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      Caveolin-1 and MLRs: A potential target for neuronal growth and neuroplasticity after ischemic stroke

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          Abstract

          Ischemic stroke is a leading cause of morbidity and mortality worldwide. Thrombolytic therapy, the only established treatment to reduce the neurological deficits caused by ischemic stroke, is limited by time window and potential complications. Therefore, it is necessary to develop new therapeutic strategies to improve neuronal growth and neurological function following ischemic stroke. Membrane lipid rafts (MLRs) are crucial structures for neuron survival and growth signaling pathways. Caveolin-1 (Cav-1), the main scaffold protein present in MLRs, targets many neural growth proteins and promotes growth of neurons and dendrites. Targeting Cav-1 may be a promising therapeutic strategy to enhance neuroplasticity after cerebral ischemia. This review addresses the role of Cav-1 and MLRs in neuronal growth after ischemic stroke, with an emphasis on the mechanisms by which Cav-1/MLRs modulate neuroplasticity via related receptors, signaling pathways, and gene expression. We further discuss how Cav-1/MLRs may be exploited as a potential therapeutic target to restore neuroplasticity after ischemic stroke. Finally, several representative pharmacological agents known to enhance neuroplasticity are discussed in this review.

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          Most cited references145

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          Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth.

          Multipotent mesenchymal stromal cells (MSCs) have potential therapeutic benefit for the treatment of neurological diseases and injury. MSCs interact with and alter brain parenchymal cells by direct cell-cell communication and/or by indirect secretion of factors and thereby promote functional recovery. In this study, we found that MSC treatment of rats subjected to middle cerebral artery occlusion (MCAo) significantly increased microRNA 133b (miR-133b) level in the ipsilateral hemisphere. In vitro, miR-133b levels in MSCs and in their exosomes increased after MSCs were exposed to ipsilateral ischemic tissue extracts from rats subjected to MCAo. miR-133b levels were also increased in primary cultured neurons and astrocytes treated with the exosome-enriched fractions released from these MSCs. Knockdown of miR-133b in MSCs confirmed that the increased miR-133b level in astrocytes is attributed to their transfer from MSCs. Further verification of this exosome-mediated intercellular communication was performed using a cel-miR-67 luciferase reporter system and an MSC-astrocyte coculture model. Cel-miR-67 in MSCs was transferred to astrocytes via exosomes between 50 and 100 nm in diameter. Our data suggest that the cel-miR-67 released from MSCs was primarily contained in exosomes. A gap junction intercellular communication inhibitor arrested the exosomal microRNA communication by inhibiting exosome release. Cultured neurons treated with exosome-enriched fractions from MSCs exposed to 72 hours post-MCAo brain extracts significantly increased the neurite branch number and total neurite length. This study provides the first demonstration that MSCs communicate with brain parenchymal cells and may regulate neurite outgrowth by transfer of miR-133b to neural cells via exosomes. Copyright © 2012 AlphaMed Press.
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            Caveolin-1 regulates cell polarization and directional migration through Src kinase and Rho GTPases

            Development, angiogenesis, wound healing, and metastasis all involve the movement of cells in response to changes in the extracellular environment. To determine whether caveolin-1 plays a role in cell migration, we have used fibroblasts from knockout mice. Caveolin-1–deficient cells lose normal cell polarity, exhibit impaired wound healing, and have decreased Rho and increased Rac and Cdc42 GTPase activities. Directional persistency of migration is lost, and the cells show an impaired response to external directional stimuli. Both Src inactivation and p190RhoGAP knockdown restore the wild-type phenotype to caveolin-1–deficient cells, suggesting that caveolin-1 stimulates normal Rho GTP loading through inactivation of the Src–p190RhoGAP pathway. These findings highlight the importance of caveolin-1 in the establishment of cell polarity during directional migration through coordination of the signaling of Src kinase and Rho GTPases.
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              Signal transduction through prion protein.

              The cellular prion protein PrPc is a glycosylphosphatidylinositol-anchored cell-surface protein whose biological function is unclear. We used the murine 1C11 neuronal differentiation model to search for PrPc-dependent signal transduction through antibody-mediated cross-linking. A caveolin-1-dependent coupling of PrPc to the tyrosine kinase Fyn was observed. Clathrin might also contribute to this coupling. The ability of the 1C11 cell line to trigger PrPc-dependent Fyn activation was restricted to its fully differentiated serotonergic or noradrenergic progenies. Moreover, the signaling activity of PrPc occurred mainly at neurites. Thus, PrPc may be a signal transduction protein.
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                Author and article information

                Journal
                Int J Med Sci
                Int J Med Sci
                ijms
                International Journal of Medical Sciences
                Ivyspring International Publisher (Sydney )
                1449-1907
                2019
                15 October 2019
                : 16
                : 11
                : 1492-1503
                Affiliations
                Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
                Author notes
                ✉ Corresponding author: Xiangqi Tang; Department of Neurology, The Second Xiangya Hospital of Central South University, Renmin Road 139#, Changsha, Hunan 410011, China. Tel: +86 13875807186 Fax: 0731-84896038; Email: txq6633@ 123456csu.edu.cn

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                ijmsv16p1492
                10.7150/ijms.35158
                6818210
                31673241
                2efc8d00-d07e-405b-be29-027d9b76f8eb
                © The author(s)

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                : 23 March 2019
                : 3 September 2019
                Categories
                Review

                Medicine
                caveolin-1,membrane lipid raft,ischemic stroke,neuronal growth,neuroplasticity,non-coding rna.

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