Cilostazol attenuates ischemia–reperfusion-induced blood–brain barrier dysfunction enhanced by advanced glycation endproducts via transforming growth factor-β1 signaling

Takeshita, Tomonori; Nakagawa, Shinsuke; Tatsumi, Rei; So, Gohei; Hayashi, Kentarō; Tanaka, Kunihiko; Deli, Mária A.; Nagata, Izumi; Níwa, Masami

doi:10.1016/j.mcn.2014.01.006

Cited by 30 publications

(21 citation statements)

References 54 publications

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“…Consequently, we studied the influence of astrocytes and OGD on an established blood-brain barrier (BBB) in vitro model based on murine cerebEND cells (Silwedel and Förster, 2006 ). CerebENDs represent an adequate BBB cell culture model forming significant tight monolayers with high TEER values comparable to models based on mouse primary brain endothelial cells (Silwedel and Förster, 2006 ; Takeshita et al, 2014 ). Moreover, cerebEND cells were successfully used for OGD studies and responded to TNFα-stimulus with a rapid increase of paracellular permeability (Silwedel and Förster, 2006 ; Neuhaus et al, 2012a ).…”

Section: Discussionmentioning

confidence: 95%

The pivotal role of astrocytes in an in vitro stroke model of the blood-brain barrier

Neuhaus¹,

Gaiser²,

Mahringer³

et al. 2014

Front. Cell. Neurosci.

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Stabilization of the blood-brain barrier during and after stroke can lead to less adverse outcome. For elucidation of underlying mechanisms and development of novel therapeutic strategies validated in vitro disease models of the blood-brain barrier could be very helpful. To mimic in vitro stroke conditions we have established a blood-brain barrier in vitro model based on mouse cell line cerebEND and applied oxygen/glucose deprivation (OGD). The role of astrocytes in this disease model was investigated by using cell line C6. Transwell studies pointed out that addition of astrocytes during OGD increased the barrier damage significantly in comparison to the endothelial monoculture shown by changes of transendothelial electrical resistance as well as fluorescein permeability data. Analysis on mRNA and protein levels by qPCR, western blotting and immunofluorescence microscopy of tight junction molecules claudin-3,-5,-12, occludin and ZO-1 revealed that their regulation and localisation is associated with the functional barrier breakdown. Furthermore, soluble factors of astrocytes, OGD and their combination were able to induce changes of functionality and expression of ABC-transporters Abcb1a (P-gp), Abcg2 (bcrp), and Abcc4 (mrp4). Moreover, the expression of proteases (matrixmetalloproteinases MMP-2, MMP-3, MMP-9, and t-PA) as well as of their endogenous inhibitors (TIMP-1, TIMP-3, PAI-1) was altered by astrocyte factors and OGD which resulted in significant changes of total MMP and t-PA activity. Morphological rearrangements induced by OGD and treatment with astrocyte factors were confirmed at a nanometer scale using atomic force microscopy. In conclusion, astrocytes play a major role in blood-brain barrier breakdown during OGD in vitro.

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Section: Discussionmentioning

confidence: 95%

The pivotal role of astrocytes in an in vitro stroke model of the blood-brain barrier

Neuhaus¹,

Gaiser²,

Mahringer³

et al. 2014

Front. Cell. Neurosci.

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“…We used a triple co-culture model termed the BBB Kit TM , which consists of endothelial cells, pericytes, and astrocytes (RBT-24H, PharmaCohee-Cell Company, Ltd., Nagasaki, Japan) as described previously. 25 This model is reconstructed by culturing both primary rat brain microvascular endothelial cells and rat brain pericytes separated by a macroporous Millicell membrane (24 wells, pore size: 3.0 mm; Millipore, Billerica, MA, USA) pre-cultured with rat astrocytes to support the tight junctions. We incubated the BBB kit at 37 C in 5% CO 2 for 5 days to establish strong tight junctions as reported previously.…”

Section: Co-culture Model For Vascular Structure and Preparationmentioning

confidence: 99%

“…We incubated the BBB kit at 37 C in 5% CO 2 for 5 days to establish strong tight junctions as reported previously. 25…”

Section: Co-culture Model For Vascular Structure and Preparationmentioning

confidence: 99%

Cilostazol ameliorates collagenase-induced cerebral hemorrhage by protecting the blood–brain barrier

Takagi

Imai

Mishiro

et al. 2016

J Cereb Blood Flow Metab

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Intracranial hemorrhage remains a devastating disease. Among antiplatelet drugs, cilostazol, a phosphodiesterase 3 inhibitor, was recently reported to prevent secondary hemorrhagic stroke in patients in a clinical trial. The aim of this study was to evaluate whether pre-treatment with cilostazol could decrease the intracranial hemorrhage volume and examine the protective mechanisms of cilostazol. We evaluated the pre-treatment effects of the antiplatelet drug cilostazol on the collagenase-induced intracranial hemorrhage volume and neurological outcomes in mice. To estimate the mechanism of collagenase injury, we evaluated various vascular components in vitro, including endothelial cells, vascular smooth muscle cells, pericytes, and a blood-brain barrier model. Cilostazol pre-treatment reduced the intracranial hemorrhage volume with sufficient inhibition of platelet aggregation, and motor function was improved by cilostazol treatment. Blood-brain barrier permeability was increased by collagenase-induced intracranial hemorrhage, and cilostazol attenuated blood-brain barrier leakage. Terminal deoxynucleotidyl transferase dUTP nick-end labeling and western blot analysis showed that cilostazol prevented pericyte cell death by inducing cyclic adenosine monophosphate-responsive element-binding protein phosphorylation. Cilostazol also prevented endothelial cell death and protected collagen type 4, laminin, and vascular endothelial- and N-cadherins from collagenase injury. In conclusion, cilostazol reduced collagenase-induced intracranial hemorrhage volume by protecting the blood-brain barrier.

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“…Saito et al found that cilostazol attenuated HSC proliferation, collagen‐I and hydroxyproline, and α‐SMA levels increased by carbon tetrachloride indicating the antifibrotic potential of cilostazol. Takeshita and his colleagues found that cilostazol inhibited TGF‐β1 signaling in brain ischemia reperfusion injury, maintained blood–brain barrier integrity and prevented neurofibrotic changes. Addition of SIRT1 inhibitor suppressed the antifibrotic effects of cilostazol.…”

Section: Discussionmentioning

confidence: 98%

Beneficial effects of cilostazol on liver injury induced by common bile duct ligation in rats: Role of SIRT1 signaling pathway

Kabil

2018

Clin Exp Pharma Physio

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Liver fibrosis is a health challenge requiring alternative therapeutic approaches. Cilostazol is a selective phosphodiesterase-3 inhibitor and possesses antioxidant, anti-inflammatory and antifibrotic properties. Sirtuin 1 (SIRT1) is a member of the silent information regulator 2 family. Cilostazol upregulates SIRT1 expression. Cilostazol protects against the cholestatic liver insults caused by bile duct obstruction. Involvement of SIRT1 pathway in this protective effect has not been studied yet. So, we hypothesized that SIRT1 signaling may have a role in cilostazol protective effects against bile duct ligation-induced liver damages. Rats were subjected to common bile duct ligation then treated with cilostazol (9 mg/kg or 27 mg/kg) in the presence or absence of specific SIRT1 inhibitor EX527. Cilostazol improved liver function, reduced inflammation, enhanced antioxidant status, ameliorated cholestatic liver injury and upregulated hepatic SIRT1. However, these protective effects were abrogated by EX527, suggesting that SIRT1 signaling may have a role in these effects. In conclusion, cilostazol in a dose-dependent way produced hepatoprotective effects via anti-inflammatory, antioxidant, antifibrotic effects which were mediated, in part, through SIRT1 upregulation.

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Cilostazol attenuates ischemia–reperfusion-induced blood–brain barrier dysfunction enhanced by advanced glycation endproducts via transforming growth factor-β1 signaling

Cited by 30 publications

References 54 publications

The pivotal role of astrocytes in an in vitro stroke model of the blood-brain barrier

The pivotal role of astrocytes in an in vitro stroke model of the blood-brain barrier

Cilostazol ameliorates collagenase-induced cerebral hemorrhage by protecting the blood–brain barrier

Beneficial effects of cilostazol on liver injury induced by common bile duct ligation in rats: Role of SIRT1 signaling pathway

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