Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice.
ABSTRACT Molecular mechanisms underlying the role of statins in the induction of brain plasticity and subsequent improvement of neurologic outcome after treatment of stroke have not been adequately investigated. Here, we use both in vivo and in vitro studies to investigate the potential roles of two prominent factors, vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF), in mediating brain plasticity after treatment of stroke with atorvastatin. Treatment of stroke in adult mice with atorvastatin daily for 14 days, starting at 24 hours after MCAO, shows significant improvement in functional recovery compared with control animals. Atorvastatin increases VEGF, VEGFR2 and BDNF expression in the ischemic border. Numbers of migrating neurons, developmental neurons and synaptophysin-positive cells as well as indices of angiogenesis were significantly increased in the atorvastatin treatment group, compared with controls. In addition, atorvastatin significantly increased brain subventricular zone (SVZ) explant cell migration in vitro. Anti-BDNF antibody significantly inhibited atorvastatin-induced SVZ explant cell migration, indicating a prominent role for BDNF in progenitor cell migration. Mouse brain endothelial cell culture expression of BDNF and VEGFR2 was significantly increased in atorvastatin-treated cells compared with control cells. Inhibition of VEGFR2 significantly decreased expression of BDNF in brain endothelial cells. These data indicate that atorvastatin promotes angiogenesis, brain plasticity and enhances functional recovery after stroke. In addition, VEGF, VEGFR2 and BDNF likely contribute to these restorative processes.
Full-textDOI: · Available from: Jieli Chen, May 29, 2015
SourceAvailable from: Gloria Patricia Cardona-Gómez[Show abstract] [Hide abstract]
ABSTRACT: Stroke is the second most common cause of death in people over 45 years of age in Colombia and is the leading cause of permanent disability worldwide. Cerebral ischemia is a stroke characterized by decreased blood flow due to the occlusion of one or more cerebral arteries, which can cause memory problems and hemiplegia or paralysis, among other impairments. The literature contains hundreds of therapies (invasive and noninvasive) that exhibit a neuroprotective effect when evaluated in animal models. However, in clinical trials, most of these drugs do not reproduce the previously demonstrated neuroprotective property, and some even have adverse effects that had not previously been detected in animal experimentation. Statins are drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis. Several studies have shown that statin therapy in an animal model of focal cerebral ischemia reduces infarct volume, as well as markers of neurodegeneration, activates neuronal survival pathways, and improves performance on learning and memory tests. Given the implied therapeutic benefit and the limited understanding of the mechanism of action of statins in brain repair, it is necessary to address the biochemical and tissue effects of these drugs on synaptic proteins, such as NMDA receptors, synaptic adhesion proteins, and cytoskeletal proteins; these proteins are highly relevant therapeutic targets, which, in addition to giving a structural account of synaptic connectivity and function, are also indicators of cellular communication and the integrity of the blood–brain barrier, which are widely affected in the long term post-cerebral infarct but, interestingly, are protected by statins when administered during the acute phase.Journal of Translational Medicine 04/2015; 13(1):118. DOI:10.1186/s12967-015-0472-6 · 3.99 Impact Factor
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ABSTRACT: Angiogenesis is essential for recovery from various neurovascular diseases, such as ischemic stroke. Previous studies have revealed the regulatory role of MicroRNAs in angiogenesis in various types of cancer cells. However, the role of miR-487b in angiogenesis and how it regulates the angiogenic process of endothelial cells remain unclear. In this study, we found miR-487b was up-regulated in the plasma of ischemic stroke patients. Further, over-expression of miR-487b enhanced cell proliferation, migration, invasion and tube formation in human umbilical vein endothelial cells. Using bioinformatic analysis, we found a putative binding site of miR-487b in the 3' untranslated regions of Thrombospondin 1 mRNA, an endogenous inhibitor of angiogenesis. This direct binding was confirmed by luciferase assay. These results demonstrate that miR-487b regulates angiogenesis by directly targeting THBS1 in HUVECs, indicating that miR-487b may contribute to angiogenesis and the functional recovery from ischemic stroke. miR-487b could represent a potential therapeutic option for neurovascular disease. Copyright © 2015. Published by Elsevier Ireland Ltd.Neuroscience Letters 02/2015; 591. DOI:10.1016/j.neulet.2015.02.002 · 2.06 Impact Factor
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ABSTRACT: The aims of this study was to assessed the ability of a combination treatment of bone marrow stromal cell (BMSC) and atorvastatin in a rat model of spinal cord injury (SCI) as an appropriate substitute for current SCI treatments. In the present study, the female Wistar rats were divided into five groups (n = 20) after SCI by New York University Device: SCI, sham, atorvastatin, graft BMSC and graft BMSC plus atorvastatin. Locomotion was assessed using Basso, Beattie and Bresnahan (BBB) test and walking test after SCI. In addition, microvessel density (MVD) was calculated by immunohistochemistry after SCI. We also investigate the vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) expression level by western blot after drug treatment. The results showed that BBB scores and walking test were increased in atorvastatin plus BMSC group compared to single atorvastatin and BMSC groups (P < 0.05). In addition, MVD also significantly increased in combination group compared to single treatment group. Compared to sole drug, VEGF and BDNF expression were significantly up-regulated in atorvastatin combination with BMSC group (P < 0.05). These results imply that the combined use of atorvastatin and BMSC treatment may represent a promising strategy for clinically applicable pharmacological therapy for initiation of neuroprotection after SCI.International Journal of Clinical and Experimental Medicine 01/2014; 7(12):4967-74. · 1.42 Impact Factor