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      Limb Remote Ischemic Conditioning Promotes Myelination by Upregulating PTEN/Akt/mTOR Signaling Activities after Chronic Cerebral Hypoperfusion

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          Abstract

          Limb Remote ischemic conditioning (LRIC) has been proved to be a promising neuroprotective method in white matter lesions after ischemia; however, its mechanism underlying protection after chronic cerebral hypoperfusion remains largely unknown. Here, we investigated whether LRIC promoted myelin growth by activating PI3K/Akt/mTOR signal pathway in a rat chronic hypoperfusion model. Thirty adult male Sprague Dawley underwent permanent double carotid artery (2VO), and limb remote ischemic conditioning was applied for 3 days after the 2VO surgery. Cognitive function, oligodendrocyte counts, myelin density, apoptosis and proliferation activity, as well as PTEN/Akt/mTOR signaling activity were determined 4 weeks after treatment. We found that LRIC significantly inhibited oligodendrocytes apoptosis ( p<0.05), promoted myelination ( p<0.01) in the corpus callosum and improved spatial learning impairment ( p<0.05) at 4 weeks after chronic cerebral hypoperfusion. Oligodendrocytes proliferation, along with demyelination, in corpus callosum were not obviously affected by LRIC ( p>0.05). Western blot analysis indicated that LRIC upregulated PTEN/Akt/mTOR signaling activities in corpus callosum ( p<0.05). Our results suggest that LRIC exerts neuroprotective effect on white matter injuries through activating PTEN/Akt/mTOR signaling pathway after chronic cerebral hypoperfusion.

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          Most cited references34

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          White matter in learning, cognition and psychiatric disorders.

          White matter is the brain region underlying the gray matter cortex, composed of neuronal fibers coated with electrical insulation called myelin. Previously of interest in demyelinating diseases such as multiple sclerosis, myelin is attracting new interest as an unexpected contributor to a wide range of psychiatric disorders, including depression and schizophrenia. This is stimulating research into myelin involvement in normal cognitive function, learning and IQ. Myelination continues for decades in the human brain; it is modifiable by experience, and it affects information processing by regulating the velocity and synchrony of impulse conduction between distant cortical regions. Cell-culture studies have identified molecular mechanisms regulating myelination by electrical activity, and myelin also limits the critical period for learning through inhibitory proteins that suppress axon sprouting and synaptogenesis.
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            Regulation of neuronal survival by the serine-threonine protein kinase Akt.

            A signaling pathway was delineated by which insulin-like growth factor 1 (IGF-1) promotes the survival of cerebellar neurons. IGF-1 activation of phosphoinositide 3-kinase (PI3-K) triggered the activation of two protein kinases, the serine-threonine kinase Akt and the p70 ribosomal protein S6 kinase (p70(S6K)). Experiments with pharmacological inhibitors, as well as expression of wild-type and dominant-inhibitory forms of Akt, demonstrated that Akt but not p70(S6K) mediates PI3-K-dependent survival. These findings suggest that in the developing nervous system, Akt is a critical mediator of growth factor-induced neuronal survival.
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              Lacunar stroke is associated with diffuse blood-brain barrier dysfunction.

              Lacunar stroke is common (25% of ischemic strokes) and mostly because of an intrinsic cerebral microvascular disease of unknown cause. Although considered primarily to be an ischemic process, the vessel and tissue damage could also be explained by dysfunctional endothelium or blood-brain barrier (BBB) leak, not just ischemia. We tested for subtle generalized BBB leakiness in patients with lacunar stroke and control patients with cortical ischemic stroke. We recruited patients with lacunar and mild cortical stroke. We assessed BBB leak in gray matter, white matter, and cerebrospinal fluid, at least 1 month after stroke, using magnetic resonance imaging before and after intravenous gadolinium. We measured tissue enhancement for 30 minutes after intravenous gadolinium by two image analysis approaches (regions of interest and tissue segmentation). We compared the enhancement (leak) between lacunar and cortical patients, and associations with key variables, using general linear modeling. We recruited 51 lacunar and 46 cortical stroke patients. Signal enhancement after gadolinium was higher in lacunar than cortical stroke patients in white matter (p < 0.001) and cerebrospinal fluid (p < 0.003) by both analysis methods, independent of other variables. Signal enhancement after gadolinium was also associated with increasing age and enlarged perivascular spaces, but these did not explain the lacunar-cortical difference. Patients with lacunar stroke have subtle, diffuse BBB dysfunction in white matter. Further studies are required to determine the relative contributions of BBB dysfunction and/or ischemia to the microvascular and brain abnormalities in lacunar stroke.
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                Author and article information

                Journal
                Aging Dis
                Aging Dis
                Aging and Disease
                JKL International LLC
                2152-5250
                July 2017
                21 July 2017
                : 8
                : 4
                : 392-401
                Affiliations
                [1-ad-8-4-392] 1Institute of Hypoxia Medicine, Xuanwu hospital, Capital Medical University, Beijing 100053, China
                [2-ad-8-4-392] 2Department of China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
                [3-ad-8-4-392] 3Cerebrovascular Diseases Research Institute, Xuanwu Hospital, Capital Medical University, Beijing, China
                [4-ad-8-4-392] 4Center for Neuroscience Discovery, Institute for Healthy Aging, University of North Texas Health Science Center at Fort Worth, Texas 76107, USA
                [5-ad-8-4-392] 5Emergency department, Xuanwu hospital, Capital Medical University, Beijing 100053, China
                [6-ad-8-4-392] 6Beijing Key Laboratory of Hypoxia Translational Medicine, Beijing 100053, China
                Author notes
                [* ]Correspondence should be addressed to: Dr. Xunming Ji and Dr. Yinghao Luo, Xuanwu hospital, Capital Medical University, Beijing, China. Email: jixm@ 123456ccmu.edu.cn and yhluochina@ 123456163.com.
                Article
                ad-8-4-392
                10.14336/AD.2016.1227
                5524802
                28840054
                84701c2d-351b-487b-bcde-46fc130d6b37
                Copyright: © 2016 Li X et al.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

                History
                : 13 November 2016
                : 19 December 2016
                : 27 December 2016
                Categories
                Original Article

                cerebral hypoperfusion,white matter,vascular dementia,oligodendrocyte,ischemic conditioning,pi3k/akt/mtor

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