Protective effect of the phosphodiesterase III inhibitor cilostazol on amyloid β-induced cognitive deficits associated with decreased amyloid β accumulation

Park, Sun Haeng; Kim, Ji Hyun; Bae, Sun Sik; Hong, Ki Whan; Lee, Dong‐Seok; Leem, Jae Yoon; Choi, Byung Tae; Shin, Hwa Kyoung

doi:10.1016/j.bbrc.2011.04.068

Cited by 94 publications

(67 citation statements)

References 25 publications

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“…A very recent study showed an improved cognitive function in an Alzheimer disease model mice by decreasing ␤-amyloid accumulation by cilostazol. 7 In the present study, a possible pleiotropic effect of cilostazol resulted in the reduction of spontaneous infarct volume and preservation of motor and spatial cognitive functions. An increase in IGF-1R-positive cells and IGF-1R expression in the hippocampus could also play an important role in preserving spatial cognitive function.…”

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

confidence: 50%

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

confidence: 50%

“…Cilostazol also improved cognitive function for Alzheimer disease in a mouse model. 7 Therefore, in the present study, we first investigated the difference in efficacy of 3 antiplatelet drugs on stroke, motor, and cognitive functions for SHR-SP in relation to oxidative stress markers and insulin-like growth factor 1 receptor (IGF-1R).…”

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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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“…In addition, cilostazol (OPC-13013, 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl) butoxy]-3,4-dihydro-2-(1H)-quinolinone) increases intracellular cAMP levels by inhibiting type 3 phosphodiesterase, and recently, was reported to improve memory impairment induced by an intracerebroventricular injection of Aβ 25–35 in C57BL/6J mice [16]. …”

Section: Introductionmentioning

confidence: 99%

Concurrent Treatment with Taxifolin and Cilostazol on the Lowering of β-Amyloid Accumulation and Neurotoxicity via the Suppression of P-JAK2/P-STAT3/NF-κB/BACE1 Signaling Pathways

et al. 2016

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Taxifolin is a potent flavonoid that exerts anti-oxidative effect, and cilostazol increases intracellular cAMP levels by inhibiting phosphodiesterase 3 that shows antiinflammatory actions. BACE1 (β-site APP cleaving enzyme 1) is the rate-limiting enzyme responsible for the β-cleavage of amyloid precursor proteins to Aβ peptides. In this study, endogenous Aβ and C99 accumulation was explored in N2a Swe cells exposed to 1% FBS medium. Increased Aβ and C99 levels were significantly attenuated by taxifolin alone and in combination with cilostazol. Increased phosphorylated JAK2 at Tyr1007/1008 (P-JAK), phosphorylated STAT3 at Tyr 705 (P-STAT3) expressions and increased expressions of BACE1 mRNA and protein in the activated N2a Swe cells were significantly attenuated by taxifolin (10~50 μM), cilostazol (10~50 μM) alone and in combination at minimum concentrations. In these cells, decreased cytosol IκBα expression was elevated, and increased nuclear NF-κB p65 level and nuclear NF-κB p65 DNA binding activity were significantly reduced by taxifolin and cilostazol in a similar manner. Following STAT3 gene (~70% reduction) knockdown in N2a cells, Aβ-induced nuclear NF-κB and BACE1 expressions were not observed. Taxifolin, cilostazol, or resveratrol significantly stimulated SIRT1 protein expression. In SIRT1 gene-silenced (~50%) N2a cells, taxifolin, cilostazol, and resveratrol all failed to suppress Aβ1-42-stimulated P-STAT3 and BACE1 expression. Consequently, taxifolin and cilostazol were found to significantly decrease lipopolysaccharide (1–10 μg/ml)-induced iNOS and COX-2 expressions, and nitrite production in cultured BV-2 microglia cells and to increase N2a cell viability. In conclusion, taxifolin and cilostazol strongly inhibited amyloidogenesis in a synergistic manner by suppressing P-JAK2/P-STAT3-coupled NF-κB-linked BACE1 expression via the up-regulation of SIRT1.

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“…Increasing evidence suggests that cilostazol offers endothelial protection, via an inhibition of apoptosis in endothelial cells [6], attenuates the phenotypic modulation of vascular smooth muscle cells [7], and sustains blood flow by endothelium-independent vasodilation [8]. Intriguingly, cilostazol has been shown to decrease amyloid β (Aβ) accumulation and protect Aβ-induced cognitive deficits in an experimental model [9], [10]. In a pilot study for 10 patients with moderate Alzheimer's disease (mean Mini-Mental Examination (MMSE) score, 11.9 points) who received donepezil, cilostazol add-on treatment for 5–6 months demonstrated significantly increased MMSE score in comparison to baseline [11].…”

Section: Introductionmentioning

confidence: 99%

Cilostazol Add-On Therapy in Patients with Mild Dementia Receiving Donepezil: A Retrospective Study

et al. 2014

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GoalCombinatorial therapy directed at both vascular and neurodegenerative aspects of dementia may offer a promising strategy for treatment of dementia, which often has a multifactorial basis in the elderly. We investigated whether the phosphodiesterase III inhibitor cilostazol, which is often used in the prevention of stroke and peripheral artery disease, may delay cognitive decline in the elderly receiving donepezil.MethodsMedical records were retrospectively surveyed to identify patients who had received donepezil for more than one year and had undergone Mini-Mental State Examination (MMSE) at least at two time points. Those with an initial MMSE score of less than 27 points were subjected to analysis (n = 156), with a cut-point of 21/22 applied to assign them to mild (n = 70) and moderate/severe (n = 86) dementia. The change of total MMSE score per year was compared between patients who had received donepezil and those given both donepezil and cilostazol.FindingsIn patients with mild dementia who had received donepezil and cilostazol (n = 34; 77.2±6.8 years old), the annual change in MMSE score was −0.5±1.6 during an observational period of 28.6±11.7 months, with those receiving donepezil only (n = 36; 78.4±6.5 years old) scoring less (−2.2±4.1) during 30.4±12.8 months with a statistical intergroup difference (p = 0.022). Multivariate analysis showed that absence of cilostazol treatment was the only significant predictor of MMSE decline. A positive effect of cilostazol was found in three subscale scores of MMSE, orientation for time or place and delayed recall. By clear contrast, in patients with moderate/severe dementia, there were no intergroup differences in decrease of total or subscale MMSE scores between the two groups.ConclusionsThese results suggest potential for cilostazol treatment in the suppression of cognitive decline in patients receiving donepezil with mild dementia but not in those with moderate/severe dementia.

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Protective effect of the phosphodiesterase III inhibitor cilostazol on amyloid β-induced cognitive deficits associated with decreased amyloid β accumulation

Cited by 94 publications

References 25 publications

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

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

Concurrent Treatment with Taxifolin and Cilostazol on the Lowering of β-Amyloid Accumulation and Neurotoxicity via the Suppression of P-JAK2/P-STAT3/NF-κB/BACE1 Signaling Pathways

Cilostazol Add-On Therapy in Patients with Mild Dementia Receiving Donepezil: A Retrospective Study

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