Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice. J Cereb Blood Flow Metab

Department of Physics, Oakland University, Рочестер, Michigan, United States
Journal of Cerebral Blood Flow & Metabolism (Impact Factor: 5.41). 03/2005; 25(2):281-90. DOI: 10.1038/sj.jcbfm.9600034
Source: PubMed


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.

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Available from: Jieli Chen
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    • "The relationship between BDNF and synaptogenesis is widely studied. Chen et al. [76] have shown that statin, a BDNF upregulation inductor, is related to an increase of synaptophysin expression and to functional recovery after stroke. Pozzo-Miller et al. [77] have shown that BDNF knockout mice have a reduced level of synaptophysin in hippocampal synaptosomes. "
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    ABSTRACT: Polyphenols have neuroprotective effects after brain ischemia. It has been demonstrated that rosmarinic acid (RA), a natural phenolic compound, possesses antioxidant and anti-inflammatory properties. To evaluate the effectiveness of RA against memory deficits induced by permanent middle cerebral artery occlusion (pMCAO) mice were treated with RA (0.1, 1, and 20mg/kg/day, i. p. before ischemia and during 5 days). Animals were evaluated for locomotor activity and working memory 72h after pMCAO, and spatial and recognition memories 96h after pMCAO. In addition, in another set of experiments brain infarction, neurological deficit score and myeloperoxidase (MPO) activity were evaluates 24h after the pMCAO. Finally, immunohistochemistry, and western blot, and ELISA assay were used to analyze glial fibrillary acidic protein (GFAP), and synaptophysin (SYP) expression, and BDNF level, respectively. The working, spatial, and recognition memory deficits were significantly improved with RA treatment (20mg/kg). RA reduced infarct size and neurological deficits caused by acute ischemia. The mechanism for RA neuroprotection involved, neuronal loss suppression, and increase of synaptophysin expression, and increase of BDNF. Furthermore, the increase of MPO activity and GFAP immunireactivity were prevented in MCAO group treated with RA. These results suggest that RA exerts memory protective effects probably due to synaptogenic activity and anti-inflammatory action.
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    • "Previous studies have shown that ATV promotes angiogenesis and brain plasticity and enhances functional recovery after stroke and that BDNF contributes to these restorative processes (Chen et al., 2005b). We evaluated BDNF levels in the somatosensory cerebral cortex and found reductions at 72 hr and 15 days in ischemic animals treated with placebo compared with sham-operated animals (P 0.05). "

    Full-text · Dataset · Mar 2015
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    • "Moreover, both environmental enrichment and administration of growth factors (i.e. BDNF or VEGF) increase post-ischemia progenitor cell proliferation and neurogenesis in the SGZ and SVZ (Chen et al., 2005; Matsumori et al., 2006a). Given that growth factors function in large part via activation of the MAPK/ERK signaling cascade, our data on the role of MSK1 as a mediator of both environmental enrichment-(Karelina et al., 2012) and cerebral ischemia-induced progenitor cell proliferation indicate that this process is induced by the same mechanism. "
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    ABSTRACT: Pathophysiological conditions such as cerebral ischemia trigger the production of new neurons from the neurogenic niche within the subgranular zone (SGZ) of the dentate gyrus. The functional significance of ischemia-induced neurogenesis is believed to be the regeneration of lost cells, thus contributing to post-ischemia recovery. However, the cell signaling mechanisms by which this process is regulated are still under investigation. Here, we investigated the role of mitogen and stress-activated protein kinases (MSK1/2) in the regulation of progenitor cell proliferation and neurogenesis after cerebral ischemia. Using the endothelin-1 model of ischemia, wild-type (WT) and MSK1(-/-)/MSK2(-/-) (MSK dKO) mice were injected with BrdU and sacrificed 2days, 4weeks, or 6weeks later for the analysis of progenitor cell proliferation, neurogenesis, and neuronal morphology, respectively. We report a decrease in SGZ progenitor cell proliferation in MSK dKO mice compared to WT mice. Moreover, MSK dKO mice exhibited reduced neurogenesis and a delayed maturation of ischemia-induced newborn neurons. Further, structural analysis of neuronal arborization revealed reduced branching complexity in MSK dKO compared to WT mice. Taken together, this dataset suggests that MSK1/2 plays a significant role in the regulation of ischemia-induced progenitor cell proliferation and neurogenesis. Ultimately, revealing the cell signaling mechanisms that promote neuronal recovery will lead to novel pharmacological approaches for the treatment of neurodegenerative diseases such as cerebral ischemia. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.
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