Statins for Neuroprotection After Acute Ischemic Stroke

Kelly, Peter

doi:10.1161/strokeaha.117.018725

Cited by 8 publications

(4 citation statements)

References 9 publications

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“…The mechanism of cerebral blood flow regulation by eNOS is shown in Figure 3. Therefore, statins are beneficial in the treatment of brain ischemia because they increase the expression of eNOS by inhibiting changes in Rho-mediated actin cytoskeleton [99]. Expression of eNOS is decreased in some neurological injuries, such as strokes and cerebral artery occlusion [57].…”

Section: Neuroprotectionmentioning

confidence: 99%

“…Since no alteration in these markers was observed in atorvastatin-treated eNOS knockout mice, the changes in platelet function have been attributed to the increased eNOS expression by statins [12]. treatment of brain ischemia because they increase the expression of eNOS by inhibiting changes in Rho-mediated actin cytoskeleton [99]. Expression of eNOS is decreased in some neurological injuries, such as strokes and cerebral artery occlusion [57].…”

Section: Neuroprotectionmentioning

confidence: 99%

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Statin-Induced Nitric Oxide Signaling: Mechanisms and Therapeutic Implications

Gorabi

Kiaie

Hajighasemi

et al. 2019

JCM

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In addition to their cholesterol-lowering effects, statins are associated with pleiotropic effects including improvements in heart failure (HF), reduced blood pressure, prevention of the rupture of atherosclerotic plaques and improved angiogenesis. In addition to these cardiovascular benefits, statins have been implicated in the treatment of neurological injuries, cancer, sepsis, and cirrhosis. These cholesterol-independent beneficial effects of statins are predominantly mediated through signaling pathways leading to increased production and bioavailability of nitric oxide (NO). In this review, the mechanistic pathways and therapeutic effects of statin-mediated elevations of NO are described and discussed.

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Section: Neuroprotectionmentioning

confidence: 99%

Section: Neuroprotectionmentioning

confidence: 99%

Statin-Induced Nitric Oxide Signaling: Mechanisms and Therapeutic Implications

Gorabi

Kiaie

Hajighasemi

et al. 2019

JCM

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“…However, how to inhibit the secondary and morphological injury of healthy neurons in the peri-infarct region must still be explored. While inflammation-induced hypoxia-ischemia neuronal damage has been previously reported [2, 12], the direct effect of secretions from microglia after cerebral ischemia on healthy neurons will be studied, which we believe may be a possible cause of penumbra formation. Actually, atorvastatin has no direct neuron protection effects [13], while rosuvastatin induces delayed preconditioning against oxygen-glucose deprivation in cultured cortical neurons [14].…”

Section: Introductionmentioning

confidence: 98%

HMG-CoA Reductase Inhibitors Attenuate Neuronal Damage by Suppressing Oxygen Glucose Deprivation-Induced Activated Microglial Cells

Shen

Mai

et al. 2019

Neural Plasticity

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Ischemic stroke is usually followed by inflammatory responses mediated by microglia. However, the effect of statins on directly preventing posthypoxia microglia inflammatory factors to prevent injury to surrounding healthy neurons is unclear. Atorvastatin and rosuvastatin, which have different physical properties regarding their lipid and water solubility, are the most common HMG-CoA reductase inhibitors (statins) and might directly block posthypoxia microglia inflammatory factors to prevent injury to surrounding neurons. Neuronal damage and microglial activation of the peri-infarct areas were investigated by Western blotting and immunofluorescence after 24 hours in a middle cerebral artery occlusion (MCAO) rat model. The decrease in neurons was in accordance with the increase in microglia, which could be reversed by both atorvastatin and rosuvastatin. The effects of statins on blocking secretions from posthypoxia microglia and reducing the secondary damage to surrounding normal neurons were studied in a coculture system in vitro. BV2 microglia were cultured under oxygen glucose deprivation (OGD) for 3 hours and then cocultured following reperfusion for 24 hours in the upper wells of transwell plates with primary neurons being cultured in the bottom wells. Inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and cyclooxygenase-2 (COX2), which are activated by the nuclear factor-kappa B (NF-κB) signaling pathway in OGD-induced BV2 microglia, promoted decreased release of the anti-inflammatory cytokine IL-10 and apoptosis of neurons in the coculture systems according to ELISA and Western blotting. However, pretreatment with atorvastatin or rosuvastatin significantly reduced neuronal death, synaptic injury, and amyloid-beta (Aβ) accumulation, which might lead to increased low-density lipoprotein receptors (LDLRs) in BV2 microglia. We concluded that the proinflammatory mediators released from postischemia damage could cause damage to surrounding normal neurons, while HMG-CoA reductase inhibitors prevented neuronal apoptosis and synaptic injury by inactivating microglia through blocking the NF-κB signaling pathway.

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“…Atorvastatin is among the most commonly used drugs to treat cerebral ischemic stroke 21 ; it reportedly increases the expression of Ang-2, VEGF, and inflammatory factor matrix metallopeptidase 9 (MMP9), all of which reduce vascular maturation and stabilization, promote vascular permeability, and stimulate inflammation. 11,22 However, atorvastatin may increase the risk of intracerebral hemorrhage and reduce plasma cholesterol, enhancing cholesterol efflux from cell membranes.…”

Section: Discussionmentioning

confidence: 99%

Granulocyte colony-stimulating factor and stromal cell-derived factor-1 combination therapy: A more effective treatment for cerebral ischemic stroke

Wang

Zhang

Wei

et al. 2019

International Journal of Stroke

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Background Drugs that promote angiogenesis include statins, recombinant human granulocyte colony-stimulating factor, and stromal cell-derived factor-1. Low doses of atorvastatin could significantly increase the vascular expressions of endothelial growth factor, and the number of peripheral blood endothelial progenitor cells (EPCs), thus improving angiogenesis and local blood flow. G-CSF is an EPC-mobilization agent used in ischemia studies for targeting angiogenesis after cerebral ischemia via EPCs. In previous clinical trials, consistent conclusions have not been reached about the effectiveness of G-CSF on ischemic stroke. Therefore, the therapeutic effect of G-CSF and its combination with other medicines need further experimental verification. It is known that atorvastatin, rhG-CSF, and SDF-1 are considered the most promising neuroprotective candidates, but a comprehensive comparison of their effects is lacking. Aims To compare the effects of atorvastatin, stromal cell-derived factor-1, and recombinant human granulocyte colony-stimulating factor on ischemic stroke. Methods Adult male Sprague-Dawley rats were randomly allocated to three groups: normal, sham-operated, and middle cerebral artery occlusion operated. Middle cerebral artery occlusion operated rats were further allocated into saline, atorvastatin, recombinant human granulocyte colony-stimulating factor, and recombinant human granulocyte colony-stimulating factor + stromal cell-derived factor-1 groups. Neurological function evaluation, cerebral infarction and the blood–brain barrier integrity analysis, identification of angiogenic factors, assessment of angiogenesis, expression of growth-associated protein-43, neuroglobin, glial cell-derived neurotrophic factor, and cleaved caspase 3, were performed. Results Compared with atorvastatin or recombinant human granulocyte colony-stimulating factor alone, recombinant human granulocyte colony-stimulating factor + stromal cell-derived factor-1 treatment improved neurological performance, reduced cerebral infarction and blood–brain barrier disruption after stroke, and increased the content of stromal cell-derived factor-1, vascular endothelial growth factor, monocyte chemotactic protein 1, and basic fibroblast growth factor in peripheral blood. In addition, recombinant human granulocyte colony-stimulating factor + stromal cell-derived factor-1 promoted greater angiogenesis than atorvastatin or recombinant human granulocyte colony-stimulating factor alone and increased the expression of growth-associated protein-43, neuroglobin, and glial cell-derived neurotrophic factor, while decreasing the levels of cleaved caspase 3 in the brain after ischemic stroke. Conclusions Combination therapy with recombinant human granulocyte colony-stimulating factor and stromal cell-derived factor-1 is more effective than atorvastatin or recombinant human granulocyte colony-stimulating factor alone in protecting against stroke-induced damage and could be an optimal therapeutic strategy for stroke.

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Statins for Neuroprotection After Acute Ischemic Stroke

Cited by 8 publications

References 9 publications

Statin-Induced Nitric Oxide Signaling: Mechanisms and Therapeutic Implications

Statin-Induced Nitric Oxide Signaling: Mechanisms and Therapeutic Implications

HMG-CoA Reductase Inhibitors Attenuate Neuronal Damage by Suppressing Oxygen Glucose Deprivation-Induced Activated Microglial Cells

Granulocyte colony-stimulating factor and stromal cell-derived factor-1 combination therapy: A more effective treatment for cerebral ischemic stroke

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