PDE3 Inhibitors Repurposed as Treatments for Age-Related Cognitive Impairment

  • Shuichi Yanai
  • Shogo EndoEmail author


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.


Phosphodiesterase (PDE) inhibitor Cilostazol Memory Dementia Aging 




amyloid β


Alzheimer’s disease


adenosine triphosphate


blood-brain barrier


brain-derived neurotrophic factor




3′,5′-cyclic adenosine monophosphate


3′,5′-cyclic guanosine monophosphate


central nervous system


cAMP response element


cAMP response element-binding protein


dentate gyrus


mild cognitive impairment




cAMP-dependent-protein kinase A


senescence-accelerated mouse prone


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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