Cilostazol improves hippocampus-dependent long-term memory in mice

Yanai, Shuichi; Semba, Yuki; Ito, Hideki; Endo, Shogo

doi:10.1007/s00213-014-3442-4

Cited by 25 publications

(17 citation statements)

References 75 publications

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“…These results were consistent with the reduction of Aβ aggregation observed in N2aSwe cells and improvement of spatial learning and memory detected in Aβ 25-35 -injected mice [92]. While the aforementioned studies assessed cilostazol for its cognitive enhancing properties, Yanai et al were interested in understanding the effect of this PDE3 inhibitor on memory function [91]. To this end, the effect of cilostazol on wild-type C57BL/6J mice as they perform various behavioral tasks was examined.…”

Section: Phosphodiesterase 3 Inhibitorssupporting

confidence: 63%

“…Recent studies have demonstrated that certain PDE inhibitors ameliorate memory impairment or enhance cognitive functions in rodent models. Examples include inhibitors of PDE2 (BAY60-7550, [88][89][90]), PDE3 (cilostazol, [91][92][93]), and PDE5 (sildenafil, [19,94]). Herein, a list of well-studied cGMP-degrading PDE inhibitors that modulate the NO/cGMP/ CREB signaling pathway and their effects on learning and memory is presented.…”

Section: Phosphodiesterase Inhibitorsmentioning

confidence: 99%

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Targeting the NO/cGMP/CREB Phosphorylation Signaling Pathway in Alzheimer’s Disease

Fiorito¹,

Deng²,

Landry³

et al. 2019

Neurochemical Basis of Brain Function and Dysfunction

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Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common form of senile dementia. Recently, scientists have put significant effort into exploring the molecular mechanisms involved in the pathological processes leading to the disease. A vast number of studies have focused on understanding the nitric oxide (NO) signaling pathway, which culminates with the phosphorylation of the transcription factor cAMP-responsive element-binding protein (CREB) through the increase of the second messenger cyclic guanosine monophosphate (cGMP) and activation of cGMP-dependent protein kinase. This book chapter provides an overview of the progress being made in modulating the hippocampal synaptic transmissions, which are critical for learning and memory, by targeting the different components of the NO/cGMP/CREB phosphorylation signaling pathway. Furthermore, a description of recent research on this pathway through the use of phosphodiesterase inhibitors is emphasized.

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Section: Phosphodiesterase 3 Inhibitorssupporting

confidence: 63%

Section: Phosphodiesterase Inhibitorsmentioning

confidence: 99%

Targeting the NO/cGMP/CREB Phosphorylation Signaling Pathway in Alzheimer’s Disease

Fiorito¹,

Deng²,

Landry³

et al. 2019

Neurochemical Basis of Brain Function and Dysfunction

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show abstract

“…Yanai et al demonstrated that Cilostazol enhanced context-dependent long-term fear memory in mice by utilizing the, “Morris water maze probe test” (MWM). In their study, Cilostazol notably improved the number of phosphorylated-CREB-positive cells in the mouse hippocampal dentate gyrus, reflecting the effects of this PDE3 inhibitor on memory and learning through increasing intracellular cyclic AMP in the hippocampus [257]. A study by Hiramatsu et al revealed the effects of Cilostazol on amyloid β peptide (25–35)-induced memory impairment in mice.…”

Section: The Utility Of Pde Inhibitors For Neuroprotection and Neumentioning

confidence: 99%

Phosphodiesterase Inhibitors as a Therapeutic Approach to Neuroprotection and Repair

Knott

Assi

Rao

et al. 2017

IJMS

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A wide diversity of perturbations of the central nervous system (CNS) result in structural damage to the neuroarchitecture and cellular defects, which in turn are accompanied by neurological dysfunction and abortive endogenous neurorepair. Altering intracellular signaling pathways involved in inflammation and immune regulation, neural cell death, axon plasticity and remyelination has shown therapeutic benefit in experimental models of neurological disease and trauma. The second messengers, cyclic adenosine monophosphate (cyclic AMP) and cyclic guanosine monophosphate (cyclic GMP), are two such intracellular signaling targets, the elevation of which has produced beneficial cellular effects within a range of CNS pathologies. The only known negative regulators of cyclic nucleotides are a family of enzymes called phosphodiesterases (PDEs) that hydrolyze cyclic nucleotides into adenosine monophosphate (AMP) or guanylate monophosphate (GMP). Herein, we discuss the structure and physiological function as well as the roles PDEs play in pathological processes of the diseased or injured CNS. Further we review the approaches that have been employed therapeutically in experimental paradigms to block PDE expression or activity and in turn elevate cyclic nucleotide levels to mediate neuroprotection or neurorepair as well as discuss both the translational pathway and current limitations in moving new PDE-targeted therapies to the clinic.

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“…In support of this, clearance of fluorescent soluble Aβ tracers is significantly enhanced in cilostazol-treated CAA model mice, thereby resulting in maintenance of vascular integrity, amelioration of Aβ deposits (Figure 4 ), and prevention of cognitive decline (Maki et al, 2014 ). Memory-preserving activity of cilostazol has been demonstrated in aged wild-type mice (Yanai et al, 2014 ) and a rat model of chronic cerebral hypoperfusion (Watanabe et al, 2006 ), suggesting that cilostazol could be a potential disease modifying therapy of AD and other dementing disorders.…”

Section: Convincing Effects Of Phosphodiesterase Inhibitormentioning

confidence: 99%

New Therapeutic Approaches for Alzheimerâ€™s Disease and Cerebral Amyloid Angiopathy

Saitô

Ihara

2014

Front. Aging Neurosci.

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Accumulating evidence has shown a strong relationship between Alzheimer’s disease (AD), cerebral amyloid angiopathy (CAA), and cerebrovascular disease. Cognitive impairment in AD patients can result from cortical microinfarcts associated with CAA, as well as the synaptic and neuronal disturbances caused by cerebral accumulations of β-amyloid (Aβ) and tau proteins. The pathophysiology of AD may lead to a toxic chain of events consisting of Aβ overproduction, impaired Aβ clearance, and brain ischemia. Insufficient removal of Aβ leads to development of CAA and plays a crucial role in sporadic AD cases, implicating promotion of Aβ clearance as an important therapeutic strategy. Aβ is mainly eliminated by three mechanisms: (1) enzymatic/glial degradation, (2) transcytotic delivery, and (3) perivascular drainage (3-“d” mechanisms). Enzymatic degradation may be facilitated by activation of Aβ-degrading enzymes such as neprilysin, angiotensin-converting enzyme, and insulin-degrading enzyme. Transcytotic delivery can be promoted by inhibition of the receptor for advanced glycation end products (RAGE), which mediates transcytotic influx of circulating Aβ into brain. Successful use of the RAGE inhibitor TTP488 in Phase II testing has led to a Phase III clinical trial for AD patients. The perivascular drainage system seems to be driven by motive force generated by cerebral arterial pulsations, suggesting that vasoactive drugs can facilitate Aβ clearance. One of the drugs promoting this system is cilostazol, a selective inhibitor of type 3 phosphodiesterase. The clearance of fluorescent soluble Aβ tracers was significantly enhanced in cilostazol-treated CAA model mice. Given that the balance between Aβ synthesis and clearance determines brain Aβ accumulation, and that Aβ is cleared by several pathways stated above, multi-drugs combination therapy could provide a mainstream cure for sporadic AD.

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Cilostazol improves hippocampus-dependent long-term memory in mice

Abstract: These results suggest that cilostazol may exert its beneficial effects on learning and memory by enhancing the cAMP system in hippocampus, where it increases intracellular cAMP activity.

Cited by 25 publications

References 75 publications

Targeting the NO/cGMP/CREB Phosphorylation Signaling Pathway in Alzheimer’s Disease

Targeting the NO/cGMP/CREB Phosphorylation Signaling Pathway in Alzheimer’s Disease

Phosphodiesterase Inhibitors as a Therapeutic Approach to Neuroprotection and Repair

New Therapeutic Approaches for Alzheimerâ€™s Disease and Cerebral Amyloid Angiopathy

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