Long-term cilostazol administration prevents age-related decline of hippocampus-dependent memory in mice

Yanai, Shuichi; Ito, Hideki; Endo, Shogo

doi:10.1016/j.neuropharm.2017.11.008

Cited by 13 publications

(27 citation statements)

References 126 publications

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“…The effect of light condition on center time is not replicable in previous studies using aged mice (Yanai et al, 2018;Yanai & Endo, 2021). This inconsistency of behavior might be something to do with aging, further examination is required to validate center time in our experimental condition.…”

Section: Open Field Testmentioning

confidence: 56%

“…The delay between the conditioning and the first test was 1 h (short-term memory), and the delay for the second test was 24 h (long-term memory). Despite the age-related hearing loss reported in C57BL/6J mice (Yu et al, 2011), aged mice show significant conditioned fear in our protocol (Yanai et al, 2018;Yanai & Endo, 2021). Finally, long-term contextual fear memory was tested at a delay of 48 h.…”

Section: Pavlovian Fear Conditioning Taskmentioning

confidence: 94%

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Reversal of spatial memory impairment by phosphodiesterase 3 inhibitor cilostazol is associated with reduced neuroinflammation and increased cerebral glucose uptake in aged male mice

et al. 2022

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The nucleotide second messenger 3′, 5′-cyclic adenosine monophosphate (cAMP) and 3′, 5′-cyclic guanosine monophosphate (cGMP) mediate fundamental functions of the brain, including learning and memory. Phosphodiesterase 3 (PDE3) can hydrolyze both cAMP and cGMP and appears to be involved in the regulation of their contents in cells. We previously demonstrated that long-term administration of cilostazol, a PDE3 inhibitor, maintained good memory performance in aging mice. Here, we report on studies aimed at determining whether cilostazol also reverses already-impaired memory in aged male mice. One month of oral 1.5% cilostazol administration in 22-month-old mice reversed age-related declines in hippocampus-dependent memory tasks, including the object recognition and the Morris water maze. Furthermore, cilostazol reduced neuroinflammation, as evidenced by immunohistochemical staining, and increased glucose uptake in the brain, as evidence by positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG). These results suggest that already-expressed memory impairment in aged male mice that depend on cyclic nucleotide signaling can be reversed by inhibition of PDE3. The reversal of age-related memory impairments may occur in the central nervous system, either through cilostazol-enhanced recall or strengthening of weak memories that otherwise may be resistant to recall.

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Section: Open Field Testmentioning

confidence: 56%

Section: Pavlovian Fear Conditioning Taskmentioning

confidence: 94%

Reversal of spatial memory impairment by phosphodiesterase 3 inhibitor cilostazol is associated with reduced neuroinflammation and increased cerebral glucose uptake in aged male mice

et al. 2022

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“…Swim speed during acquisition training was also age-dependent, as indicated by a significant main effect of age ( Figure 7C ; F [4,112] = 6.814, p < 0.001) and post hoc tests. Considering that swim speeds become slower in an age-dependent manner, the use of swimming distance to evaluate spatial learning ability is appropriate ( Yanai and Endo, 2016 ; Yanai et al, 2018 ).…”

Section: Resultsmentioning

confidence: 99%

“…Spatial memory was also tested in the Morris water maze task ( Morris, 1981 ; Morris et al, 1982 ), which shares some features of the Barnes maze. The water maze task was conducted as described previously ( Yanai et al, 2014 , 2018 ; Takahashi et al, 2019 ). During acquisition training, individual mice were allowed to swim freely for a maximum of 60 s in the pool (100 cm in diameter) to find the submerged escape platform.…”

Section: Methodsmentioning

confidence: 99%

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Functional Aging in Male C57BL/6J Mice Across the Life-Span: A Systematic Behavioral Analysis of Motor, Emotional, and Memory Function to Define an Aging Phenotype

Yanai

Endo

2021

Front. Aging Neurosci.

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100

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Aging is characterized generally by progressive and overall physiological decline of functions and is observed in all animals. A long line of evidence has established the laboratory mouse as the prime model of human aging. However, relatively little is known about the detailed behavioral and functional changes that occur across their lifespan, and how this maps onto the phenotype of human aging. To better understand age-related changes across the life-span, we characterized functional aging in male C57BL/6J mice of five different ages (3, 6, 12, 18, and 22 months of age) using a multi-domain behavioral test battery. Spatial memory and physical activities, including locomotor activity, gait velocity, and grip strength progressively declined with increasing age, although at different rates; anxiety-like behaviors increased with aging. Estimated age-related patterns showed that these functional alterations across ages are non-linear, and the patterns are unique for each behavioral trait. Physical function progressively declines, starting as early as 6 months of age in mice, while cognitive function begins to decline later, with considerable impairment present at 22 months of age. Importantly, functional aging of male C57BL/6J mouse starts at younger relative ages compared to when it starts in humans. Our study suggests that human-equivalent ages of mouse might be better determined on the basis of its functional capabilities.

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PDE3 Inhibitors Repurposed as Treatments for Age-Related Cognitive Impairment

Yanai

Endo

2018

Mol Neurobiol

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Long-term cilostazol administration prevents age-related decline of hippocampus-dependent memory in mice

Cited by 13 publications

References 126 publications

Reversal of spatial memory impairment by phosphodiesterase 3 inhibitor cilostazol is associated with reduced neuroinflammation and increased cerebral glucose uptake in aged male mice

Reversal of spatial memory impairment by phosphodiesterase 3 inhibitor cilostazol is associated with reduced neuroinflammation and increased cerebral glucose uptake in aged male mice

Functional Aging in Male C57BL/6J Mice Across the Life-Span: A Systematic Behavioral Analysis of Motor, Emotional, and Memory Function to Define an Aging Phenotype

PDE3 Inhibitors Repurposed as Treatments for Age-Related Cognitive Impairment

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