Effect Of Cilostazol Research Articles

Design and Rationale of the Intima-Medial Thickness Sub-Study of the PreventIon of CArdiovascular Events in iSchemic Stroke Patients with High Risk of Cerebral hemOrrhage (PICASSO-IMT) Study

Atherosclerosis is one of the main mechanisms of stroke and cardiovascular diseases and is associated with increased risk of recurrent stroke and cardiovascular events. Intima-medial thickness (IMT) is a well-known surrogate marker of atherosclerosis and has been used to predict stroke and cardiovascular events. However, the clinical significance of IMT and IMT change in stroke has not been investigated in well-designed studies. The PreventIon of CArdiovascular events in iSchemic Stroke patients with high risk of cerebral hemOrrhage-Intima-Media Thickness (PICASSO-IMT) sub-study is designed to investigate the effects of cilostazol, probucol, or both on IMT in patients with stroke. PICASSO-IMT is a prospective sub-study of the PICASSO study designed to measure IMT and plaque score at 1, 13, 25, 37, and 49 months after randomization. The primary outcome is the change in mean carotid IMT, which is defined as the mean of the far-wall IMTs of the right and left common carotid arteries, between baseline and 13 months after randomization. PICASSO-IMT will provide the largest IMT data set in a stroke population and will provide valuable information about the clinical significance of IMT in patients with ischemic stroke.

Effects of Cilostazol and Diltiazem Hydrochloride on Ischemia-Reperfusion Injury in a Rat Hindlimb Model.

Free radicals and neutrophils are potent sources of ischemia-reperfusion injury (I/R) and they can be limited by the use of exogenous application of some therapeutic agents. The objective of this study was to compare the effects of cilostazol and diltiazem hydrochloride in a rat hind limb model of I/R injury.Methods: Skeletal muscles submitted to 2 hours of ischemia by placing an aneurysm clip to femoral artery and reperfused after 1, 2 and 4 hours. Seventy-two Wistar-Albino rats were randomly divided into mainly four groups according to treatment agents: Group I (control group) was treated with saline; Group II was treated with diltiazem hydrochloride; Group III was treated with cilostazol in 30% dimethyl sulphoxide; and Group IV was treated with 30% dimethyl sulphoxide intraperitoneally. These four main groups also subdivided into three subgroups according to duration of the reperfusion times. Blood samples were taken and all rats were sacrificed.Results: Cilostazol-treated groups demonstrated a significant decrease in tissue and serum malondialdehyde (MDA) levels, and tissue myeloperoxidase (MPO ) activity compared with other groups. Increase in serum nitric oxide (NOx) level was significantly higher in all subgroups of cilastazol, diltiazem hydrochloride, and dimethyl sulphoxide groups versus the control group. Although these results suggest the beneficial effects of cilostazol and diltiazem hydrochloride on I/R injury, the effect of cilostazol on I/R injury seems to be more efficient than diltiazem hydrochloride.

Investigation the effects of cilostazol and rosuvastatin on kidney and heart: An experimental acute kidney and heart injury model

Investigation the effects of cilostazol and rosuvastatin on kidney and heart: An experimental acute kidney and heart injury model

873 The effect of Cilostazol on hair growth: A novel therapeutic option for the treatment of hair loss

873 The effect of Cilostazol on hair growth: A novel therapeutic option for the treatment of hair loss

Effect of cilostazol in treating diabetes-associated microvascular complications.

Cilostazol (Pletal), a phosphodiesterase-3 inhibitor, was approved in the United States in 1999 to reduce symptoms of intermittent claudication. Cyclic adenosine monophosphate levels increase from inhibition of phosphodiesterase resulting in anti-platelet, anti-inflammatory, and vasodilatory effects. Diabetes mellitus is a chronic disease that causes endothelial and platelet dysfunction leading to both microvascular and macrovascular complications. This mini-review highlights the emerging evidence suggesting benefits of using cilostazol in treating microvascular complications associated with diabetes mellitus. A review of literature was conducted using PubMed and Embase databases focusing on cilostazol use in diabetes mellitus. Cilostazol demonstrated renoprotective effects in patients with diabetic nephropathy by reducing serum soluble adhesion molecule-1 and monocyte chemoattractant protein-1. Cilostazol's anti-inflammatory actions predictably attenuate glomerular damage from increased leukocyte adherence. Additionally, cilostazol delayed renal dysfunction secondary to type 2 diabetes mellitus as albuminuria was reduced most likely resulting from inhibition of nuclear factor kappa-induced inflammatory and endothelial markers. Cilostazol's anti-inflammatory actions in addition to its vasodilatory actions relieved retinal hypoxia and decreased excessive production of retinal blood vessels suggesting benefit in diabetic retinopathy. Cilostazol did not improve neuropathy symptom scores signifying that it may not be as beneficial in patients with diabetic peripheral neuropathy without diabetic nephropathy or diabetic retinopathy. Cilostazol's pleiotropic effects may be beneficial in patients with type 2 diabetes mellitus and diabetic nephropathy. Additional, larger studies need to be conducted to assess the benefits and risks of using cilostazol as an alternative agent in treating patients with diabetic microvascular complications.

Oral administration of cilostazol improves survival rate after rat liver ischemia/reperfusion injury

BackgroundCilostazol is a type III phosphodiesterase inhibitor used to treat the symptoms of intermittent claudication. Recent studies have shown that cilostazol decreases ischemia/reperfusion (I/R) injury in several organs. Materials and methodsWe evaluated the effects of cilostazol in a rat model of liver I/R injury. Thirty male Wistar rats with liver I/R injury were divided into a cilostazol or saline (control) group (n = 15 each). Each rat was orally administered cilostazol or saline for 3 d before I/R injury. Liver I/R injury was induced via 1 h of warm ischemia of the median and left lateral liver lobes, followed by 3 h of reperfusion. The rats were then euthanized. Serum aspartate aminotransferase, alanine aminotransferase, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α levels were measured. The Mann–Whitney U test was used to compare the differences between the treatment groups. Histologic examination was performed on the liver tissues. We also conducted a survival study to confirm the effect of cilostazol on the mortality rate in rats. For the survival study, a liver I/R injury model with an ischemia time of 1.5 h was used, and the rats were observed for 1 wk. ResultsSerum aspartate aminotransferase, alanine aminotransferase, IL-1β, and IL-6 levels were significantly lower in the cilostazol group than in the saline group. Treatment with cilostazol significantly improved pathological findings associated with liver I/R injury and increased survival rate compared to that in controls. ConclusionsCilostazol reduced mortality and alleviated the effects of liver I/R injury in Wistar rats.

Cilostazol induces C-fos expression in the trigeminal nucleus caudalis and behavioural changes suggestive of headache with the migraine-like feature photophobia in female rats.

Introduction Research in development of new migraine therapeutics is hindered by the lack of suitable, predictive animal models. Cilostazol provokes headache in healthy humans and migraineurs by increasing intracellular cAMP levels. We aimed to investigate whether cilostazol could provoke headache-like behaviours and c-fos expression in rats. In order to evaluate the predictive validity of the model, we examined the response to the migraine specific drug sumatriptan. Methods The effect of cilostazol (125 mg/kg p.o.) in female Sprague Dawley rats was evaluated on a range of spontaneous behavioural parameters, light sensitivity and mechanical sensitivity thresholds. We also measured c-fos expression in the trigeminal nucleus caudalis. Results Cilostazol increased light sensitivity and grooming behaviour. These manifestations were not inhibited by sumatriptan. Cilostazol also induced c-fos expression in the trigeminal nucleus caudalis. Furthermore, trigeminal - but not hind paw hyperalgesia was observed. Conclusion The altered behaviours are suggestive of cilostazol induced headache with migraine-like features, but not specific. The presence of head specific hyperalgesia and the c-fos response in the trigeminal nucleus caudalis imply that the model involves trigeminal nociception. The model will be useful for studying mechanisms related to the cAMP pathway in headache, but its predictive properties appear to be more limited due to the lack of response to sumatriptan.

Amelioration of high fat diet-induced nephropathy by cilostazol and rosuvastatin.

Multiple comorbidities of metabolic disorders are associated with facilitated chronic kidney disease progression. Anti-platelet cilostazol is used for the treatment of peripheral artery disease. In this study, we investigated the potential beneficial effects of cilostazol and rosuvastatin on metabolic disorder-induced renal dysfunctions. C57BL/6 mice that received high fat diet (HFD) for 22weeks and a low dose of streptozotocin (STZ, 40mg/kg) developed albuminuria and had increased urinary cystatin C excretion, and cilostazol treatment (13weeks) improved these markers. Histopathological changes, including glomerular mesangial expansion, tubular vacuolization, apoptosis, and lipid accumulation were ameliorated by cilostazol treatment. Tubulointerstitial fibrosis that was indicated by the increases in collagen and transforming growth factor-β1 subsided by cilostazol. Renoprotective effects were also observed in rosuvastatin-treated mice, and combinatorial treatment with cilostazol and rosuvastatin demonstrated enhanced ameliorative effects in histopathological evaluations. Notably, repressed renal heme oxygenase-1 (Ho-1) level in HFD/STZ mice was restored in cilostazol group. Further, we demonstrated that cilostazol enhanced Nrf2/Ho-1 signaling in cultured proximal tubular epithelial cells. Collectively, these results suggest the potential advantageous use of cilostazol as an adjunctive therapy with statins for the amelioration of metabolic disorder-associated renal injury.

Oral Administration of Cilostazol Increases Ocular Blood Flow in Patients with Diabetic Retinopathy

PurposeTo investigate the effect of cilostazol on ocular hemodynamics and to determine whether the administration of cilostazol increases the ocular blood flow in patients with diabetic retinopathy.MethodsThis prospective observational study investigated the effect of orally administered cilostazol on diabetic retinopathy. Before and after administration for 1 week, pulsatile ocular blood flow (POBF) and retrobulbar hemodynamics were measured using a POBF analyzer and transcranial Doppler imaging, respectively. Visual acuity, intraocular pressure, and blood pressure were also evaluated before and after treatment.ResultsTwenty-five eyes of 25 patients were included in this study. POBF increased significantly (16.8 ± 4.6 µL/sec vs. 19.6 ± 6.2 µL/sec, p < 0.001) after administration of cilostazol, while no significant change was identified in visual acuity, intraocular pressure, and blood pressure. Mean flow velocity in the ophthalmic artery as measured with transcranial Doppler imaging also increased significantly after medication (23.5 ± 5.6 cm/sec vs. 26.0 ± 6.9 cm/sec, p = 0.001). The change in POBF directly correlated with the change in mean flow velocity (r = 0.419, p = 0.007).ConclusionsCilostazol was effective in increasing ocular blood flow in patients with diabetic retinopathy, possibly by modulating retrobulbar circulation.

Reduction of MMP-9 and MIF Levels is Associated with the Beneficial Effects of Cilostazol in the Patients with Silent Brain Infarcts

Silent brain infarcts (SBIs) are cerebral infarcts seen on brain computed tomography (CT) or magnetic resonance imaging (MRI) in the absence of any clinical symptoms of stroke. In a previous study, cilostazol was shown to prevent the appearance or progression of SBIs. The present study aimed to evaluate the possible mechanisms of cilostazol in its beneficial effects on patients with SBIs by serially measuring inflammation- and angiogenesisassociated biomarkers such as matrix metalloproteinase-9 (MMP-9), macrophage migration inhibitory factor(MIF), visceral fat–derived adipokine (visfatin), C-X-C motif ligand 12 (CXCL12), and vascular endothelial growth factor (VEGF). We consecutively enrolled 26 patients with SBIs. SBIs were interpreted by two neuroradiologists and two neurologists. MMP-9, MIF, visfatin, CXCL12, and VEGF were measured in fasting blood samples from these 26 patients and 10 healthy volunteers at baseline and after taking cilostazol (200 mg/day) for one week and for 3 months. Serum MMP-9 was higher in patients with SBIs than in healthy controls at baseline (p<0.05), and levels of MMP-9 and MIF decreased after taking cilostazol for 3 months (p<0.01). MMP-9 levels were also lower at 1 week in the cilostazol group (p<0.05). Cilostazol had no significant effect on the other inflammatory biomarkers such as visfatin, CXCL12 and VEGF. Cilostazol decreases the inflammatory biomarkers MMP-9 and MIF in patients with SBIs and it may contribute to its beneficial effects in these patients.

Cilostazol에 의한 뇌혈관내피세포의 세포이동 증진 효과연구

Cilostazol is known to be a selective inhibitor of phosphodiesterase III and is generally used to treat stroke. Our previous findings showed that cilostazol enhanced capillary density through angiogenesis after focal cerebral ischemia. Angiogenesis is an important physiological process for promoting revascularization to overcome tissue ischemia. It is a multistep process consisting of endothelial cell proliferation, migration, and tubular structure formation. Here, we examined the modulatory effect of cilostazol at each step of the angiogenic mechanism by using human brain microvascular endothelial cells (HBMECs). We found that cilostazol increased the migration of HBMECs in a dose-dependent manner. However, it did not enhance HBMEC proliferation and capillary-like tube formation. We used a cDNA microarray to analyze the mechanisms of cilostazol in cell migration. We picked five candidate genes that were potentially related to cell migration, and we confirmed the gene expression levels by real-time PCR. The genes phosphoserine aminotransferase 1 (PSAT1) and CCAAT/enhancer binding protein β (C/EBPβ) were up-regulated. The genes tissue factor pathway inhibitor 2 (TFPI2), retinoic acid receptor responder 1 (RARRES1), and RARRES3 were down-regulated. Our observations suggest that cilostazol can promote angiogenesis by promoting endothelial migration. Understanding the cilostazol-modulated regulatory mechanisms in brain endothelial cells may help stimulate blood vessel formation for the treatment of ischemic diseases.

Te Comparison of the Effects of the Cilostazol on the Stiffness Parameters in Different Arterial Systems in the Patients with Peripheral Arterial Disease

Objective : Object of this study is to determine the effect of cilostazol on arterial compliance, distensibilty and vascular stiffness in carotid, femoral and brachial arteries through non-invasive methods in patients with stable IC/PAD. Material and Methods: Twenty-nine patients (22 male, 7 female) who had been treated with cilostazol 100 mg twice daily during six month were included in the study. Ultrasound measurements of carotid, femoral and brachial arteries were performed at baseline, at 3 and 6 months afer starting of treatment and the evaluation of the arterial stiffness measurements were performed by the pre-defned method. Results : Te mean age of the participants was 64 years. Pulsatility index, resistive index, systolic/diastolic velocity ratio, intima-media thickness and elastic modulus values were decreased while cross-sectional compliance, cross-sectional distensibility and diastolic wall stress values were increased with treatment in carotid, femoral and brachial arteries. Carotid, femoral and brachial arteries have similar rates of change. Conclusion : Cilostazol treatment reduced the progression of atherosclerosis without increasing the risk of bleeding in patients with peripheral arterial disease during a long-term follow-up

Cilostazol and enzymatically modified isoquercitrin attenuate experimental colitis and colon cancer in mice by inhibiting cell proliferation and inflammation

We previously reported the anti-inflammatory effects of cilostazol, a selective inhibitor of phosphodiesterase 3, and two antioxidants, enzymatically modified isoquercitrin and α-lipoic acid in a dextran sodium sulphate-induced colitis mouse model. We further examined the chemopreventive effects of these substances in a murine azoxymethane/dextran sodium sulphate -induced colorectal carcinoma model and compared the effects with those of the well-known anticancer natural plant pigment, anthocyanin. In addition, the effects on cell proliferation activity were evaluated in colon cancer cell lines and mucosal epithelial cells in a model of acute dextran sodium sulphate-induced colitis. Cilostazol and enzymatically modified isoquercitrin improved the outcome of azoxymethane/dextran sodium sulphate-induced colorectal cancer along with anthocyanin though inhibiting inflammation and cell proliferation, but the effect of α-lipoic acid was minimal. Inhibition of cell proliferation by cilostazol was confirmed in vitro. In the acute dextran sodium sulphate-induced colitis model, cilostazol and enzymatically modified isoquercitrin prevented the decrease in epithelial proliferative cells. These results indicate that cilostazol and enzymatically modified isoquercitrin first exhibited an anti-dextran sodium sulphate effect at the initial stage of colitis and then showed antitumour effects throughout subsequent inflammation-related cancer developmental stages.

Cilostazol protects against microvascular brain injury in a rat model of type 2 diabetes

Cilostazol, a pluripotent phosphodiesterase III-specific inhibitor with anti-platelet and vasculogenic effects, is useful for preventing recurrent brain vascular events, particularly in stroke patients with diabetes mellitus (DM). However, it is unclear whether cilostazol affects autoregulatory responses in small cerebral arteries. Thus, we investigated the effect of cilostazol on diabetic brain vasculopathy in a model of type II DM using male OLETF rats. OLETF rats were treated with either cilostazol (CG) or vehicle (VG) and subjected to microangiography with monochromatic synchrotron radiation to investigate middle cerebral artery (MCA) vasoreactivity following an injection of acetylcholine (Ach). Ach administration led to MCA diameter contraction in the VG, but MCA dilation in the CG. We also evaluated morphological changes in the small intracranial vessels and found that in the CG, the endothelial cell structure in the small artery was not destroyed. Moreover, protein levels of phosphorylated endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) were higher in each evaluated brain region in CG rats vs. VG rats. Our results suggest that cilostazol could potentially improve autoregulatory responses in the small cerebral arteries by increasing eNOS phosphorylation and VEGF expression in DM, and thus, may act as a neurovascular protectant.

Cilostazol inhibits uremic toxin-induced vascular smooth muscle cell dysfunction: role of Axl signaling.

Chronic kidney disease (CKD) is associated with increased cardiovascular mortality, and vascular smooth muscle cell (VSMC) dysfunction plays a pivotal role in uremic atherosclerosis. Axl signaling is involved in vascular injury and is highly expressed in VSMCs. Recent reports have shown that cilostazol, a phosphodiesterase type 3 inhibitor (PDE3), can regulate various stages of the atherosclerotic process. However, the role of cilostazol in uremic vasculopathy remains unclear. This study aimed to identify the effect of cilostazol in VSMCs in the experimental CKD and to investigate whether the regulatory mechanism occurs through Axl signaling. We investigated the effect of P-cresol and cilostazol on Axl signaling in A7r5 rat VSMCs and the rat and human CKD models. From the in vivo CKD rats and patients, aortic tissue exhibited significantly decreased Axl expression after cilostazol treatment. P-cresol increased Axl, proliferating of cell nuclear antigen (PCNA), focal adhesion kinase (FAK), and matrix metalloproteinase-2 (MMP-2) expressions, decreased caspase-3 expression, and was accompanied by increased cell viability and migration. Cilostazol significantly reversed P-cresol-induced Axl, downstream gene expressions, and cell functions. Along with the increased Axl expression, P-cresol activated PLCγ, Akt, and ERK phosphorylation and cilostazol significantly suppressed the effect of P-cresol. Axl knockdown significantly reversed the expressions of P-cresol-induced Axl-related gene expression and cell functions. Cilostazol with Axl knockdown have additive changes in downstream gene expression and cell functions in P-cresol culture. Both in vitro and in vivo experimental CKD models elucidate a new signal transduction of cilostazol-mediated protection against uremic toxin-related VSMCs dysfunction and highlight the involvement of the Axl signaling and downstream pathways.

The protective effect of cilostazol on transverse rectus abdominis myocutaneous flap in rats

Objective: Transverse Rectus Abdominis Myocutaneous (TRAM) flap is commonly used in breast reconstruction. The aim of this study is to demonstrate the effects of cilostazol on TRAM flap viability in a rat TRAM model.Methods: Twenty-four Wistar rats were used. They were divided into four groups. Rats in Group 1 were applied TRAM flap. In Group 2, cilostazol 30 mg/kg was administered to rats via oral gavage 3 hours before the flap surgery. After the flap surgery, cilostazol 30 mg/kg was administered via oral gavage twice a day for 7 days. In Group 3 before the flap surgery, cilostazol 30 mg/kg was administered via oral gavage twice a day for 7 days, and treatment continued for 7 more days after the flap surgery. In Group 4 before the flap surgery, cilostazol 30 mg/kg was administered via oral gavage twice a day for 7 days and treatment was discontinued after the flap surgery.Result: The mean necrosis rate in Group 1 was 41.69%, in Group 2 it was 27.0%, in Group 3 it was 6.66%, and in Group 4 it was 11.2%. The necrosis rate in Group 1 was found to be statistically significantly higher than other groups (p < .01), the necrosis rate in Group 2 was found to be statistically significant higher than Groups 3 and 4 (p < .01), and the necrosis rate in Group 4 was found to be statistically significant higher than Group 3 (p < .01).Conclusion: Cilostazol treatment seemed to increase the viability of TRAM flap, especially when administered as adjuvant therapy.

Abstract P303: Cilostazol Attenuates Angii-induced Cardiac Fibrosis in Mice

Background: Cilostazol, a phosphodiesterase-3 inhibitor, plays vasoprotective roles such as an improvement of endothelial function, a vasodilatation and a suppression of proliferation of vascular smooth muscle cells. The aim of study was to investigate a cardioprotective effect of cilostazol. Method: Male apolipoprotein E deficient mice (8-12 weeks old) were fed with either normal chow diet or cilostazol-containing (0.1% wt/v) diet. After 1 week of cilostazol administration, mice were infused subcutaneously with either angiotensin II (AngII, 1,000 ng/kg/min, n = 16 - 19) or saline (n = 5 - 6) by osmotic minipumps for 4 weeks. Results: AngII equivalently increased systolic blood pressure, irrespective of cilostazol administration. Cilostazol had no effect on serum cholesterol concentrations, triglycerides, high-density lipoprotein-cholesterol, body weights, heart rates, and systolic blood pressures. AngII increased heart weight but was attenuated by cilostazol administration (6.7±0.8 to 6.0±0.7 mg/gBW, p &lt; 0.05). Cilostazol prevented both perivascular and interstitial cardiac fibrosis induced by AngII (p &lt; 0.05, each). Quantitative real-time PCR revealed that mRNA expressions of Ctgf , Collagen I , Collagen III , Tgf- , Hgf and Spp-1 increased by AngII infusion but were attenuated by cilostazol administration (p &lt; 0.05). Immunohistochemical analysis demonstrated that AngII administration enhanced OPN expression in heart but was suppressed by cilostazol administration. Further, to investigate the mechanism, human cardiac myocytes were cultured and stimulated with AngII (1x10 -7 M). Co-treatment of Cilostazol (1x10 -7 to 1x10 -5 M) attenuated AngII-induced increase of Spp-1 gene expression in dose-dependent manner. This effect was mimic by a treatment with forskolin, which was diminished by co-treatment with H-89. Conclusion: Cilostazol attenuated AngII-induced cardiac fibrosis in vivo. Cilostazol attenuated AngII-induced increment of Spp-1 gene expression through cAMP-PKA dependent pathway.

Cilostazol Effect on Amikacin-Induced Ototoxicity: An Experimental Study

Objectives: To find out the possible protective effect of cilostazol against amikacin-induced ototoxicity. Methods: This study was carried out on 24 adult male rats classified into 4 equal groups of 6 animals each. (1) The control group was administered saline (1 ml/day, p.o.) for 14 days. (2) The amikacin group was administered amikacin (200 mg/kg, i.m.) once daily for 14 days. (3) The cilostazol-amikacin (14 days) group was administered cilostazol (30 mg/kg, p.o.) once daily and amikacin (200 mg/kg, i.m.) once daily for 14 days. (4) The cilostazol (28 days)-amikacin (14 days) group was administered cilostazol (30 mg/kg, p.o.) once daily for 28 days and amikacin (200 mg/kg, i.m.) once daily for 14 days. Changes in the transient evoked otoacoustic emissions (TEOAEs) in the 4 groups were interpreted statistically. Results: No reported significant differences in TEOAE levels were detected between the groups at the start of the study. In all frequency bands, TEOAEs disappeared after amikacin treatment in the amikacin-alone group and remained absent in the amikacin-cilostazol (14 days) group, while TEOAEs reappeared in the amikacin-cilostazol (28 days) group. Conclusion: Cilostazol treatment for 28 days had a protective effect against amikacin-induced ototoxicity in rats.

Cilostazol Modulates Autophagic Degradation of β-Amyloid Peptide via SIRT1-Coupled LKB1/AMPKα Signaling in Neuronal Cells.

A neuroprotective role of autophagy mediates the degradation of β-amyloid peptide (Aβ) in Alzheimer’s disease (AD). The previous study showed cilostazol modulates autophagy by increasing beclin1, Atg5 and LC3-II expressions, and depletes intracellular Aβ accumulation. This study elucidated the mechanisms through which cilostazol modulates the autophagic degradation of Aβ in neurons. In N2a cells, cilostazol (10–30 μM), significantly increased the expression of P-AMPKα (Thr 172) and downstream P-ACC (acetyl-CoA carboxylase) (Ser 79) as did resveratrol (SIRT1 activator), or AICAR (AMPK activator), which were blocked by KT5720, compound C (AMPK inhibitor), or sirtinol. Furthermore, phosphorylated-mTOR (Ser 2448) and phosphorylated-P70S6K (Thr 389) expressions were suppressed, and LC3-II levels were elevated in association with decreased P62/Sqstm1 by cilostazol. Cilostazol increased cathepsin B activity and decreased p62/SQSTM 1, consequently decreased accumulation of Aβ1–42 in the activated N2aSwe cells, and these results were blocked by sirtinol, compound C and bafilomycin A1 (autophagosome blocker), suggesting enhanced autophagosome formation by cilostazol. In SIRT1 gene-silenced N2a cells, cilostazol failed to increase the expressions of P-LKB1 (Ser 428) and P-AMPKα, which contrasted with its effect in negative control cells transfected with scrambled siRNA duplex. Further, N2a cells transfected with expression vectors encoding pcDNA SIRT1 showed increased P-AMPKα expression, which mimicked the effect of cilostazol in N2a cells; suggesting cilostazol-stimulated expressions of P-LKB1 and P-AMPKα were SIRT1-dependent. Unlike their effects in N2a cells, in HeLa cells, which lack LKB1, cilostazol and resveratrol did not elevate SIRT1 or P-AMPKα expression, indicating cilostazol and resveratrol-stimulated expressions of SIRT1 and P-AMPKα are LKB1-dependent. In conclusion, cilostazol upregulates autophagy by activating SIRT1-coupled P-LKB1/P-AMPKα and inhibiting mTOR activation, thereby decreasing Aβ accumulation.

Preventive effects of cilostazol against the development of shunt-dependent hydrocephalus after subarachnoid hemorrhage.

OBJECTIVE Chronic hydrocephalus develops in association with the induction of tenascin-C (TNC), a matricellular protein, after aneurysmal subarachnoid hemorrhage (SAH). The aim of this study was to examine if cilostazol, a selective inhibitor of phosphodiesterase Type III, suppresses the development of chronic hydrocephalus by inhibiting TNC induction in aneurysmal SAH patients. METHODS The authors retrospectively reviewed the factors influencing the development of chronic shunt-dependent hydrocephalus in 87 patients with Fisher Grade 3 SAH using multivariate logistic regression analyses. Cilostazol (50 or 100 mg administered 2 or 3 times per day) was administered from the day following aneurysmal obliteration according to the preference of the attending neurosurgeon. As a separate study, the effects of different dosages of cilostazol on the serum TNC levels were chronologically examined from Days 1 to 12 in 38 SAH patients with Fisher Grade 3 SAH. RESULTS Chronic hydrocephalus occurred in 12 of 36 (33.3%), 5 of 39 (12.8%), and 1 of 12 (8.3%) patients in the 0 mg/day, 100 to 200 mg/day, and 300 mg/day cilostazol groups, respectively. The multivariate analyses showed that older age (OR 1.10, 95% CI 1.13-1.24; p = 0.012), acute hydrocephalus (OR 23.28, 95% CI 1.75-729.83; p = 0.016), and cilostazol (OR 0.23, 95% CI 0.05-0.93; p = 0.038) independently affected the development of chronic hydrocephalus. Higher dosages of cilostazol more effectively suppressed the serum TNC levels through Days 1 to 12 post-SAH. CONCLUSIONS Cilostazol may prevent the development of chronic hydrocephalus and reduce shunt surgery, possibly by the inhibition of TNC induction after SAH.