee BioMed Central Ltd. 2014
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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
                Date received : 18 April 2014
                Date accepted : 30 September 2014
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2014

                ScienceOpen disciplines: Neurosciences
                Keywords: blood-brain barrier,icam-1,inflammation,ischemic stroke,metformin
                Data availability:
                ScienceOpen disciplines: Neurosciences
                Keywords: blood-brain barrier, icam-1, inflammation, ischemic stroke, metformin

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