Sildenafil Improves Vascular and Metabolic Function in Patients with Alzheimer’s Disease

Sheng, Min; Lu, Hanzhang; Liu, Peiying; Li, Yang; Ravi, Harshan; Peng, Shin‐Lei; Diaz‐Arrastia, Ramon; Devous, Michael D.; Womack, Kyle

doi:10.3233/jad-161006

Cited by 55 publications

(52 citation statements)

References 82 publications

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“…In patients, an especially promising finding is that 50 mg sildenafil increased the cerebral metabolic rate of oxygen [127]. This effect might be accounted for totally by the increases in the cerebral blood flow [127], or it may have been partially mediated as well by PGC1␣-regulated mitochondrial biogenesis. However, none of the studies reviewed measured PGC1␣ mRNA, protein, or acetylation levels, nor other markers of mitochondrial biogenesis, making it impossible to evaluate this possibility.…”

Section: Discussionmentioning

confidence: 99%

“…Ultimately, a randomized control trial of sildenafil should be undertaken in AD patients to assess the clinical benefits of long-term sildenafil administration in this population compared to elderly controls. This RCT should use the 50 mg/day dosage [127]. As outcome measures, the RCT should test cognition on the MMSE and the Alzheimer's Disease Assessment Scale-Cognitive Subscale, comorbid depression on the Geriatric Depression Scale [56], amyloid and tau pathology binding with 2-(1-6-[ (2-[F-18]fluoroethyl)(methyl)amino]-2naphthylethylidene)malononitrile positron emission tomography (FDDNP-PET) [166,167], cerebral blood flow with MRI [127], the cerebral metabolic rate of oxygen with MRI [127,168,169], the cerebral metabolic rate of glucose with 18 Ffluoro-deoxyglucose positron emission tomography (FDG-PET) [34,35,[170][171][172][173][174], inflammation with CSF IL-1␤, IL-6, and TNF-␣ [124-126, 147, 175-182], NOS/NO/sGC/cGMP/PGC1␣ pathway dysfunction with CSF cGMP [55,56], and antioxidant enzyme activity with urine 8-oxo-2'deoxyguanosine as an indirect biomarker [45,69,71,72,183].…”

Section: Discussionmentioning

confidence: 99%

“…In 10 AD patients, a single 50 mg dose of sildenafil significantly decreased spontaneous neural activity in the right hippocampus as shown by the fractional amplitude of low-frequency fluctuations recorded on functional magnetic resonance imaging of the blood oxygen level-dependent signal, a parameter that had been shown to be aberrantly increased in AD patients' hippocampi and parahippocampal gyri [152]. In 12 elderly patients with AD, a single dosage of 50 mg of sildenafil significantly increased the cerebral metabolic rate of oxygen and cerebral blood flow [127]. In 8 AD patients, it decreased cerebrovascular reactivity [127].…”

Section: Sildenafil In Ad Patientsmentioning

confidence: 98%

“…In 12 elderly patients with AD, a single dosage of 50 mg of sildenafil significantly increased the cerebral metabolic rate of oxygen and cerebral blood flow [127]. In 8 AD patients, it decreased cerebrovascular reactivity [127].…”

Section: Sildenafil In Ad Patientsmentioning

confidence: 98%

“…Regarding the effect of sildenafil in depression, NOS/NO/sGC/cGMP and serotonin signaling tend to oppose each other. cGMP triggers cerebral vasodilation [127], whereas serotonin induces cerebral vasoconstriction [128,129]. NOS/NO/sGC/cGMP/PKG signaling activates the serotonin transporter (SERT), inducing serotonin reuptake [130][131][132].…”

Section: Sildenafil and Ad Comorbidities And Risk Factorsmentioning

confidence: 99%

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Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review

Sanders

2020

Journal of Alzheimer's Disease Reports

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Nitric oxide/cyclic guanosine monophosphate (cGMP) signaling is compromised in Alzheimer's disease (AD), and phosphodiesterase 5 (PDE5), which degrades cGMP, is upregulated. Sildenafil inhibits PDE5 and increases cGMP levels. Integrating previous findings, we determine that most doses of sildenafil (especially low doses) likely activate peroxisome proliferator-activated receptor-␥ coactivator 1␣ (PGC1␣) via protein kinase G-mediated cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) phosphorylation and/or Sirtuin-1 activation and PGC1␣ deacetylation. Via PGC1␣ signaling, low-dose sildenafil likely suppresses ␤-secretase 1 expression and amyloid-␤ (A␤) generation, upregulates antioxidant enzymes, and induces mitochondrial biogenesis. Plus, sildenafil should increase brain perfusion, insulin sensitivity, long-term potentiation, and neurogenesis while suppressing neural apoptosis and inflammation. A systematic review of sildenafil in AD was undertaken. In vitro, sildenafil protected neural mitochondria from A␤ and advanced glycation end products. In transgenic AD mice, sildenafil was found to rescue deficits in CREB phosphorylation and memory, upregulate brain-derived neurotrophic factor, reduce reactive astrocytes and microglia, decrease interleukin-1␤, interleukin-6, and tumor necrosis factor-␣, decrease neural apoptosis, increase neurogenesis, and reduce tau hyperphosphorylation. All studies that tested A␤ levels reported significant improvements except the two that used the highest dosage, consistent with the doselimiting effect of cGMP-induced phosphodiesterase 2 (PDE2) activation and cAMP depletion on PGC1␣ signaling. In AD patients, a single dose of sildenafil decreased spontaneous neural activity, increased cerebral blood flow, and increased the cerebral metabolic rate of oxygen. A randomized control trial of sildenafil (ideally with a PDE2 inhibitor) in AD patients is warranted.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Sildenafil In Ad Patientsmentioning

confidence: 98%

Section: Sildenafil In Ad Patientsmentioning

confidence: 98%

Section: Sildenafil and Ad Comorbidities And Risk Factorsmentioning

confidence: 99%

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Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review

Sanders

2020

Journal of Alzheimer's Disease Reports

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A pilot study to explore the effect of udenafil on cerebral hemodynamics in older adults

Wang

Shin

et al. 2023

Ann Clin Transl Neurol

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Objective Phosphodiesterase‐5 inhibitors (PDE5Is) enhance vasodilation. We investigated the effects of PDE5I on cerebral hemodynamics during cognitive tasks using functional near‐infrared spectroscopy (fNIRS). Methods This study used a crossover design. Twelve cognitively healthy men participants (mean age, 59 ± 3 years; range, 55–65 years) were recruited and randomly assigned to the experimental or control arm, then the experimental and control arm were exchanged after 1 week. Udenafil 100 mg was administered to participants in the experimental arm once daily for 3 days. We measured the fNIRS signal during the resting state and four cognitive tasks three times for each participant: at baseline, in the experimental arm, and in the control arm. Results Behavioral data did not show a significant difference between the experimental and control arms. The fNIRS signal showed significant decreases in the experimental arm compared to the control arm during several cognitive tests: verbal fluency test (left dorsolateral prefrontal cortex, T = −3.02, p = 0.014; left frontopolar cortex, T = −4.37, p = 0.002; right dorsolateral prefrontal cortex, T = −2.59, p = 0.027), Korean‐color word Stroop test (left orbitofrontal cortex, T = −3.61, p = 0.009), and social event memory test (left dorsolateral prefrontal cortex, T = −2.35, p = 0.043; left frontopolar cortex, T = −3.35, p = 0.01). Interpretation Our results showed a paradoxical effect of udenafil on cerebral hemodynamics in older adults. This contradicts our hypothesis, but it suggests that fNIRS is sensitive to changes in cerebral hemodynamics in response to PDE5Is.

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The PASTIS trial: Testing tadalafil for possible use in vascular cognitive impairment

Pauls

Binnie

Benjamin

et al. 2022

Alzheimer's & Dementia

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Introduction: There are few randomized clinical trials in vascular cognitive impairment (VCI). This trial tested the hypothesis that the PDE5 inhibitor tadalafil, a widely used vasodilator, increases cerebral blood flow (CBF) in older people with symptomatic small vessel disease, the main cause of VCI. Methods:In a double-blind, placebo-controlled, cross-over trial, participants received tadalafil (20 mg) and placebo on two visits ≥7 days apart (randomized to order of treatment). The primary endpoint, change in subcortical CBF, was measured by arterial spin labelling.Results: Tadalafil increased CBF non-significantly in all subcortical areas (N = 55, age: 66.8 (8.6) years) with greatest treatment effect within white matter hyperintensities (+9.8%, P = .0960). There were incidental treatment effects on systolic and diastolic blood pressure (-7.8, -4.9 mmHg; P < .001). No serious adverse events were observed.

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Sildenafil Improves Vascular and Metabolic Function in Patients with Alzheimer’s Disease

Cited by 55 publications

References 82 publications

Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review

Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review

A pilot study to explore the effect of udenafil on cerebral hemodynamics in older adults

The PASTIS trial: Testing tadalafil for possible use in vascular cognitive impairment

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