Sildenafil protects neuronal cells from mitochondrial toxicity induced by β-amyloid peptide via ATP-sensitive K+ channels

Son, Yonghae; Kim, Koanhoi; Cho, Hyok-rae

doi:10.1016/j.bbrc.2018.04.128

Cited by 21 publications

(11 citation statements)

References 30 publications

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“…HT-22 hippocampal neuronal cells treated with A␤ 25−35 exhibited mitochondrial calcium overload, which was associated with ATP depletion, ROS generation, permeability transition pore opening, caspase-9 activation, and cell death. Sildenafil prevented these effects by promoting the opening of ATP-sensitive K + channels [140]. In cultured HT-22 hippocampal neuronal cells, exposure to advanced glycation end products [141] (a risk factor for AD [142]) induced mitochondrial ROS generation, depleted intracellular ATP, opened the mitochondrial permeability transition pore, released cytochrome C, activated caspase-3, and initiated apoptosis.…”

Section: Resultsmentioning

confidence: 99%

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

Sanders

2020

ADR

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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: Resultsmentioning

confidence: 99%

“…Interestingly, in vitro studies found that sildenafil protected mitochondria from A␤ or AGEs via ATP-sensitive K + channels or HO1 upregulation, respectively [140,141], suggesting that sildenafil may promote mitochondrial function via multiple mechanisms, some of which may be independent of PGC1␣.…”

Section: Discussionmentioning

confidence: 99%

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

Sanders

2020

ADR

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“…Recent evidence has demonstrated the cardioprotective activity of sildenafil against myocardial injury by ischemia/reperfusion, heart failure, cardiac hypertrophy, and diabetic cardiomyopathy ( 10 , 11 ). Furthermore, a variety of studies have revealed the neuroprotective role of sildenafil and have suggested that sildenafil could be repurposed as a potential therapeutic drug for the treatment of several neuronal disorders ( 12 , 13 ). Moreover, the anti-inflammatory effects of sildenafil have been proposed to show therapeutic benefit in cardiac and inflammatory complications ( 10 ).…”

Section: Introductionmentioning

confidence: 99%

Phosphodiesterase Type 5 Inhibitors Synergize Vincristine in Killing Castration-Resistant Prostate Cancer Through Amplifying Mitotic Arrest Signaling

et al. 2020

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Combination therapies that display cancer-killing activities through either coexistent targeting of several cellular factors or more efficient suppression of a specific pathway are generally used in cancer treatment. Sildenafil, a specific phosphodiesterase type 5 (PDE5) inhibitor, has been suggested to display both cardioprotective and neuroprotective activities that provide a rationale for the combination with vincristine on the treatment against castration-resistant prostate cancer (CRPC). In the present work, vincristine arrested cells in the metaphase stage of mitosis. Vincristine-induced mitotic arrest was identified by Cdk1 activation (i.e., increased Cdk1 Thr161 phosphorylation and decreased Cdk1 Tyr15 phosphorylation), cyclin B1 upregulation, and increased phosphorylation of multiple mitotic proteins and stathmin. Sildenafil synergistically potentiated vincristine-induced mitotic arrest and a dramatic increase of mitotic index. Furthermore, sildenafil potentiated vincristine-induced mitochondrial damage, including Mcl-1 downregulation, Bcl-2 phosphorylation and downregulation, Bak upregulation and loss of mitochondrial membrane potential, and sensitized caspase-dependent apoptotic cell death. Sildenafil-mediated synergistic effects were mimicked by other PDE5 inhibitors including vardenafil and tadalafil, and also by PDE5A knockdown in cells, suggesting PDE5-involved mechanism. Notably, sildenafil amplified vincristine-induced phosphorylation and cleavage of BUBR1, a protein kinase in spindle assembly checkpoint (SAC) function and chromosome segregation. Sildenafil also significantly decreased kinetochore tension during SAC activation. Moreover, sildenafil synergized with vincristine on suppressing tumor growth in an in vivo model. In conclusion, the data suggest that sildenafil, in a PDE5-dependent manner, potentiates vincristine-induced mitotic arrest signaling, and sensitizes mitochondria damage–involved apoptosis in CRPC. Both in vitro and in vivo data suggest the combination potential of PDE5 inhibitors and vincristine on CRPC treatment.

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“…In vitro sildenafil prevented the Aβ-induced oxi-dative stress and cell death [ 24 ]. Another study corroborated these findings by demonstrating decreased caspase activation and apoptosis after treatment with sildenafil in hippocampal cells [ 25 ].…”

Section: Phosphodiesterase (Pde) Inhibitorsmentioning

confidence: 99%

Repurposing Licensed Drugs for Use Against Alzheimer’s Disease

Norins¹

2021

JAD

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Substantial evidence, composed of drug mechanisms of action, in vivo testing, and epidemiological data, exists to support clinical testing of FDA-approved drugs for repurposing to the treatment of Alzheimer’s disease (AD). Licensed compound investigation can often proceed at a faster and more cost-effective manner than un-approved compounds moving through the drug pipeline. As the prevalence of AD increases with life expectancy, the current rise in life expectancy amalgamated with the lack of an effective drug for the treatment of AD unnecessarily burdens our medical system and is an urgent public health concern. The unfounded reluctance to examine repurposing existing drugs for possible AD therapy further impedes the possibility of improving the quality of patient lives with a terminal disease. This review summarizes some evidence which exists to suggest certain already-approved drugs may be considered for the treatment of AD and will perhaps encourage physicians to off-label prescribe these safe therapeutics.

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Sildenafil protects neuronal cells from mitochondrial toxicity induced by β-amyloid peptide via ATP-sensitive K+ channels

Cited by 21 publications

References 30 publications

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

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

Phosphodiesterase Type 5 Inhibitors Synergize Vincristine in Killing Castration-Resistant Prostate Cancer Through Amplifying Mitotic Arrest Signaling

Repurposing Licensed Drugs for Use Against Alzheimer’s Disease

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