Cilostazol, a Phosphodiesterase Inhibitor, Attenuates Photothrombotic Focal Ischemic Brain Injury in Hypertensive Rats

Ito, Hideki; Hashimoto, Ayako; Matsumoto, Yutaka; Yao, Hiroshi; Miyakoda, Goro

doi:10.1038/jcbfm.2009.220

Cited by 38 publications

(34 citation statements)

References 37 publications

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“…This protective effect of cilostazol is in accordance with the previous findings that cilostazol improved cerebral infarction by reducing cytotoxic edema in rats (Lee et al 2003;Ito et al 2010;Wajima et al 2011). Cilostazol also reversed the reduction of claudin-5 expression and normalized the increase of MMP-9 activity to prevent tissue plasminogen activator (tPA)-associated hemorrhagic transformation induced by focal cerebral ischemia in mice treated with tPA (Ishiguro et al 2010).…”

Section: Effect Of Cilostazol On Barrier Function Of Rbec Damaged By supporting

confidence: 78%

Cilostazol Strengthens Barrier Integrity in Brain Endothelial Cells

et al. 2012

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We studied the effect of cilostazol, a selective inhibitor of phosphodiesterase 3 (PDE3), on barrier functions of blood-brain barrier (BBB)-related endothelial cells, primary rat brain capillary endothelial cells (RBEC) and the immortalized human brain endothelial cell line hCMEC/D3. The pharmacological potency of cilostazol was also evaluated on ischemia-related BBB dysfunction using a triple co-culture BBB model (BBB Kit TM ) subjected to 6-h oxygen glucose deprivation (OGD) and 3-h reoxygenation. There was expression of phosphodiesterase 3B mRNA in RBEC, and a significant increase in intracellular cAMP content was detected in RBEC treated with both 1 µM and 10 µM cilostazol. Cilostazol increased the transendothelial electrical resistance (TEER), an index of barrier tightness of interendothelial tight junctions (TJs), and decreased the endothelial permeability of sodium fluorescein through the RBEC monolayer. The effects on these barrier functions were significantly reduced in the presence of protein kinase A inhibitor H-89.Microscopic observation revealed smooth and even localization of occludin immunostaining at TJs and F-actin fibers at the cell borders in cilostazol-treated RBEC.

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Section: Effect Of Cilostazol On Barrier Function Of Rbec Damaged By supporting

confidence: 78%

Cilostazol Strengthens Barrier Integrity in Brain Endothelial Cells

et al. 2012

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“…17 Previous studies have shown that cilostazol increases rCBF in a rat model of chronic cerebral hypoperfusion, 18,19 and that cilostazol improves rCBF in the penumbral region in a rat model of middle cerebral artery occlusion. 20 In clinical studies, cilostazol also increases rCBF compared with ticlopidine at the chronic stage of cerebral infarction with a vasodilating effect. 21 In the present study, cilostazol tended to maintain rCBF compared with vehicle and the other 2 antiplatelet drugs (Figure 1).…”

Section: Omote Et Al Pleiotropic Effect Of Cilostazol In Shr-spmentioning

confidence: 99%

Clinical and Pathological Improvement in Stroke-Prone Spontaneous Hypertensive Rats Related to the Pleiotropic Effect of Cilostazol

Omote

Deguchi

Tian

et al. 2012

Stroke

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Background and Purpose-Cerebral infarction is a major cause of death or decreasing activities of daily living. This study aimed to investigate the efficacy of commonly used antiplatelet drugs on stroke and motor and cognitive functions in relation to oxidative stress markers and insulin-like growth factor 1 receptor (IGF-1R). Methods-Stroke-prone spontaneously hypertensive rats were treated with vehicle, aspirin, clopidogrel, and cilostazol from 8 to 10 weeks of age. Physiological parameters, regional cerebral blood flow, and serum lipids were examined. Motor and cognitive functions were evaluated weekly by the Rotorod and water maze task. Spontaneous infarct volume, oxidative stress markers for lipid, protein, and DNA at the ischemic boundary zone of spontaneous infarction, and the IGF-1R-positive cell ratio in the hippocampus were immunohistochemically examined in brain sections. IGF-1R␤ expression in the hippocampus was assessed by Western blotting. Results-The antiplatelet drugs, cilostazol and clopidogrel, reduced the spontaneous infarct volume more than aspirin.Only cilostazol improved motor and cognitive functions with a significant increase (PϽ0.05) in the memory-related IGF-1R-positive ratio and IGF-1R␤ expression in the hippocampus. Cilostazol reduced the 4 oxidative stress markers in affected neurons in stroke-prone spontaneously hypertensive rats regardless of blood pressure, regional cerebral blood flow, or serum lipid levels. Conclusions-The

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“…11,12 Several studies showed that short-term pretreatment and post-treatment with cilostazol attenuated ischemic brain injury by increasing NO production and eNOS activation. [13][14][15] However, the comparative effects of cilostazol and aspirin on cerebrovascular function have not been investigated.We hypothesized that chronic cilostazol treatment, in contrast to aspirin treatment, (1) can prevent hypertensioninduced cerebrovascular dysfunction through increased eNOS-Ser 1177 phosphorylation and the eNOS-dependent CBF …”

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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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Cilostazol, a Phosphodiesterase Inhibitor, Attenuates Photothrombotic Focal Ischemic Brain Injury in Hypertensive Rats

Cited by 38 publications

References 37 publications

Cilostazol Strengthens Barrier Integrity in Brain Endothelial Cells

Cilostazol Strengthens Barrier Integrity in Brain Endothelial Cells

Clinical and Pathological Improvement in Stroke-Prone Spontaneous Hypertensive Rats Related to the Pleiotropic Effect of Cilostazol

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

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