title: Long-term cilostazol administration ameliorates memory decline in senescence-accelerated mouse prone 8 (SAMP8) through a dual effect on cAMP and blood-brain barrier.
abstract: Phosphodiesterases (PDEs), which hydrolyze and inactivate 3', 5'-cyclic adenosine monophosphate (cAMP) and 3', 5'-cyclic guanosine monophosphate (cGMP), play an important role in synaptic plasticity that underlies memory. Recently, several PDE inhibitors were assessed for their possible therapeutic efficacy in treating cognitive disorders. Here, we examined how cilostazol, a selective PDE3 inhibitor, affects brain functions in senescence-accelerated mouse prone 8 (SAMP8), an animal model of age-related cognitive impairment. Long-term administration of cilostazol restored the impaired context-dependent conditioned fear memory of SAMP8 to match that in normal aging control substrain SAMR1. Cilostazol also increased the number of cells containing phosphorylated cAMP-responsive element binding protein (CREB), a downstream component of the cAMP pathway. Finally, cilostazol improves blood-brain barrier (BBB) integrity, demonstrated by reduced extravasation of 2-deoxy-2-18F-fluoro-d-glucose and Evans Blue dye in the brains of SAMP8. This improvement in BBB integrity was associated with an increased amount of zona occludens protein 1 (ZO-1) and occludin proteins, components of tight junctions integral to the BBB. The results suggest that long-term administration of cilostazol exerts its beneficial effects on age-related cognitive impairment through a dual mechanism: by enhancing the cAMP system in the brain and by maintaining or improving BBB integrity.
authors.affiliation: Aging Neuroscience Research Team, Tokyo Metropolitan Institute of Gerontology, Itabashi, Tokyo 173-0015, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Yanai
authors.affiliation: Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Itabashi, Tokyo 173-0015, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Toyohara
authors.affiliation: Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Itabashi, Tokyo 173-0015, Japan; Institute of Cyclotron and Drug Discovery Research, Southern TOHOKU Research Institute for Neuroscience, Koriyama, Fukushima 963-8052, Japan; Department of Biofunctional Imaging, Fukushima Medical University, Fukushima 960-1295, Japan.
authors.forename: Kiichi
authors.initials: K
authors.lastname: Ishiwata
authors.affiliation: Department of CNS Research, Otsuka Pharmaceutical Co., Ltd., Tokushima 771-0192, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Ito
authors.affiliation: Aging Neuroscience Research Team, Tokyo Metropolitan Institute of Gerontology, Itabashi, Tokyo 173-0015, Japan. Electronic address: sendo@tmig.or.jp.
authors.forename: Shogo
authors.initials: S
authors.lastname: Endo
mesh_terms: D000375:Aging / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000523:psychology; D000679:Amygdala / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D000077407:Cilostazol; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D018891:Dentate Gyrus / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005239:Fear / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D018697:Nootropic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D013777:Tetrazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D018697:Nootropic Agents; D013777:Tetrazoles; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; D000242:Cyclic AMP; D005947:Glucose; D000077407:Cilostazol
keywords: (18)F-FDG PET; BBB; CREB phosphorylation; Cilostazol; Memory; Senescence-accelerated mouse (SAM); cilostazol (PubChem ID: 2754)