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PDE3 Inhibitors Repurposed as Treatments for Age-Related Cognitive Impairment

  • Shuichi Yanai
  • Shogo Endo
Article

Abstract

As the population of older individuals grows worldwide, researchers have increasingly focused their attention on identifying key molecular targets of age-related cognitive impairments, with the aim of developing possible therapeutic interventions. Two such molecules are the intracellular cyclic nucleotides, cAMP and cGMP. These second messengers mediate fundamental aspects of brain function relevant to memory, learning, and cognitive function. Consequently, phosphodiesterases (PDEs), which hydrolyze cAMP and cGMP, are promising targets for the development of cognition-enhancing drugs. Inhibitors that target PDEs work by elevating intracellular cAMP. In this review, we provide an overview of different PDE inhibitors, and then we focus on pharmacological and physiological effects of PDE3 inhibitors in the CNS and peripheral tissues. Finally, we discuss findings from experimental and preliminary clinical studies and the potential beneficial effects of the PDE3 inhibitor cilostazol on age-related cognitive impairments. In the innovation pipeline of pharmaceutical development, the antiplatelet agent cilostazol has come into the spotlight as a novel treatment for mild cognitive impairment. Overall, the repurposing of cilostazol may represent a potentially promising way to treat mild cognitive impairment, Alzheimer’s disease, and vascular dementia. In this review, we present a brief summary of cAMP signaling and different PDE inhibitors, followed by a discussion of the pharmacological and physiological role of PDE3 inhibitors. In this context, we discuss the repurposing of a PDE3 inhibitor, cilostazol, as a potential treatment for age-related cognitive impairment based on recent research.

Keywords

Phosphodiesterase (PDE) inhibitor Cilostazol Memory Dementia Aging 

Abbreviations

AChE

acetylcholinesterase

amyloid β

AD

Alzheimer’s disease

ATP

adenosine triphosphate

BBB

blood-brain barrier

BDNF

brain-derived neurotrophic factor

BChE

butyrylcholinesterase

cAMP

3′,5′-cyclic adenosine monophosphate

cGMP

3′,5′-cyclic guanosine monophosphate

CNS

central nervous system

CRE

cAMP response element

CREB

cAMP response element-binding protein

DG

dentate gyrus

MCI

mild cognitive impairment

PDE

phosphodiesterase

PKA

cAMP-dependent-protein kinase A

SAMP

senescence-accelerated mouse prone

Notes

Funding Information

This work was supported in part by the Japan Foundation of Aging and Health, the Naito Foundation, and JSPS KAKENHI (24730642, 25560382, 26115532, 15H03103, 18K07460).

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Aging Neuroscience Research TeamTokyo Metropolitan Institute of GerontologyTokyoJapan

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