sildenafil-citrate and Alzheimer-Disease

Alzheimer's disease (AD), characterized by a progressive impairment of memory and cognition, is a major health problem in both developing and developed countries. Currently, no drugs can reverse the progression of AD. Phosphodiesterase 5 (PDE5) is a critical component of the cyclic guanosine monophosphate/protein kinase G (cGMP/PKG) signaling pathway in neurons, the inhibition of which has produced neuroprotective effects, and PDE5 inhibitors have recently been thought to be potential therapeutic agents for AD. In this paper, we summarized the outstanding progress that has been made in PDE5 inhibitors as anti-AD agents with encouraging results in animal studies, clinical trials and the investigations on the underlying mechanisms. The novel PDE5 inhibitors reported recently in the treatment of AD were also reviewed and discussed.

Topics: Alzheimer Disease; Animals; Cognition; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 5; Flavonoids; Humans; Neurons; Neuroprotective Agents; Phosphodiesterase 5 Inhibitors; Purinones; Pyrimidines; Signal Transduction; Sildenafil Citrate; Sulfonamides; Tadalafil; Vardenafil Dihydrochloride

We developed an endophenotype disease module-based methodology for Alzheimer's disease (AD) drug repurposing and identified sildenafil as a potential disease risk modifier. Based on retrospective case-control pharmacoepidemiologic analyses of insurance claims data for 7.23 million individuals, we found that sildenafil usage was significantly associated with a 69% reduced risk of AD (hazard ratio = 0.31, 95% confidence interval 0.25-0.39, P<1.0×10

Topics: Alzheimer Disease; Data Mining; Endophenotypes; Humans; Retrospective Studies; Sildenafil Citrate

Alzheimer's disease is a chronic neurodegenerative disease with multiple pathogenesis pathways. Sildenafil, one of the phosphodiesterase-5 inhibitors, was proven to have effective benefits in transgenic Alzheimer's disease mice. The purpose of the study was to investigate the relationship between sildenafil use and the risk of Alzheimer's disease based on the IBM® MarketScan® Database covering over 30 million employees and family members per year. Sildenafil and non-sildenafil-matched cohorts were generated using propensity-score matching with the greedy nearest-neighbor algorithm. The propensity score stratified univariate analysis and the Cox regression model showed that sildenafil use was significantly associated with a 60% risk reduction of developing Alzheimer's disease (HR=0.40; 95%CI:0.38-0.44; P<.0001) compared to the cohort of individuals who did not take sildenafil. Sex-stratified analyses revealed that sildenafil was related to a lower risk of Alzheimer's disease in subgroups of both males and females. Our findings demonstrated a significant association between sildenafil use and a lower risk of Alzheimer's disease.

Topics: Alzheimer Disease; Animals; Big Data; Female; Male; Mice; Neurodegenerative Diseases; Risk; Sildenafil Citrate

Phosphodiesterase-5 inhibitors (PDE5i) have been evaluated as a novel treatment for Alzheimer's disease and related dementias (ADRD), but two recent cohort studies have offered opposing conclusions.. We performed an unmatched case-control study using electronic medical records from a large healthcare system to evaluate the association of PDE5i use and ADRD in patients ≥65 years old.. Odds of PDE5i exposure were 64.2%, 55.7%, and 54.0% lower in patients with ADRD than controls among populations with erectile dysfunction, benign prostatic hyperplasia, and pulmonary hypertension, respectively. We observed odds ratios less than unity among males and females and with exposure to the PDE5i sildenafil (Viagra®) and tadalafil (Cialis®). We also evaluated the odds of exposure to two other common treatments for pulmonary hypertension: endothelin receptor antagonists (ERA) and calcium channel blockers (CCB). The odds of ERA exposure were 63.2% lower, but the odds of CCB exposure were 30.7% higher, in patients with ADRD than controls among the population with pulmonary hypertension.. Our results reconcile the opposing conclusions from the previous observational studies and support further research into using PDE5i for prevention and treatment of ADRD.

Topics: Aged; Alzheimer Disease; Case-Control Studies; Cyclic Nucleotide Phosphodiesterases, Type 5; Endothelin Receptor Antagonists; Female; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Tadalafil

The phosphodiesterase-5 inhibitor sildenafil was postulated to reduce the risk for Alzheimer's Disease. Since preclinical data revealed beneficial effects in Huntington's Disease (HD), we now for the first time investigated effects of sildenafil in HD patients using the database ENROLL-HD. We demonstrate beneficial effects on motoric, functional and cognitive capacities in cross-sectional data. Those effects were not explained by underlying fundamental molecular genetic or demographic data. It remains unsolved, if effects are due to behavioral differences or due to direct dose-dependent neurobiological modulations.

Topics: Alzheimer Disease; Cross-Sectional Studies; Humans; Huntington Disease; Sildenafil Citrate

Alzheimer disease (AD) is a chronic neurodegenerative disease with multi-pathways pathogenesis. Sildenafil is a selective phosphodiesterase-5 inhibitor with a potential benefit in the treatment of AD. This study investigated the possible mechanisms underlying the effect of sildenafil in AD with emphasis on vascular endothelial growth factor (VEGF), and vascular cell adhesion molecule-1 (VCAM-1). Twenty-four adult male rats were classified into four groups; control group: received vehicles, sildenafil-control: received sildenafil (15 mg/kg/day, p.o.), AD group received Aluminum (25 mg/kg/day, p.o.), AD-treated group: received sildenafil (15 mg/kg/day, p.o.) for 6 weeks. AD was assessed by memory performance test and confirmed by histopathological examination and immunostaining of, neurogenesis marker nestin and α-synuclein. The levels of VEGF-A, VCAM-1, oxidative stress markers and TNF-α in brain tissue were evaluated. AD rats showed histopathological evidences of AD; along with increased latency time in the memory test. There was a decrease in VEGF-A, and an increase in VCAM-1, TNF-α, and oxidative stress markers. Immunohistochemical study showed a significant increase in α-synuclein and a significant decrease in nestin expressions in brain tissues. Sildenafil administration ameliorated the histopathological changes and decreased latency time. Such effect was associated with a decrease in VCAM-1, TNF-α and oxidative stress as well as an increase in VEGF-A. Sildenafil caused a significant increase in nestin and a decrease in α-synuclein immunostaining. These findings suggested a protective effect of sildenafil via modulation of VEGF-A, and VCAM-1.

Topics: alpha-Synuclein; Aluminum Chloride; Alzheimer Disease; Animals; Brain; Cyclic GMP; Glutathione; Male; Malondialdehyde; Memory; Nestin; Neuroprotective Agents; Nitric Oxide; Oxidative Stress; Rats; Sildenafil Citrate; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor A

Alzheimer's disease (AD) is the most common cause of neurodegenerative cognitive impairment, defined by abnormal accumulations of amyloid-β and tau. Approaches directly targeting these proteins have not resulted in a disease modifying therapy. Neurovascular unit dysfunction is a feature of AD offering an alternative target for intervention. Sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, improves cognitive functioning in mouse models of AD. Recent work in AD patients has demonstrated increased cerebral blood flow, as well as brain oxygen utilization after a single dose of sildenafil. Its effect on nitric oxide-cGMP signaling may have downstream effects on neuroplasticity, amyloid-β processing, and improved neurovascular unit function. Fractional amplitude of low frequency fluctuations (fALFF) assesses spontaneous neural activity via resting state fMRI BOLD signal (0.01-0.08 or 0.10 Hz). In AD, other assessments have revealed increased fALFF in hippocampi and parahippocampal gyri. Here, we examined the effects of a single dose of sildenafil on fALFF in a cohort of 10 AD patients. We found a decrease (p < 0.03, α= 0.05) in fALFF an hour after sildenafil administration in the right hippocampus. Additionally, cerebral vascular reactivity in response to carbon dioxide inhalation, a measure of neural vascular reserve previously collected on most of these participants, was not significantly correlated with this decrease, implying that change in fALFF may not have been solely due to altered vascular reactivity to CO2. We demonstrate that in patients with AD, hippocampal fALFF decreases in response to sildenafil, suggesting a normalization. These findings support further investigation into the effects of sildenafil in AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain Mapping; Cognitive Dysfunction; Female; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Pilot Projects; Sildenafil Citrate; Temporal Lobe

Alzheimer's disease (AD) is the leading cause of degenerative dementia in the aging population. Patients with AD have alterations in cerebral hemodynamic function including reduced cerebral blood flow (CBF) and cerebral metabolic rate. Therefore, improved cerebrovascular function may be an attractive goal for pharmaceutical intervention in AD.. We wished to observe the acute effects of sildenafil on cerebrovascular function and brain metabolism in patients with AD.. We used several novel non-invasive MRI techniques to investigate the alterations of CBF, cerebral metabolic rate of oxygen (CMRO2), and cerebrovascular reactivity (CVR) after a single dose of sildenafil administration in order to assess its physiological effects in patients with AD. CBF, CMRO2, and CVR measurements using MRI were performed before and one hour after the oral administration of 50 mg sildenafil. Baseline Montreal Cognitive Assessment score was also obtained.. Complete CBF and CMRO2 data were obtained in twelve patients. Complete CVR data were obtained in eight patients. Global CBF and CMRO2 significantly increased (p = 0.03, p = 0.05, respectively) following sildenafil administration. Voxel-wise analyses of CBF maps showed that increased CBF was most pronounced in the bilateral medial temporal lobes. CVR significantly decreased after administration of sildenafil.. Our data suggest that a single dose of sildenafil improves cerebral hemodynamic function and increases cerebral oxygen metabolism in patients with AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Central Nervous System Agents; Cerebrovascular Circulation; Cohort Studies; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Oxygen; Pilot Projects; Sildenafil Citrate; Treatment Outcome

Age-related cognitive decline is accompanied by an increase of neuronal apoptosis and a dysregulation of neuroplasticity-related molecules such as brain-derived neurotrophic factor and neurotoxic factors including beta amyloid (Aβ) peptide. Because it has been previously demonstrated that phosphodiesterase-5 inhibitors (PDE5-Is) protect against hippocampal synaptic dysfunction and memory deficits in mouse models of Alzheimer's disease and physiological aging, we investigated the effect of a treatment with the PDE5-I, sildenafil, on cell death, pro- and antiapoptotic molecules, and Aβ production. We demonstrated that chronic intraperitoneal injection of sildenafil (3 mg/kg for 3 weeks) decreased terminal deoxyuridine triphosphate nick end labeling-positive cells in the CA1 hippocampal area of 26-30-month-old mice, downregulating the proapoptotic proteins, caspase-3 and B-cell lymphoma 2-associated X, and increasing antiapoptotic molecules such as B-cell lymphoma protein-2 and brain-derived neurotrophic factor. Also, sildenafil reverted the shifting of amyloid precursor protein processing toward Aβ42 production and the increase of the Aβ42:Aβ40 ratio in aged mice. Our data suggest that PDE5-I might be beneficial to treat age-related detrimental features in a physiological mouse model of aging.

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; bcl-2-Associated X Protein; Brain; Brain-Derived Neurotrophic Factor; CA1 Region, Hippocampal; Caspase 3; Cyclic AMP Response Element-Binding Protein; Cyclic Nucleotide Phosphodiesterases, Type 5; Deoxyuracil Nucleotides; Disease Models, Animal; Humans; Injections, Intraperitoneal; Mice; Mice, Inbred C57BL; Molecular Targeted Therapy; Neuronal Plasticity; Phosphodiesterase 5 Inhibitors; Phosphorylation; Piperazines; Proto-Oncogene Proteins c-bcl-2; Purines; Sildenafil Citrate; Sulfones

Memory deficit is a marker of Alzheimer's disease (AD) that has been highly associated with the dysfunction of cyclic GMP (cGMP) signaling and an ongoing inflammatory process. Phosphodiesterase-5 (PDE5) inhibitors prevent the breakdown of cGMP and are currently studied as a possible target for cognitive enhancement. However, it is still unknown whether inhibition of PDE5 reversed β-amyloid peptide (Aβ)-induced neuroinflammation in APP/PS1 transgenic (Tg APP/PS1) mice. The present study evaluated the cognitive behaviors, inflammatory mediators, and cGMP/PKG/pCREB signaling in 15-month-old Tg APP/PS1 mice and age-matched wild-type (WT) mice that were treated with PDE5 inhibitor sildenafil and the inhibitor of cGMP-dependent protein kinase Rp-8-Br-PET-cGMPS. In comparison with WT mice, Tg APP/PS1 mice were characterized by impaired cognitive ability, neuroinflammatory response, and down-regulated cGMP signaling. Sildenafil reversed these memory deficits and cGMP/PKG/pCREB signaling dysfunction; it also reduced both the soluble Aβ1-40 and Aβ1-42 levels in the hippocampus. These effects of sildenafil were prevented by intra-hippocampal infusion of the Rp-8-Br-PET-cGMPS. These results suggest that sildenafil could restore cognitive deficits in Tg APP/PS1 mice by the regulation of PKG/pCREB signaling, anti-inflammatory response and reduction of Aβ levels.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Cognition Disorders; Cyclic GMP; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalitis; Exploratory Behavior; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Phosphodiesterase 5 Inhibitors; Piperazines; Presenilin-1; Purines; Recognition, Psychology; RNA, Messenger; Sildenafil Citrate; Sulfones; Thionucleotides

Previous studies have demonstrated that cognitive function can be restored in mouse models of Alzheimer's disease (AD) following administration of sildenafil, a specific PDE5 inhibitor (Puzzo et al., 2009; Cuadrado-Tejedor et al.). Another very potent PDE5 inhibitor with a longer half-life and safe in chronic treatments, tadalafil, may represent a better alternative candidate for AD therapy. However, tadalafil was proven unable to achieve similar benefits than those of sildenafil in AD animal models (Puzzo et al., 2009). The lack of efficacy was attributed to inability to cross the blood-brain barrier (BBB). In this paper we first measured the blood and brain levels of tadalafil to prove that the compound crosses BBB and that chronic treatment leads to accumulation in the brain of the J20 transgenic mouse model of AD. We demonstrated the presence of PDE5 mRNA in the brain of the mice and also in the human brain. After a 10 week treatment with either of these PDE5 inhibitors, the performance of the J20 mice in the Morris water maze test improved when compared with the transgenic mice that received vehicle. Biochemical analysis revealed that neither sildenafil nor tadalafil altered the amyloid burden, although both compounds reduced Tau phosphorylation in the mouse hippocampus. This study provides evidence of the potential benefits of a chronic tadalafil treatment in AD therapy. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Topics: Alzheimer Disease; Animals; Blood-Brain Barrier; Brain; Carbolines; Cognition Disorders; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Female; Gene Expression Regulation, Enzymologic; Half-Life; Humans; Macaca fascicularis; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nootropic Agents; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Species Specificity; Sulfones; Tadalafil; Tissue Distribution

Inhibitors of phosphodiesterase 5 (PDE5) affect signalling pathways by elevating cGMP, which is a second messenger involved in processes of neuroplasticity. In the present study, the effects of the PDE5 inhibitor, sildenafil, on the pathological features of Alzheimer's disease and on memory-related behaviour were investigated.. Sildenafil was administered to the Tg2576 transgenic mouse model of Alzheimer's disease and to age-matched negative littermates (controls). Memory function was analysed using the Morris water maze test and fear conditioning tasks. Biochemical analyses were performed in brain lysates from animals treated with saline or with sildenafil.. Treatment of aged Tg2576 animals with sildenafil completely reversed their cognitive impairment. Such changes were accompanied in the hippocampus by a reduction of tau hyperphosphorylation and a decrease in the activity of glycogen synthase kinase 3β (GSK3β) and of cyclin-dependent kinase 5 (CDK5) (p25/p35 ratio). Moreover, sildenafil also increased levels of brain-derived neurotrophic factor (BDNF) and the activity-regulated cytoskeletal-associated protein (Arc) in the hippocampus without any detectable modification of brain amyloid burden.. Sildenafil improved cognitive functions in Tg2576 mice and the effect was not related to changes in the amyloid burden. These data further strengthen the potential of sildenafil as a therapeutic agent for Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain-Derived Neurotrophic Factor; Cognition; Cytoskeletal Proteins; Fear; Immunohistochemistry; Maze Learning; Mice; Mice, Transgenic; Nerve Tissue Proteins; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; tau Proteins

Memory loss, synaptic dysfunction, and accumulation of amyloid beta-peptides (A beta) are major hallmarks of Alzheimer's disease (AD). Downregulation of the nitric oxide/cGMP/cGMP-dependent protein kinase/c-AMP responsive element-binding protein (CREB) cascade has been linked to the synaptic deficits after A beta elevation. Here, we report that the phosphodiesterase 5 inhibitor (PDE5) sildenafil (Viagra), a molecule that enhances phosphorylation of CREB, a molecule involved in memory, through elevation of cGMP levels, is beneficial against the AD phenotype in a mouse model of amyloid deposition. We demonstrate that the inhibitor produces an immediate and long-lasting amelioration of synaptic function, CREB phosphorylation, and memory. This effect is also associated with a long-lasting reduction of A beta levels. Given that side effects of PDE5 inhibitors are widely known and do not preclude their administration to a senile population, these drugs have potential for the treatment of AD and other diseases associated with elevated A beta levels.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Conditioning, Classical; Cyclic AMP Response Element-Binding Protein; Cyclic GMP; Disease Models, Animal; Immunohistochemistry; Injections, Intraperitoneal; Memory; Mice; Mice, Transgenic; Mutation; Neuropsychological Tests; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Phosphorylation; Piperazines; Polymerase Chain Reaction; Psychomotor Performance; Purines; Sildenafil Citrate; Spatial Behavior; Sulfones; Synaptic Transmission; Time Factors; Treatment Outcome