Additive Effects of Statin and Dipyridamole on Cerebral Blood Flow and Stroke Protection

Kim, Hyung-Hwan; Sawada, Naoki; Soydan, Guray; Lee, Hoseong; Zhou, Zhipeng; Hwang, Seo-Kyoung; Waeber, Christian; Moskowitz, Michael A.; Liao, James K.

doi:10.1038/jcbfm.2008.24

Cited by 40 publications

(27 citation statements)

References 39 publications

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“…Is it possible that some form of endothelial protection may contribute to potential beneficial properties of dipyridamole in cerebral ischemia? A recent study demonstrated that subtherapeutic doses of dipyridamole combined with simvastatin were able to exert additive NO-dependent vascular effects on a mouse stroke model with increased cerebral blood flow, leading to decreased stroke volume and improved neurologic outcomes [33]. Further investigations appear warranted to truly dissect these neurovascular pathways of dipyridamole in the context of stroke and cerebrovascular disease.…”

Section: Discussionmentioning

confidence: 99%

Amelioration of Inflammation and Cytotoxicity by Dipyridamole in Brain Endothelial Cells

Guo¹,

Stins

Ning³

et al. 2010

Cerebrovasc Dis

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Background: Increasing evidence suggests that beyond its antiplatelet properties, dipyridamole may have pleiotropic effects on other cells within the neurovascular elements of the brain. In this experimental cellular study, we asked whether dipyridamole can ameliorate brain endothelial injury after exposure to inflammatory and metabolic insults. Methods: Human brain endothelial cells were grown in culture, and exposed to TNFα (continuously for 20 h) or subjected to oxygen-glucose deprivation (OGD; 6 h of insult followed by 18 h recovery). Expression of ICAM-1, VCAM-1 and PECAM-1 were measured by immunoblotting. Matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in the conditioned media were quantified via zymography. MTT mitochondrial activity was measured to assess endothelial cell viability. Results: Exposure of human brain endothelial cells to TNFα (12.5–50 ng/ml) induced a clear increase in protein levels of ICAM-1, VCAM-1 and MMP-9. TNFα did not alter PECAM-1. Dipyridamole (1–5 µM) significantly attenuated ICAM-1 and MMP-9 levels after this inflammatory insult. No significant effects of dipyridamole were noted for VCAM-1. Six-hour OGD induced moderate endothelial cell death accompanied by a release of MMP-9. Dipyridamole significantly decreased MMP-9 levels and cell death after this metabolic insult. Conclusions: These results suggest that dipyridamole may ameliorate brain endothelial injury after inflammation and/or metabolic insults. How these putative cellular mechanisms may relate to clinical outcomes and conditions in stroke patients remains to be elucidated.

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Section: Discussionmentioning

confidence: 99%

Amelioration of Inflammation and Cytotoxicity by Dipyridamole in Brain Endothelial Cells

Guo¹,

Stins

Ning³

et al. 2010

Cerebrovasc Dis

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“…It was shown that dipyramidol augmented the neuroprotective effects of statins in an eNOS-dependent way (Kim et al, 2008). The putative mechanism involves an increase in eNOS S1177 phosphorylation, as demonstrated in spontaneously hypertensive rats (Oyama et al, 2011) based on the reduction in postischemic brain damage following pretreatment with PDE inhibitor cilostazol.…”

Section: Phosphodiesterase Inhibitorsmentioning

confidence: 99%

Nitric Oxide: Considerations for the Treatment of Ischemic Stroke

Terpolilli¹,

Moskowitz

Plesnila³

2012

J Cereb Blood Flow Metab

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128

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Some 40 years ago it was recognized by Furchgott and colleagues that the endothelium releases a vasodilator, endothelium-derived relaxing factor (EDRF). Later on, several groups identified EDRF to be a gas, nitric oxide (NO). Since then, NO was identified as one of the most versatile and unique molecules in animal and human biology. Nitric oxide mediates a plethora of physiological functions, for example, maintenance of vascular tone and inflammation. Apart from these physiological functions, NO is also involved in the pathophysiology of various disorders, specifically those in which regulation of blood flow and inflammation has a key role. The aim of the current review is to summarize the role of NO in cerebral ischemia, the most common cause of stroke.

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“…Dipyridamole, a phosphodiesterase-5 inhibitor, has been shown to decrease the cerebral infarct size, and the combination of subtherapeutic doses of statin and dipyridamole increased eNOS activity and cerebral blood flow and reduced infarct volume. 30 In addition to these phosphodiesterase inhibitors, it has been reported that several modalities, such as statin, angiotensin II type 1 receptor blocker, Rho kinase inhibitor, and L-arginine, upregulated eNOS expression, increased eNOS activity, and inhibited oxidative stress. 3,6,8,[31][32][33] All of these modalities increase endothelium-derived NO availability and have been shown to enhance CBF, resulting in neuroprotection after cerebral ischemia.…”

mentioning

confidence: 99%

Cilostazol, Not Aspirin, Reduces Ischemic Brain Injury via Endothelial Protection in Spontaneously Hypertensive Rats

Oyama

Yagita

Kawamura

et al. 2011

Stroke

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Background and Purpose-It is well-established that hypertension leads to endothelial dysfunction in the cerebral artery.Recently, cilostazol has been used for the secondary prevention of ischemic stroke. Among antiplatelet drugs, phosphodiesterase inhibitors including cilostazol have been shown to have protective effects on endothelial cells. The aim of the present study is to investigate the effects of cilostazol and aspirin on endothelial nitric oxide synthase (eNOS) phosphorylation in the cerebral cortex, endothelial function, and infarct size after brain ischemia in spontaneously hypertensive rats (SHR). Methods-Five-week-old male SHR received a 5-week regimen of chow containing 0.1% aspirin, 0.1% cilostazol, 0.3% cilostazol, or the vehicle control. The levels of total and Ser 1177 -phosphorylated eNOS protein in the cerebral cortex were evaluated by Western blot. To assess the contribution of eNOS in maintaining cerebral blood flow, we monitored cerebral blood flow by laser-Doppler flowmetry after L-N 5 -(1-iminoethyl)ornithine infusion. Additionally, we evaluated residual microperfusion using fluorescence-labeled serum protein and infarct size after transient focal brain ischemia. Results-In SHR, the blood pressure and heart rate were similar among the groups. Cilostazol-treated SHR had a significantly higher ratio of phospho-eNOS/total eNOS protein than vehicle-treated and aspirin-treated SHR. Treating with cilostazol, but not aspirin, significantly improved cerebral blood flow response to L-N 5 -(1-iminoethyl)ornithine. Cilostazol also increased residual perfusion of the microcirculation and reduced brain damage after ischemia compared to vehicle control and aspirin. Conclusions-These findings indicate that cilostazol, but not aspirin, can attenuate ischemic brain injury by maintaining endothelial function in the cerebral cortex of SHR. (Stroke. 2011;42:2571-2577.)Key Words: brain ischemia Ⅲ endothelial function Ⅲ hypertension Ⅲ phosphodiesterase-3 inhibitor H ypertension is one of the most important risk factors for cerebrovascular disease and is closely associated with endothelial dysfunction. Some studies observed endothelial dysfunction in patients with hypertension or cerebrovascular disease. 1,2 In hypertensive animal models, hypertension impairs endothelium-dependent vasodilatation, cerebrovascular autoregulation, and cerebral blood flow (CBF) responses, and it exacerbates ischemic brain damage. [3][4][5][6] Endothelial dysfunction is often characterized by a decrease in the bioavailability of endothelium-derived nitric oxide (NO). In endothelial cells, NO is produced by endothelial nitric oxide synthase (eNOS), and eNOS activity is regulated primarily by calcium-calmodulin activation and multisite phosphorylation of specific serine or threonine residues. Most importantly, phosphorylation of eNOS-Ser 1177 is thought to play a crucial role in eNOS activation. In a cerebral ischemia model, modification of the eNOS-Ser 1177 phosphorylation state modulated CBF and the outcome of ischemic injury. 7 Th...

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Additive Effects of Statin and Dipyridamole on Cerebral Blood Flow and Stroke Protection

Cited by 40 publications

References 39 publications

Amelioration of Inflammation and Cytotoxicity by Dipyridamole in Brain Endothelial Cells

Amelioration of Inflammation and Cytotoxicity by Dipyridamole in Brain Endothelial Cells

Nitric Oxide: Considerations for the Treatment of Ischemic Stroke

Cilostazol, Not Aspirin, Reduces Ischemic Brain Injury via Endothelial Protection in Spontaneously Hypertensive Rats

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