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Post-acute delivery of memantine promotes post-ischemic neurological recovery, peri-infarct tissue remodeling, and contralesional brain plasticity.

ABSTRACT: The NMDA antagonist memantine preferentially inhibits extrasynaptic NMDA receptors, which are overactivated upon stroke and thought to disturb neuroplasticity. We hypothesized that memantine enhances post-ischemic neurological recovery, brain remodeling, and plasticity. C57BL6/j mice were exposed to intraluminal middle cerebral artery occlusion. Starting 72 hours post-stroke, vehicle or memantine (4 or 20?mg/kg/day) were subcutaneously delivered over 28 days. Neurological recovery, perilesional tissue remodeling and contralesional pyramidal tract plasticity were evaluated over 49 days. Memantine, delivered at 20 but not 4?mg/kg/day, persistently improved motor-coordination and spatial memory. Secondary striatal atrophy was reduced by memantine. This delayed neuroprotection was associated with reduced astrogliosis and increased capillary formation around the infarct rim. Concentrations of BDNF, GDNF, and VEGF were bilaterally elevated by memantine in striatum and cortex. Anterograde tract tracing studies revealed that memantine increased contralesional corticorubral sprouting across the midline in direction to the ipsilesional red nucleus. In the contralesional motor cortex, the NMDA receptor subunit GluN2B, which is predominantly expressed in extrasynaptic NMDA receptors, was transiently reduced by memantine after 14 days, whereas GluN2A and PSD-95, which preferentially co-localize with synaptic NMDA receptors, were increased after 28 days. Our data suggest the utility of memantine for enhancing post-acute stroke recovery.

SUBMITTER: Wang YC

PROVIDER: S-EPMC5363474 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Post-acute delivery of memantine promotes post-ischemic neurological recovery, peri-infarct tissue remodeling, and contralesional brain plasticity.

Wang Ya-Chao YC Sanchez-Mendoza Eduardo H EH Doeppner Thorsten R TR Hermann Dirk M DM

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20160720 3

The NMDA antagonist memantine preferentially inhibits extrasynaptic NMDA receptors, which are overactivated upon stroke and thought to disturb neuroplasticity. We hypothesized that memantine enhances post-ischemic neurological recovery, brain remodeling, and plasticity. C57BL6/j mice were exposed to intraluminal middle cerebral artery occlusion. Starting 72 hours post-stroke, vehicle or memantine (4 or 20 mg/kg/day) were subcutaneously delivered over 28 days. Neurological recovery, perilesional ...[more]

PMID: 27170698

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Project description:BackgroundStroke is the leading cause of disability worldwide, resulting in severe damage to the central nervous system and disrupting neurological functions. There is no effective therapy for promoting neurological recovery. Growing evidence suggests that the composition of exosomes from different microenvironments may benefit stroke. Therefore, it is reasonable to assume that exosomes secreted in response to infarction microenvironment could have further therapeutic effects.MethodsIn our study, cerebral infarct tissue extracts were used to pretreat umbilical cord mesenchymal stem cells (UCMSC). Infarct-preconditioned exosomes were injected into rats via tail vein after middle cerebral artery occlusion (MCAO). The effect of infarct-preconditioned exosomes on the neurological recovery of rats was examined using Tunel assay, 2,3,5-triphenyltetrazolium chloride (TTC) assay, magnetic resonance imaging (MRI) analyses, modified Neurological Severity Score (mNSS), Morris water maze (MWM), and vascular remodeling analysis. Mi-RNA sequencing and functional enrichment analysis were used to validate the signal pathway involved in the effect of infarct-preconditioned exosomes. Human umbilical vein endothelial cells (HUVECs) were co-cultured with the isolated exosomes. Cell Counting Kit-8 (CCK-8) assay, scratch healing, and Western blot analysis were used to detect the biological behavior of HUVECs.ResultsThe results showed that compared with normal exosomes, infarct-preconditioned exosomes further promoted vascular remodeling and recovery of neurological function after stroke. The function of upregulated miRNAs and their target genes which is beneficial to vascular smooth muscle cells verified the importance of vascular remodeling in improving stroke. Better resistance to oxygen-glucose deprivation/reoxygenation (OGD/R), reduced apoptosis, and enhanced migration were observed in infarct-preconditioned exosomes-treated umbilical vein endothelial cells.ConclusionsOur results demonstrated that infarct-preconditioned exosomes promoted neurological recovery after stroke by enhancing vascular endothelial remodeling, suggested that infarct-preconditioned exosomes could be a novel way to alleviate brain damage following a stroke.

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Post-acute delivery of memantine promotes post-ischemic neurological recovery, peri-infarct tissue remodeling, and contralesional brain plasticity.

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Post-acute delivery of memantine promotes post-ischemic neurological recovery, peri-infarct tissue remodeling, and contralesional brain plasticity.

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