Cilostazol but not sildenafil prevents memory impairment after chronic cerebral hypoperfusion in middle-aged rats

Godinho, Jacqueline; Oliveira, Janaina Nicolau de; Ferreira, Emilene Dias Fiuza; Zaghi, Gislene Gonçalves Dias; Bacarin, Cristiano Correia; Oliveira, Rúbia Maria Weffort de; Milani, Humberto

doi:10.1016/j.bbr.2015.01.026

Cited by 17 publications

(6 citation statements)

References 40 publications

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“…Also, its safety profile is well established. In addition to these peripheral actions, cilostazol also reverses cognitive impairment in several rodent models, and it reduces cognitive impairment related to chronic cerebral hypoperfusion ( Lee et al, 2006 ; Watanabe et al, 2006 ; Hiramatsu et al, 2010 ; Park et al, 2011 ; Godinho et al, 2015 ; Kitamura et al, 2017 ). In preliminary clinical studies using human patients, cilostazol is also demonstrated to be effective for treating mild cognitive impairment ( Taguchi et al, 2013 ; Ihara et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…Sildenafil and tadalafil increased neuronal survival in these brain areas following severe brain hypoperfusion (Godinho et al, 2015, Dias Fiuza Ferreira et al, 2013, Romanini et al, 2010, Ko et al, 2009.…”

Section: Angiogenesis and Cerebral Blood Flowmentioning

confidence: 93%

“…One study found a positive effect on young rats (8-12 weeks) but not aged rats (18 months) following embolic MCAO (Zhang et al, 2005). PDE5 inhibition reduced mortality in two studies (Novitzky et al, 2016, Romanini et al, 2010) and had no effect in four studies (Godinho et al, 2015, Dias Fiuza Ferreira et al, 2013, Royl et al, 2009, Zhang et al, 2005.…”

Section: Functional Outcome and Mortalitymentioning

confidence: 99%

“…Apoptosis, oxidative stress, and inflammation 4-vessel occlusion (4-VO) and bilateral common carotid artery occlusion (BCCAO), two methods often used to induce severe hypoperfusion to the brain, cause significant cell death in the hippocampal areas (Godinho et al, 2015, Ko et al, 2009 and cortex (Godinho et al, 2015).…”

Section: Angiogenesis and Cerebral Blood Flowmentioning

confidence: 99%

“…The positive effects of PDE5i on functional outcome were abolished when inhibitors of NOS Singh, 2014b, Gulati andSingh, 2014a), PKG or sGC (Chen et al, 2014b, Chen et al, 2014a, were co-administered with tadalafil. Five studies found no improvement of functional outcome and memory performance after PDE5 inhibition (Godinho et al, 2015, Dias Fiuza Ferreira et al, 2013, Gaur and Kumar, 2010a, Royl et al, 2009. One study found a positive effect on young rats (8-12 weeks) but not aged rats (18 months) following embolic MCAO (Zhang et al, 2005).…”

Section: Functional Outcome and Mortalitymentioning

confidence: 99%

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Phosphodiesterase 5 inhibition as a therapeutic target for ischemic stroke: A systematic review of preclinical studies

Ölmestig

Marlet

Hainsworth

et al. 2017

Cellular Signalling

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Phosphodiesterase 5 inhibitors (PDE5i), such as sildenafil (Viagra®) are widely used for erectile dysfunction and pulmonary hypertension. Preclinical studies suggest that PDE5i may improve functional outcome following ischemic stroke. In this systematic review we aimed to evaluate the effects of selective PDE5i in animal models of brain ischaemia. A systematic search in Medline, Embase, and The Cochrane Library was performed including studies in English assessing the effects of selective PDE5i. 32 publications were included describing outcome in 3646 animals. Neuroprotective effects of PDE5i were dependent on the NO-cGMP-PKG-pathway. These included reduced neuronal apoptosis (n=3 studies), oxidative stress (n=5), and neuroinflammation (n=2). PDE5i increased angiogenesis and elevated regional cerebral blood flow in the ischemic penumbra, and improved functional recovery. Some studies found that PDE5i treatment reduced lesion volume (n=9), others found no effect (n=9). Treatment was effective when administered within 24h post-ischemia, though treatment delayed to seven days improved outcome in one study. This review demonstrates both neuroprotective and neurorestorative effects of PDE5i in animal models of stroke, though the specific underlying signaling pathways relating to PDE5 inhibition and cGMP may remain serendipitous in some studies. There is currently limited evidence on the effects of selective PDE5i in human stroke patients, hence translation of preclinical results into clinical trials may be warranted.

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PDE3 Inhibitors Repurposed as Treatments for Age-Related Cognitive Impairment

Yanai

Endo

2018

Mol Neurobiol

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Cilostazol but not sildenafil prevents memory impairment after chronic cerebral hypoperfusion in middle-aged rats

Cited by 17 publications

References 40 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

Phosphodiesterase 5 inhibition as a therapeutic target for ischemic stroke: A systematic review of preclinical studies

PDE3 Inhibitors Repurposed as Treatments for Age-Related Cognitive Impairment

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