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2020 Sildenafil for the rT eatment of Alzheimer’s Disease: A Systematic Review
Owen Sanders Portland State University, [email protected]
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Citation Details Sanders, O. (2020). Sildenafil for the rT eatment of Alzheimer’s Disease: A Systematic Review. Journal of Alzheimer's Disease Reports, 4(1), 91-106
This Article is brought to you for free and open access. It has been accepted for inclusion in OHSU-PSU School of Public Health Faculty Publications and Presentations by an authorized administrator of PDXScholar. Please contact us if we can make this document more accessible: [email protected]. Journal of Alzheimer’s Disease Reports 4 (2020) 91–106 91 DOI 10.3233/ADR-200166 IOS Press Review
Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review
Owen Sanders∗ Portland State University, Portland, OR, USA
Accepted 31 March 2020
Abstract. 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 dose- limiting 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.
Keywords: Alzheimer’s disease, cyclic GMP, mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, sildenafil citrate
INTRODUCTION tau protein hyperphosphorylation and neurofibrillary tangle formation, metal ion dyshomeostasis [1–9], Alzheimer’s disease (AD) is the leading cause of oxidative stress and lipid, nucleic acid, and protein dementia worldwide, and AD patients and their fam- damage [10–13], abortive cell cycle reentry [14–26], ilies urgently require novel therapeutics to prevent neuroinflammation and microbial dysbiosis [27–33], and slow the progression of this devastating disorder. insulin resistance [34, 35], cerebrovascular dysfunc- Hallmarks of AD include amyloid- (A) pep- tion [36–38], synaptic dysfunction [39, 40], neuronal tide secretion and deposition into neuritic plaques, loss, endoplasmic reticulum stress [41–44], and mito- chondrial dysfunction [45–48]. ∗ Sildenafil (Viagra) is a drug used to treat erectile Correspondence to: Owen Sanders, 1777 NW 173rd Ave, #610, Beaverton, OR 97006, USA. Tel.: +1 503 809 1333; E-mail: dysfunction and pulmonary arterial hypertension that [email protected]. inhibits phosphodiesterase 5 (PDE5) (Fig. 1). PDE5
ISSN 2542-4823/20/$35.00 © 2020 – IOS Press and the authors. All rights reserved This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License (CC BY-NC 4.0). 92 O. Sanders / Sildenafil for Alzheimer’s Disease
or particulate guanylyl cyclase) activity was found to be decreased by 50% in AD patients’ superior temporal cortices compared to controls [54]. cGMP levels were found to be significantly lower in AD patients’ cerebrospinal fluid (CSF) compared to con- trols, and decreases in levels of cGMP correlated with CSF A42 levels [55], comorbid depression [56], and cognitive decline as measured by Mini-Mental State Examination (MMSE) [55, 57]. Fig. 1. Sildenafil mechanism of action. Potentially contributing to this cGMP depletion, PDE5 protein levels have been found to be sig- degrades cyclic guanosine monophosphate (cGMP). nificantly upregulated in AD patients’ temporal Upstream of cGMP, normally, the amino acid L- cortices [55], and PDE5 mRNA levels are signifi- arginine is converted by three varieties of the enzyme cantly elevated in AD patients’ entorhinal cortices nitric oxide synthase (NOS) into nitric oxide (NO). compared to controls according to a meta-analysis NO is a small cell-permeable gas molecule that dif- of mRNA datasets (p = 0.001, FDR = 0.018; Fig. 2) fuses across the plasma membrane and activates [58]. Granted, low PDE5 mRNA expression in the soluble guanylyl cyclase (sGC). sGC converts guano- human CNS has been reported relative to periph- sine triphosphate (GTP) into cGMP [49]. However, eral tissue [59–61], and no specific hybridization in AD, the activity of the NOS/NO/cGMP pathway signal was observed for PDE5 mRNA in the brains is severely impaired. NOS activity is significantly of aged and AD patients using radioactive in situ decreased in AD patients’ superior frontal gyri and hybridization histochemistry in one study, drawing hippocampi compared to age-matched controls [50], skepticism as to whether PDE5 inhibition has rele- even though aberrant neuronal NOS (nNOS) protein vance to AD [62–64]. Regardless though, the weight expression has been observed in a subpopulation of of the evidence suggests that PDE5 is expressed isocortical pyramidal neurons in AD patients’ brains (albeit relatively less than in peripheral tissues) in [51, 52] and the intensity of astrocyte endothelial the normal human brain [58–61] and that, moreover, NOS (eNOS) and inducible NOS (iNOS) expression it is upregulated in the AD entorhinal and temporal had increased in AD patients’ deep cortical layers cortices [55, 58], supporting the notion that PDE5 [52, 53]. NO-induced soluble sGC (but not basal sGC may be an important therapeutic target in AD.
Fig. 2. PDE5A mRNA levels upregulated in the AD entorhinal cortex. O. Sanders / Sildenafil for Alzheimer’s Disease 93 cGMP/PGC1α signaling on cGMP concentration, duration, and crosstalk with cAMP signaling mediated by phosphodiesterase This multi-mechanism NOS/NO/cGMP signaling 3 (PDE3) and phosphodiesterase 2 (PDE2) activ- dysfunction is an important therapeutic target in AD ity. Low concentrations of cGMP compete for for multiple reasons. One reason is that cGMP is the active site of PDE3 [76], thereby imped- responsible for increasing the expression and activ- ing PDE3 from degrading cAMP and increasing ity of peroxisome proliferator-activated receptor-␥ cAMP levels. By contrast, high cGMP concentra- coactivator 1␣ (PGC1␣). PGC1␣ overexpression tions allosterically activate PDE2, thereby promoting (or low-dose NO) suppresses the expression of - cAMP degradation [76, 77]. Mirroring this, low- secretase 1 (BACE1) [65], the rate-limiting enzyme dose sildenafil (up to 1 M) inhibits PDE3, resulting in A generation, suggesting that PGC1␣ activ- in cAMP accumulation [76], whereas high-dose ity suppresses A generation. In addition, PGC1␣ sildenafil (10 and 100 M) activates PDE2, result- is a master transcriptional regulator of mitochon- ing in cAMP degradation [76] and suppression drial biogenesis, oxidative respiration [66, 67], of the cAMP/EPAC/adenosine monophosphate- fatty acid -oxidation [68], and antioxidant defense activated protein kinase (AMPK) pathway [76, 78, [69]. PGC1␣ upregulates multiple antioxidant genes, 79]. For this reason, excessively high doses of including mitochondrial manganese superoxide dis- sildenafil resulted in inferior therapeutic responses mutase (MnSOD), when bound to Forkhead box O3a compared to low doses in preclinical models of non- (Foxo3a) and deacetylated by Sirtuin-1 (SIRT1) [69]. alcoholic hepatic steatosis and obesity [76]. This However, PGC1␣ protein levels are significantly caveat may be relevant to AD as well. The dose- lower in AD patients’ hippocampi compared to con- dependent effect of sildenafil and cGMP signaling trols [48], and mitochondrial biogenesis and MnSOD on cAMP levels should affect PGC1␣ regula- expression are impaired there [45, 48]. Sildenafil has tion since cAMP is required for robust PGC1␣ the potential to reverse the hippocampal PGC1␣ sup- expression and mitochondrial biogenesis in AD pression in AD. 10 M sildenafil treatment for 24 [48, 67]. On top of this, although NO/sGC/cGMP hours in vitro and 0.3 mg/kg sildenafil in vivo have signaling typically promotes PGC1␣ activity, it been shown to induce PGC1␣ expression and mito- also simultaneously activates the protein kinase G chondrial biogenesis by increasing cGMP in renal (PKG)/phosphoinositide 3-kinase (PI3K)/Akt sig- proximal tubular cells and mouse renal cortex, respec- naling cascade, which decreases PGC1␣ activity tively [70]. In addition, sildenafil has been shown to [80–83]; opposing this negative regulation of PGC1␣ upregulate SOD and catalase activities in rat liver by cGMP, cAMP inhibits Akt via PKA and Rap1b (1.48 mg/kg sildenafil) and human blood (100 mg (Fig. 4) [84]. In other words, cGMP per se simul- sildenafil one time dosage) [71, 72]. taneously increases and decreases PGC1␣ signaling by distinct mechanisms, with crosstalk with cAMP Multiphasic regulation of PGC1α by sildenafil pathways probably determining whether PGC1␣ is and cGMP activated or inhibited overall. Therefore, since high doses of sildenafil activate PDE2 and decrease cAMP NOS/NO/sGC/cGMP signaling upregulates levels, high-dose sildenafil would be expected to be PGC1␣ in diverse cell types, including not only less effective than low-dose sildenafil at activating renal proximal tubular cells [70], but also brown PGC1␣, inducing mitochondrial biogenesis, upregu- adipocytes, U937 monocytic cells, HeLa cervical lating antioxidant genes, and downregulating BACE1 cancer-derived cells, white 3T3-L1 adipocytes [73, [76]. 74], and probably neurons [75]. In mice, subcortical brain tissue responded to hypoxia with PGC1␣ Low and high but not moderate cGMP levels upregulation (as well as with mitochondrial biogen- activate PGC1α? esis) in a manner that depended on nNOS expression [75], so the nNOS/NO/cGMP/PGC1␣ pathway does Consistent with the dose-dependent effect of silde- appear to be active in neurons. nafil and cGMP on PGC1␣,10M of 8-Br-cGMP An important caveat to the claim that silde- treatment for 24 hours upregulated PGC1␣ mRNA nafil and cGMP activate PGC1␣ though is that expression and mitochondrial biogenesis in renal NOS/NO/cGMP appears to be a multiphasic rheo- proximal tubular cells [70]. By contrast, in endothe- stat of PGC1␣ signaling whose outcome depends lial cells, 100 M 8-Br-cGMP treatment for 6–24 94 O. Sanders / Sildenafil for Alzheimer’s Disease hours downregulated PGC1␣ [80, 83]. In addition, treatment for less than 12 hours with NO donors decreased PGC1␣ expression, whereas treatment for 24 hours or more increased PGC1␣ expression [83]. NO-triggered PGC1␣ downregulation and conse- quent reactive oxygen species (ROS) production were required for endothelial cell migration, an effect that was mediated by NO-activated PI3K/Akt signaling and Akt phosphor-inhibition of Foxo3a [80]. Surprisingly though, much higher dosages of ␣ cGMP than 100 M upregulate PGC1 like lower Fig. 3. Multiphasic dose response of PGC1␣ expression to cGMP doses do: for example, PGC1␣ was upregulated in concentration. brown adipocytes treated with 1 mM 8-Br-cGMP for 4 days [73]. In human monocytic U937 cells, rat L6 myotubes, and rat PC12 neurosecretory cells, 3 mM 8-Br-cGMP treatment every day for 6 days upregulated PGC1␣, as well as Nrf1 and Tfam, mito- chondrial proteins Cox IV and Cytochrome C, and mitochondrial DNA content [66]. Furthermore, 6 days of 3 mM 8-Br-cGMP in these three cell types resulted in increased oxidative phosphorylation- coupled oxygen consumption [66]. Therefore, there appears to be a U-shaped dose- response curve between cGMP concentrations and PGC1␣ expression, with PGC1␣ being downregu- lated by 100 M cGMP for 6–24 hours [80, 83] but upregulated by 10 M cGMP or 1–3 mM cGMP for 24 hours or longer (Fig. 3) [66, 70, 73]. This might be because 100 M cGMP corresponds to the 10–100 M dosage of sildenafil that is suf- ficient to activate PDE2 and lower cAMP [76], Fig. 4. How sildenafil and cGMP may regulate PGC1␣. whereas much higher dosages of cGMP and silde- nafil nevertheless stimulate mitochondrial biogenesis In addition to this complex but clinically rele- and PGC1␣ transcription [66, 73] because supraphys- vant dose-specific effect, the mechanism by which iological cGMP signaling is sufficient to overcome NO/cGMP typically upregulates PGC1␣ remains the cAMP depletion to induce robust PGC1␣ activ- unresolved [67]. Two potential mechanisms involv- ity independently of cAMP, perhaps via cAMP ing either CREB or SIRT1 will now be described. response element binding protein (CREB) phospho- rylation and SIRT1 activation (see next subsection). How sildenafil and cGMP activate PGC1α If so, this would not be unprecedented: in fibrob- lasts, PDE2 overexpression was sufficient to lower In the hippocampus during long-term potentiation cAMP levels and induce a transition into a pro- and in other neural tissues, both the cGMP/PKG fibrotic myofibroblast phenotype, an alternation that and the cAMP/PKA pathways contribute to CREB cGMP elevating agents reversed, suggesting that suf- phosphorylation [85–90], and PKA-mediated CREB ficiently high cGMP levels can overcome the deficits phosphorylation promotes PGC1␣ transcription [67], to cellular signaling induced by PDE2-mediated so cGMP/PKG/CREB signaling might promote cAMP depletion [77]. Therefore, it appears that, for PGC1␣ expression as well. In addition, cGMP may optimal PGC1␣ expression, mitochondrial biogene- contribute to the post-translational regulation of sis, and BACE1 downregulation, either sufficiently PGC1␣. Once transcribed and translated, the stabil- low or high sildenafil dosages must be used, or ity, subcellular localization, and co-activator activity sildenafil must be co-administered with a PDE2 of PGC1␣ proteins are regulated by multiple post- inhibitor. translational modifications. For example, PGC1␣ can O. Sanders / Sildenafil for Alzheimer’s Disease 95
genesis [120–123], so it might slow the loss of AD neurons and promote the replenishment of new ones. Furthermore, sildenafil improves insulin sensitivity and endothelial inflammation in patients [124–126], so sildenafil might also promote insulin sensitiv- ity and suppress inflammation in AD brains. Since cGMP/PKG signaling mediates long-term poten- tiation via CREB phosphorylation [85–90, 117], sildenafil should improve the learning and memory Fig. 5. PGC1␣ post-translational regulation. impairments associated with AD. Therefore, in the- ory, most doses of sildenafil should improve multiple be inhibited via phosphorylation by Akt [81, 82], hallmarks of AD, including excessive A genera- S6 Kinase [91], or glycogen synthase kinase 3 tion, impaired mitochondrial biogenesis, oxidative (GSK3) [74, 92], or via acetylation by general con- stress, neuroinflammation, hypoperfusion, insulin trol of amino acid synthesis 5 (GCN5) [81, 93–95] resistance, neuron loss, insufficient neurogenesis, and or p300 [96]. Conversely, PGC1␣ can be activated memory deficits. via phosphorylation by adenosine monophosphate activated protein kinase (AMPK) [97–101] or p38 Sildenafil and AD comorbidities and risk factors mitogen activated protein kinase (MAPK) [101, 102], via methylation by protein arginine methyltrans- It is also important to consider the effects of silde- ferase 1 (PRMT1) [103], or via deacetylation by nafil on common AD comorbidities and/or risk factor SIRT1 (Fig. 5) [69, 93, 94, 96, 101, 104–107]. conditions, such as type II diabetes, cardiovascular Interestingly given the SIRT1-mediated activation diseases, and depression, since many AD patients of PGC1␣, sildenafil has been shown to upregulate suffer from one or more of these conditions. SIRT1 in heart, cardiomyocytes [108], serum, and Regarding the effect of sildenafil in depression, subcutaneous adipose tissue [109]. cGMP analogues NOS/NO/sGC/cGMP and serotonin signaling tend to upregulated SIRT1 expression in white adipose tis- oppose each other. cGMP triggers cerebral vasodila- sue [110, 111] and in osteoblasts [112]. Mice with tion [127], whereas serotonin induces cerebral vaso- osteoblast-specific PKGII overexpression exhibited constriction [128, 129]. NOS/NO/sGC/cGMP/PKG increased SIRT1 expression [112]. The PKG inhibitor signaling activates the serotonin transporter (SERT), KT-5823 blocked the relief of spinal allodynia inducing serotonin reuptake [130–132]. For this rea- induced by resveratrol, a SIRT1 activator [113, 114]. son, sildenafil might be expected to make selective In hypoxic myocardial cells, 1 M sildenafil treat- serotonin reuptake inhibitor (SSRI) antidepressants ment decreased PGC1␣ protein acetylation [115, less effective. However, there do not appear to be any 116]. Therefore, it is possible that sildenafil may reports of this being the case, and sildenafil has been promote PGC1␣ deacetylation in some contexts via used safely and successfully to treat erective dys- cGMP/PKG/SIRT1 signaling (Fig. 5). function in patients taking SSRIs [133]. Moreover, sildenafil itself has been shown to exert an antide- Benefits of sildenafil in AD pressant effect in mice [134]. Regarding the effects of sildenafil in type II Since most doses of sildenafil/cGMP activate diabetes, it has been found in a randomized, double- PGC1␣ and PGC1␣ signaling induces mitochondrial blind, placebo-controlled study that 25 mg thrice biogenesis [67, 70], upregulates antioxidant enzymes daily for 3 months sildenafil increases insulin sen- [69], and suppresses BACE1 expression [65], silde- sitivity in patients with pre-diabetes, indicating that nafil should provide significant benefits to patients sildenafil might be beneficial for patients with AD with AD. In addition to its PGC1␣-specific benefits, and type II diabetes [125]. Regarding the effects of sildenafil promotes smooth muscle relaxation and sildenafil and cardiovascular diseases, despite early vasodilation via cGMP [117], which might provide concerns [135], sildenafil usage does not appear to additional benefit to patients with AD since hypoper- contribute to myocardial infarction or sudden cardiac fusion is also a significant impairment in AD patients’ death risk [136]. In fact, treatment of erectile dysfunc- brains [37, 38, 118]. Sildenafil suppresses apoptosis tion in patients who had had a myocardial infarction in hypoxic neurons [117, 119] and promotes neuro- with PDE5 inhibitors (but not alprostadil) correlated 96 O. Sanders / Sildenafil for Alzheimer’s Disease with a reduced risk of mortality and hospitaliza- In mice with cholinergic dysfunction mimicking tion for heart failure (n = 43,145) [137]. Preclinically, AD due to scopolamine injection, sildenafil rescued in a mouse model of hypercholesterolemia, silde- maze performance, with 3 mg/kg appearing to be nafil decreased aortic atherosclerotic plaques by more efficacious than the 1.5 or 4.5 mg/kg dosages 40% [138]. Furthermore, sildenafil decreases cardiac [143]. hypertrophy [139]. Therefore, sildenafil treatment in In hippocampal slices from transgenic amyloid AD patients with comorbid cardiovascular diseases precursor protein (APP)/presenilin 1 (PS1) AD mice, would be expected to be safe and potentially benefi- 50 nM sildenafil rescued the deficits in tetanus- cial. induced long-term potentiation in the Schaffer collateral pathway caused by the APP/PS1 genotype [144]. In vivo sildenafil treatment produced simi- MATERIALS AND METHODS lar results. In APP/PS1 mice, a one-time dosage of 3 mg/kg sildenafil rescued contextual fear mem- Todetermine the current progress in studying silde- ory. Daily intraperitoneal dosages for 2-3 weeks of nafil and AD, we searched PubMed for “sildenafil 3 mg/kg sildenafil partially rescued spatial working Alzheimer’s.” Both preclinical and clinical studies memory deficits on the radial arm water maze test. were reviewed. Results that were not about the effect Similar benefits were found for daily dosages of of sildenafil on patients or preclinical models with 3 mg/kg sildenafil 9–12 weeks after treatment ces- AD (e.g., studies about the interaction between cGMP sation, indicating a long-term benefit that persists and A in long-term potentiation) were discarded. To even after treatment cessation. Sildenafil also rescued ensure clinical relevancy, studies about derivates of long-term spatial reference memory on the Morris sildenafil were also discarded. water maze and the probe trial. Sildenafil treatment rescued tetanus-induced CREB phosphorylation in RESULTS the CA1 hippocampus to normal levels. 3 weeks of daily 3 mg/kg sildenafil was sufficient to reduce As per the methods section, two in vitro studies, A40 and A42 levels in cerebral cortex samples ten rodent studies, one systematic review, and two [144]. pilot studies in patients were included. Overall, all In APP/PS1 mice administered sildenafil 6 mg/kg the studies supported the use of sildenafil in AD (see intraperitoneally daily for 3 months, significant Table 1 for a summary of results). improvements were documented in behavioral tests HT-22 hippocampal neuronal cells treated with (nesting behavior, arm entries in the Y maze, Mor- A25−35 exhibited mitochondrial calcium overload, ris water maze escape latency and path length), as which was associated with ATP depletion, ROS well as immunoreactivity of inflammatory microglial generation, permeability transition pore opening, and astrocytic markers ionized calcium binding adap- caspase-9 activation, and cell death. Sildenafil pre- tor molecule 1 (Iba1) and glial fibrillary acidic vented these effects by promoting the opening of protein (GFAP), neurogenesis as shown by NeuN- ATP-sensitive K+ channels [140]. In cultured HT-22 positive neurons and doublecortin (DCX)-positive hippocampal neuronal cells, exposure to advanced cells in dentate gyrus, and amyloid plaque burden glycation end products [141] (a risk factor for [145]. AD [142]) induced mitochondrial ROS generation, In APP/PS1 AD mice, 2 mg/kg sildenafil twice depleted intracellular ATP, opened the mitochondrial daily for 4 months rescued cognition as shown permeability transition pore, released cytochrome C, by spontaneous alternation and escape from elec- activated caspase-3, and initiated apoptosis. Treat- trical stimulation in the Y-maze test, decreased ment with sildenafil upregulated heme oxygenase amyloid pathology as shown by decreased corti- 1 (HO1), protected mitochondria from permeabil- cal and hippocampal APP, A40, and A42 levels, ity transition pore opening and cytochrome C decreased PDE5 expression, and increased nNOS, release, and decreased caspase-3 activation and eNOS, iNOS, NO, and cGMP levels [146]. apoptosis [141]. HO1 expression was required for Sub-chronic intraperitoneal sildenafil treatment in sildenafil-induced protection of mitochondrial reduc- APP/PS1 mice was found to improve memory as tive capacity and permeability transition pore opening shown by novel object recognition preference, down- [141], suggesting that sildenafil protected mitochon- regulated proinflammatory cytokines interleukin-1 dria via HO1 upregulation. (IL-1), intereukin-6 (IL-6), and tumor necrosis O. Sanders / Sildenafil for Alzheimer’s Disease 97
Table 1 Literature review results Dosage Population Results Study 10–100 M sildenafil HT-22 hippocampal Sildenafil rescued mitochondrial Ca2+ [140] neuronal cells exposed to overload and dysfunction due to A25−35 by + A25−35 opening ATP-sensitive K channels 20 M sildenafil HT-22 hippocampal Sildenafil decreased mitochondrial [141] neuronal cells exposed to permeability transition pore opening and advanced glycation end apoptosis via HO1 upregulation products Variable, 3 mg/kg Scopolamine-induced Sildenafil rescued memory [143] cholinergic dysfunction mice Variable, primarily 3 mg/kg/day APP/PS1 mice Sildenafil rescued long-term potentiation, [144] intraperitoneal sildenafil CREB phosphorylation, memory, and decreased A levels 6 mg/kg, intraperitoneal daily for APP/PS1 mice Sildenafil improved memory, amyloid [145] 3 months plaque load, inflammation, and neurogenesis 2 mg/kg sildenafil twice daily for APP/PS1 mice Sildenafil rescued memory and amyloid [146] 4 months pathology, downregulated PDE5, and increased NOS, NO, and cGMP levels Sildenafil was dissolved in 0.9% APP/PS1 mice Sildenafil improved memory, decreased [147] saline at a concentration of levels of A, IL-1, IL-6 and TNF-␣, and 1.0 mg/ml. 10.0 mg/kg of this increased p-CREB solution was administered intraperitoneally with an injection volume of 0.1 ml/10 g. 15 mg/kg sildenafil daily for 10 J20 mice Sildenafil improved memory, tau [61] weeks in water hyperphosphorylation, and Akt and GSK3 phosphorylation, but not prefrontal cortex A42 levels 15 mg/kg daily sildenafil, Tg2576 AD mice Sildenafil improved memory, tau but not [148] intraperitoneal frontal cortex amyloid pathology, inhibited GSK3, decreased CDK5 p25/35 ratio, upregulated BDNF and Arc Variable Aged mice Sildenafil improved spatial memory [64] retention but not acquisition 3 mg/kg intraperitoneal sildenafil Aged mice Sildenafil decreased double-stranded DNA [149] daily for 3 weeks breaks and pro-apoptotic caspase-3 and Bax and upregulated antiapoptotic Bcl2 and BDNF 7.5 mg/kg sildenafil SAMP8 mice Sildenafil improved amyloid and tau [145, 150] intraperitoneally once daily for 4 pathology, memory, and gliosis weeks 7.5 mg/kg sildenafil SAMP8 mice Sildenafil decreased JNK [151] intraperitoneally once daily for 4 phosphor-activation in the hippocampus, tau weeks phosphorylation, and memory deficits 50 mg sildenafil, single dosage 10 AD patients Sildenafil decreased spontaneous neural [152] activity in right hippocampus 50 mg sildenafil, single dosage 14 AD patients Sildenafil increased cerebral metabolic rate [127] of oxygen and cerebral blood flow in 12 patients, decreased cerebral vascular reactivity in 8 patients factor-␣ (TNF-␣) in the hippocampus, decreased hip- PDE5 is not located in brain structures critical for AD pocampal soluble A40 and A42 expression, and based on the lack of specific hybridization of a PDE5 increased CREB phosphorylation [147]. mRNA probe [62–64], but as noted, other groups have A recent systematic review found that, on the Mor- found increased PDE5 mRNA or protein expression ris water maze and the T-maze, sildenafil improved in AD patients’ entorhinal [58] or temporal cortices spatial memory retention but not acquisition in aged [55], respectively, and PDE5 mRNA expression has mice [64]. Interestingly, this review reported that been found by multiple groups in the normal human 98 O. Sanders / Sildenafil for Alzheimer’s Disease brain, albeit at lower levels than in peripheral tissues blood oxygen level-dependent signal, a parameter [58–61]. that had been shown to be aberrantly increased in In J20 AD mice, 15 mg/kg sildenafil daily for AD patients’ hippocampi and parahippocampal gyri 10 weeks in drinking water resulted in improved [152]. In 12 elderly patients with AD, a single dosage performance on the Morris water maze, decreased of 50 mg of sildenafil significantly increased the cere- tau hyperphosphorylation, and increased Akt and bral metabolic rate of oxygen and cerebral blood flow GSK3 phosphorylation, but it did not alter pre- [127]. In 8 AD patients, it decreased cerebrovascular frontal cortex A42 levels [61]. reactivity [127]. In Tg2576 AD mice, 15 mg/kg/day intraperitoneal sildenafil significantly rescued learning and memory deficits as shown by the Morris water maze and fear DISCUSSION conditioning tasks, reduced hippocampal tau hyper- phosphorylation, GSK3 activity, and the CDK5 As predicted in the introduction, preclinical studies p25/p35 ratio, upregulated hippocampal p-CREB that tested these parameters have found that sildenafil and c-Fos following fear conditioning training, and rescued CREB phosphorylation, long-term potentia- increased hippocampal expression of brain-derived tion, and learning and memory [61, 143–148, 150, neurotrophic factor (BDNF) and activity-regulated 151], increased neurogenesis [145], and decreased cytoskeletal-associated protein (Arc) (an immediate neuroinflammation [145, 147, 150]. In addition, these early response gene involved in memory encoding) studies consistently found that sildenafil decreased [148]. However, sildenafil did not affect total A42 tau hyperphosphorylation and related parameters [61, levels in the frontal cortex [148]. 145, 148, 150, 151]. This might be in part because In aged mice, 3 mg/kg intraperitoneal sildenafil the MnSOD downregulation in AD hippocampal daily for 3 weeks decreased double-stranded DNA neurons contributes to tau hyperphosphorylation breaks and apoptotic cells as visualized by the ter- [45,153], and low-dose sildenafil appears to upreg- minal deoxyuridine triphosphate nick end labeling ulate MnSOD via PGC1␣ activation [69–72]. The (TUNEL) assay in the CA1 hippocampus, down- relatively high 15 mg/kg dosages appear to have regulated proapoptotic proteins caspase-3 and B-cell resulted in decreased tau hyperphosphorylation pre- lymphoma 2-associated X (Bax), upregulated anti- dominantly because high-dose sildenafil activated the apoptotic B-cell lymphoma protein-2 (Bcl2) and cGMP/PKG/PI3K/Akt pathway, leading to increased BDNF, downregulated APP expression, and sup- inhibitory Ser9 phosphorylation of tau kinase GSK3 pressed the age-associated shift in the A42/A40 [61, 80, 148]. ratio [149]. Discrepancies have been reported, however, In the senescence accelerated mouse-prone 8 regarding the effect of sildenafil on A levels: most (SAMP8) mouse model of accelerated aging and spo- of the studies showed that sildenafil decreases A radic AD, 7.5 mg/kg sildenafil for 4 weeks improved levels [144–147, 150], but the two studies using cognitive performance as shown by the Morris water the highest dosages (15 mg/kg) reported no effect maze and the passive avoidance test [145, 150, 151], on frontal cortex A levels [61, 148]. This can be tau hyperphosphorylation [145, 151], inflammation understood through the lens of the U-shaped dose- as shown by GFAP downregulation, and amyloid response curve of sildenafil and cGMP on PGC1␣ pathology as shown by downregulation of BACE1, signaling documented in the introduction: low-dose cathepsin B, and hippocampal A42 [150]. Sildenafil sildenafil and cGMP appear to activate PGC1␣ and also activated Akt and inhibited GSK3, calpain, suppress BACE1 expression [65, 70, 76], whereas cyclin-dependent kinase 5 (CDK5) [145, 150], and high-dose sildenafil and 100 M cGMP appear to c-Jun N-terminal kinase (JNK) [151]. inhibit PGC1␣ due to crosstalk with cAMP and PDE2 signaling, failing to suppress BACE1 expres- Sildenafil in AD patients sion. In other words, it is possible that the 15 mg/kg sildenafil studies may not have decreased A levels In 10 AD patients, a single 50 mg dose of sildenafil significantly [61, 148] because that dosage activates significantly decreased spontaneous neural activity PDE2, depletes cAMP [76], and inhibits cAMP- in the right hippocampus as shown by the fractional signaled PGC1␣ activation and BACE1 repression amplitude of low-frequency fluctuations recorded [65, 67]. Another intriguing observation is that only on functional magnetic resonance imaging of the the 15 mg/kg studies reported Akt activation and/or O. Sanders / Sildenafil for Alzheimer’s Disease 99
GSK3 inhibition [61, 148], suggesting the possibil- moderate AD patients in 5 phase III clinical trials ity that the 15 mg/kg dosages activated Akt [61, 148] [158–164]. Intriguingly, a recent review by Heckman and may have consequently repressed PGC1␣ expres- and colleagues opined that, based on the preclini- sion and its anti-amyloidogenic properties (Fig. 4) cal evidence, inhibition of PDE2, PDE4, and PDE5 [80–82]. seemed to hold the most promise for the treatment of Interestingly, in vitro studies found that silde- AD [165], and sildenafil and propentofylline admin- nafil protected mitochondria from A or AGEs via istered together would potently inhibit these three ATP-sensitive K+ channels or HO1 upregulation, therapeutic targets simultaneously [157]. respectively [140, 141], suggesting that sildenafil Ultimately, a randomized control trial of sildenafil may promote mitochondrial function via multiple should be undertaken in AD patients to assess the mechanisms, some of which may be independent of clinical benefits of long-term sildenafil admin- PGC1␣. istration in this population compared to elderly In patients, an especially promising finding is that controls. This RCT should use the 50 mg/day dosage 50 mg sildenafil increased the cerebral metabolic rate [127]. As outcome measures, the RCT should of oxygen [127]. This effect might be accounted test cognition on the MMSE and the Alzheimer’s for totally by the increases in the cerebral blood Disease Assessment Scale-Cognitive Subscale, flow [127], or it may have been partially medi- comorbid depression on the Geriatric Depression ated as well by PGC1␣-regulated mitochondrial Scale [56], amyloid and tau pathology binding with biogenesis. However, none of the studies reviewed 2-(1-6-[(2-[F- 18]fluoroethyl)(methyl)amino]-2- measured PGC1␣ mRNA, protein, or acetylation naphthylethylidene)malononitrile positron emission levels, nor other markers of mitochondrial biogen- tomography (FDDNP-PET) [166, 167], cerebral esis, making it impossible to evaluate this possibility. blood flow with MRI [127], the cerebral metabolic Nor was the effect of sildenafil on SIRT1 activ- rate of oxygen with MRI [127, 168, 169], the ity or the SIRT1/PGC1␣ pathway explored in any cerebral metabolic rate of glucose with 18F- of these studies. Nor did these studies examine fluoro-deoxyglucose positron emission tomography the effect of sildenafil on markers of insulin resis- (FDG-PET) [34, 35, 170–174], inflammation with tance or antioxidant enzyme expression. Future CSF IL-1, IL-6, and TNF-␣ [124–126, 147, preclinical studies in transgenic AD mice should 175–182], NOS/NO/sGC/cGMP/PGC1␣ path- address these points directly to assess the possible way dysfunction with CSF cGMP [55, 56], and role of SIRT1 and PGC1␣ activity in sildenafil- antioxidant enzyme activity with urine 8-oxo-2’- induced A suppression, mitochondrial biogenesis, deoxyguanosine as an indirect biomarker [45, 69, and antioxidant enzyme expression in AD, as well 71, 72, 183]. as the putative effect of sildenafil on insulin resis- tance. Future studies should also assess the potential CONFLICT OF INTEREST of combining sildenafil with a PDE2 inhibitor to increase sildenafil’s maximal effective dosage con- The authors have no conflict of interest to report. tinuously throughout the treatment duration. This would bypass the dose-limiting effect of sildenafil on REFERENCES PDE2 activation and cAMP depletion [76], allowing for robust simultaneous cAMP and cGMP signaling [1] Li X, Jiang LH (2018) Multiple molecular mecha- and therefore maximal PGC1␣ activity, mitochon- nisms form a positive feedback loop driving amyloid drial biogenesis, antioxidant enzyme expression, and 42 peptide-induced neurotoxicity via activation of the TRPM2 channel in hippocampal neurons. Cell Death Dis BACE1 repression [48, 65–67, 69, 70, 73–75, 96, 108, 9, 1-16. 109, 112, 115, 116, 154–156]. The best candidate [2] Suh SW, Jensen KB, Jensen MS, Silva DS, Kesslak PJ, for this role would be propentofylline, a potent and Danscher G, Frederickson CJ (2000) Histochemically- broad-spectrum PDE inhibitor and methyl xanthine reactive zinc in amyloid plaques, angiopathy, and degenerating neurons of Alzheimer’s diseased brains. derivate like caffeine that is particularly effective Brain Res 852, 274-278. at inhibiting cGMP-stimulated PDE2 activity and [3] Yumoto S, Kakimi S, Ishikawa A (2018) Colocalization PDE4 [157]. Propentofylline would be superior to of aluminum and iron in nuclei of nerve cells in brains of other PDE2 inhibitors primarily because 300 mg of patients with Alzheimer’s disease. J Alzheimers Dis 65, 1267-1281. it taken thrice daily one hour before meals has been [4] Smith MA, Zhu X, Tabaton M, Liu G, McKeel DW, tested and found to be safe and effective in mild to Cohen ML, Wang X, Siedlak SL, Dwyer BE, Hayashi T, 100 O. Sanders / Sildenafil for Alzheimer’s Disease
Nakamura M, Nunomura A, Perry G (2010) Increased iron S-phase in the ectopic cell cycle re-entry of neurons in and free radical generation in preclinical Alzheimer dis- Alzheimer disease. Aging (Albany NY) 1, 382-388. ease and mild cognitive impairment. J Alzheimers Dis 19, [21] Zhu X, Lee H, Perry G, Smith MA (2007) Alzheimer dis- 353-372. ease, the two-hit hypothesis: An update. Biochim Biophys [5] Forbes WF, McLachlan DR (1996) Further thoughts on the Acta 1772, 494-502. aluminum-Alzheimer’s disease link. J Epidemiol Commu- [22] Zhu X, Siedlak SL, Wang Y, Perry G, Castellani RJ, nity Health 50, 401-403. Cohen ML, Smith MA (2008) Neuronal binucleation in [6] Xu L, Zhang W, Liu X, Zhang C, Wang P, Zhao X Alzheimer disease hippocampus. Neuropathol Appl Neu- (2018) Circulatory levels of toxic metals (aluminum, cad- robiol 34, 457-465. mium, mercury, lead) in patients with Alzheimer’s disease: [23] Bushman DM, Kaeser GE, Siddoway B, Westra JW, A quantitative meta-analysis and systematic review. J Rivera RR, Rehen SK, Yung YC, Chun J (2015) Alzheimers Dis 62, 361-372. Genomic mosaicism with increased amyloid precursor [7] McLachlan DR, Smith WL, Kruck TP (1993) Desfer- protein (APP) gene copy number in single neurons rioxamine and Alzheimer’s disease: Video home behavior from sporadic Alzheimer’s disease brains. Elife 4, doi: assessment of clinical course and measures of brain alu- 10.7554/eLife.05116 minum. Ther Drug Monit 15, 602-607. [24] Yang Y, Geldmacher DS, Herrup K (2001) DNA replica- [8] Perl DP, Good PF (1987) The association of aluminum tion precedes neuronal cell death in Alzheimer’s disease. Alzheimer’s disease, and neurofibrillary tangles. J Neural J Neurosci 21, 2661-2668. Transm Suppl 24, 205-211. [25] Iourov IY, Vorsanova SG, Liehr T, Yurov YB (2009) [9] Rui D, Yongjian Y (2010) Aluminum chloride induced Aneuploidy in the normal, Alzheimer’s disease and oxidative damage on cells derived from hippocampus and ataxia-telangiectasia brain: Differential expression and cortex of ICR mice. Brain Res 1324, 96-102. pathological meaning. Neurobiol Dis 34, 212-220. [10] Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Bal- [26] Mosch B, Morawski M, Mittag A, Lenz D, Tarnok A, raj EK, Jones PK, Ghanbari H, Wataya T, Shimohama Arendt T (2007) Aneuploidy and DNA replication in the S, Chiba S, Atwood CS, Petersen RB, Smith MA (2001) normal human brain and Alzheimer’s disease. J Neurosci Oxidative damage is the earliest event in Alzheimer dis- 27, 6859-6867. ease. J Neuropathol Exp Neurol 60, 759-767. [27] Miklossy J (2008) Chronic inflammation and amyloido- [11] Butterfield DA, Sultana R (2007) Redox proteomics genesis in Alzheimer’s disease – role of spirochetes. J identification of oxidatively modified brain proteins in Alzheimers Dis 13, 381-391. Alzheimer’s disease and mild cognitive impairment: [28] Alonso R, Pisa D, Fernandez-Fern´ andez´ AM, Carrasco L Insights into the progression of this dementing disorder. J (2018) Infection of fungi and bacteria in brain tissue from Alzheimers Dis 12, 61-72. elderly persons and patients with Alzheimer’s disease. [12] Bradley MAA, Markesbery WRR, Lovell MAA (2010) Front Aging Neurosci 10, 159. Increased levels of 4-hydroxynonenal and acrolein in the [29] Piacentini R, De Chiara G, Li Puma DD, Ripoli C, Mar- brain in preclinical Alzheimer disease. Free Radic Biol cocci ME, Garaci E, Palamara AT, Grassi C (2014) HSV-1 Med 48, 1570-1576. and Alzheimer’s disease: More than a hypothesis. Front [13] Lovell MA, Soman S, Bradley MA (2011) Oxidatively Pharmacol 5, 97. modified nucleic acids in preclinical Alzheimer’s disease [30] Ful¨ op¨ T, Itzhaki RF, Balin BJ, Miklossy J, Barron (PCAD) brain. Mech Ageing Dev 132, 443-448. AE (2018) Role of microbes in the development of [14] Vincent I, Jicha G, Rosado M, Dickson DW (1997) Aber- Alzheimer’s disease: State of the Art - An International rant expression of mitotic Cdc2 / Cyclin B1 kinase in Symposium Presented at the 2017 IAGG Congress in San degenerating neurons of Alzheimer’s disease brain. J Neu- Francisco. Front Genet 9, 1-16. rosci 17, 3588-3598. [31] Devanand DP (2018) Viral hypothesis and antiviral treat- [15] Nagy Z, Esiri MM, Cato AM, Smith AD (1997) Cell cycle ment in Alzheimer’s disease. Curr Neurol Neurosci Rep markers in the hippocampus in Alzheimer’s disease. Acta 18, 55. Neuropathol 94, 6-15. [32] Osorio C, Kanukuntla T, Diaz E, Jafri N, Cummings M, [16] Frade JM, Lopez-S´ anchez´ N (2010) neuronal tetraploidy Sfera A (2019) The post-amyloid era in Alzheimer’s dis- induced by p75 A novel hypothesis for Alzheimer disease ease: Trust your gut feeling. Front Aging Neurosci 11, based on neuronal tetraploidy induced by p75 NTR. Cell 143. Cycle 9, 1934-1941. [33] Moir RD, Lathe R, Tanzi RE (2018) The antimicrobial [17] Westra JW, Barral S, Chun J (2009) A reevaluation of protection hypothesis of Alzheimer’s disease. Alzheimers tetraploidy in the Alzheimer’s disease brain. Neurodegener Dement 14, 1602-1614. Dis 6, 221-229. [34] Talbot K, Wang H, Kazi H, Han L-Y, Bakshi KP, [18] Walton CC, Perea G, Frade JM, Barrio-Alonso E, Stucky A, Fuino RL, Kawaguchi KR, Samoyedny AJ, Hernandez-Vivanco´ A, Walton CC, Perea G, Frade JM Wilson RS, Arvanitakis Z, Schneider JA, Wolf BA, (2018) Cell cycle reentry triggers hyperploidization and Bennett DA, Trojanowski JQ, Arnold SE (2012) Demon- synaptic dysfunction followed by delayed cell death in strated brain insulin resistance in Alzheimer’s disease differentiated cortical neurons. Sci Rep 8, 1-14. patients is associated with IGF-1 resistance, IRS-1 dys- [19] Fuchsberger T, Lloret A, Vina˜ J, Fuchsberger T, Lloret A, regulation, and cognitive decline. J Clin Invest 122, Vina˜ J (2017) New functions of APC/C ubiquitin ligase in 1316-1338. the nervous system and its role in Alzheimer’s disease. Int [35] Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, J Mol Sci 18, 1057. Tavares R, Xu XJ, Wands JR, de la Monte SM (2005) [20] Bonda DJ, Evans TA, Santocanale C, Llosa´ JC, Vina˜ J, Impaired insulin and insulin-like growth factor expression Bajic VP, Castellani RJ, Siedlak SL, Perry G, Smith MA, and signaling mechanisms in Alzheimer’s disease - is this Lee HG (2009) Evidence for the progression through type 3 diabetes? J Alzheimers Dis 7, 63-80. O. Sanders / Sildenafil for Alzheimer’s Disease 101
[36] Ramos-Cejudo J, Wisniewski T, Marmar C, Zetterberg H, NOS-isoforms is increased in Alzheimer’s disease, in Blennow K, de Leon MJ, Fossati S (2018) Traumatic brain APP23 transgenic mice and after experimental brain lesion injury and Alzheimer’s disease: The cerebrovascular link. in rat: Evidence for an induction by amyloid pathology. EBioMedicine 28, 21-30. Brain Res 913, 57-67. [37] Ishii K, Sasaki M, YamajiS, Sakamoto S, Kitagaki H, Mori [54] Bonkale WL, Winblad B, Ravid R, Cowburn RF (1995) E (1998) Paradoxical hippocampus perfusion in mild-to- Reduced nitric oxide responsive soluble guanylyl cyclase moderate Alzheimer’s disease. J Nucl Med 39, 293-298. activity in the superior temporal cortex of patients with [38] Ishii K, Kitagaki H, Kono M, Mori E (1996) Decreased Alzheimer’s disease. Neurosci Lett 187, 5-8. medial temporal oxygen metabolism in Alzheimer’s dis- [55] Ugarte A, Gil-Bea F, Garc´ıa-Barroso C, Cedazo-Minguez ease shown by PET. J Nucl Med 37, 1159-1165. A,´ Ram´ırez MJ, Franco R, Garc´ıa-Osta A, Oyarzabal J, [39] Overk CR, Masliah E (2014) Pathogenesis of synaptic Cuadrado-Tejedor M (2015) Decreased levels of guano- degeneration in Alzheimer’s disease and Lewy body dis- sine 3’, 5’-monophosphate (cGMP) in cerebrospinal fluid ease. Biochem Pharmacol 88, 508-516. (CSF) are associated with cognitive decline and amyloid [40] Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. pathology in Alzheimer’s disease. Neuropathol Appl Neu- Science 298, 789-791. robiol 41, 471-482. [41] Ohno M (2018) PERK as a hub of multiple pathogenic [56] Hesse R, Lausser L, Gummert P, Schmid F, Wahler A, pathways leading to memory deficits and neurodegenera- Schnack C, Kroker KS, Otto M, Tumani H, Kestler HA, tion in Alzheimer’s disease. Brain Res Bull 141, 72-78. Rosenbrock H, von Arnim CAF (2017) Reduced cGMP [42] Ohno M (2014) Roles of eIF2alpha kinases in the patho- levels in CSF of AD patients correlate with severity of genesis of Alzheimer’s disease. Front Mol Neurosci 7, dementia and current depression. Alzheimers Res Ther 9, 22. 17. [43] de la Monte SM1, Re E, Longato L, Tong M (2012) [57] Ahmed NS (2019) Tadalafil: 15 years’ journey in male Dysfunctional pro-ceramide, ER stress, and insulin/IGF erectile dysfunction and beyond. Drug Dev Res 80, 683- signaling networks with progression of Alzheimer’s dis- 701. ease. J Alzheimers Dis 30(Suppl 2), S217-S229. [58] Xu M, Zhang DF, Luo R, Wu Y, Zhou H, Kong LL, Bi R, [44] de la Monte SM (2012) Triangulated mal-signaling in Yao YG (2018) A systematic integrated analysis of brain Alzheimer’s disease: Roles of neurotoxic ceramides, ER expression profiles reveals YAP1and other prioritized hub stress, and insulin resistance reviewed. J Alzheimers Dis genes as important upstream regulators in Alzheimer’s 30(Suppl 2), S231-S249. disease. Alzheimers Dement 14, 215-229. [45] Majd S, Power JHT (2018) Oxidative stress and decreased [59] Lakics V, Karran EH, Boess FG (2010) Quantitative mitochondrial superoxide dismutase 2 and peroxiredox- comparison of phosphodiesterase mRNA distribution in ins 1 and 4 based mechanism of concurrent activation of human brain and peripheral tissues. Neuropharmacology AMPK and mTOR in Alzheimer’s disease. Curr Alzheimer 59, 367-374. Res 15, 1-13. [60] Loughney K, Hill TR, Florio VA, Uher L, Rosman GJ, [46] Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Wolda SL, Jones BA, Howard ML, McAllister-Lucas Atwood CS, Johnson AB, Kress Y, Vinters H V, Tabaton LM, Sonnenburg WK, Francis SH, Corbin JD, Beavo M, Shimohama S, Cash AD, Siedlak SL, Harris PL, Jones JA, Ferguson K (1998) Isolation and characterization PK, Petersen RB, Perry G, Smith MA (2001) Mitochon- of cDNAs encoding PDE5A, a human cGMP-binding, drial abnormalities in Alzheimer’s disease. J Neurosci 21, cGMP-specific 3’,5’-cyclic nucleotide phosphodiesterase. 3017-3023. Gene 216, 139-147. [47] Moreira PI, Siedlak SL, Wang X, Santos MS, Oliveira CR, [61] Garc´ıa-Barroso C, Ricobaraza A, Pascual-Lucas M, Unc- Tabaton M, Nunomura A, Szweda LI, Aliev G, Smith MA, eta N, Rico AJ, Goicolea MA, Salles´ J, Lanciego JL, Zhu X, Perry G (2007) Autophagocytosis of mitochon- Oyarzabal J, Franco R, Cuadrado-Tejedor M, Garc´ıa-Osta dria is prominent in Alzheimer disease. J Neuropathol Exp A (2013) Tadalafil crosses the blood-brain barrier and Neurol 66, 525-532. reverses cognitive dysfunction in a mouse model of AD. [48] Sheng B, Wang X, Su B, Lee HG, Casadesus G, Perry Neuropharmacology 64, 114-123. G, Zhu X (2012) Impaired mitochondrial biogenesis [62] Reyes-Irisarri E, Markerink-Van Ittersum M, Mengod G, contributes to mitochondrial dysfunction in Alzheimer’s De Vente J (2007) Expression of the cGMP-specific phos- disease. J Neurochem 120, 419-429. phodiesterases 2 and 9 in normal and Alzheimer’s disease [49] Fiscus RR (2002) Involvement of cyclic GMP and protein human brains. Eur J Neurosci 25, 3332-3338. kinase G in the regulation of apoptosis and survival in [63] Blokland A, Menniti FS, Prickaerts J (2012) PDE Inhibi- neural cells. Neurosignals 11, 175-190. tion and cognition enhancement. Expert Opin Ther Pat 22, [50] Liu P, Fleete MS, Jing Y, Collie ND, Curtis MA, Waldvo- 349-354. gel HJ, Faull RLM, Abraham WC, Zhang H (2014) Altered [64] Devan BD, Pistell PJ, Duffy KB, Kelley-Bell B, Spangler arginine metabolism in Alzheimer’s disease brains. Neu- EL, Ingram DK (2014) Phosphodiesterase inhibition facil- robiol Aging 35, 1992-2003. itates cognitive restoration in rodent models of age-related [51] Luth¨ HJ, Holzer M, Gertz H-J, Arendt T (2000) Aberrant memory decline. Neurorehabilitation 34, 101-111. expression of nNOS in pyramidal neurons in Alzheimer’s [65] Kwak Y-D, Wang R, Li J, Zhang Y-W, Xu H, Liao F- disease is highly co-localized with p21 ras and p16 INK4a. F (2011) Differential regulation of BACE1 expression Brain Res 852, 45-55. by oxidative and nitrosative signals. Mol Neurodegener [52] Luth¨ H-JJ, Munch¨ G, Arendt T (2002) Aberrant expression 6, 17. of NOS isoforms in Alzheimer’s disease is structurally [66] Nisoli E, Falcone S, Tonello C, Cozzi V, Palomba L, Fio- related to nitrotyrosine formation. Brain Res 953, 135-143. rani M, Pisconti A, Brunelli S, Cardile A, Francolini M, [53] Luth¨ HJ, Holzer M, Gartner¨ U, Staufenbiel M, Arendt Cantoni O, Carruba MO, Moncada S, Clementi E (2004) T (2001) Expression of endothelial and inducible Mitochondrial biogenesis by NO yields functionally active 102 O. Sanders / Sildenafil for Alzheimer’s Disease
mitochondria in mammals. Proc Natl Acad SciUSA101, M (2010) Inactivation of Foxo3a and subsequent down- 16507-16512. regulation of PGC-1 alpha mediate nitric oxide-induced [67] Fernandez-Marcos PJ, Auwerx J (2011) Regulation of endothelial cell migration. Mol Cell Biol 30, 4035-4044. PGC-1␣, a nodal regulator of mitochondrial biogenesis. [81] Xiong S, Salazar G, San Martin A, Ahmad M, Patrushev Am J Clin Nutr 93, 884S-890. N, Hilenski L, Nazarewicz RR, Ma M, Ushio-Fukai M, [68] Wang H, Peiris TH, Mowery A, Lay J Le, Gao Y, Green- Alexander RW (2010) PGC-1␣serine 570 phosphorylation baum LE (2008) CCAAT/enhancer binding protein- and GCN5-mediated acetylation by angiotensin II drive is a transcriptional regulator of peroxisome-proliferator- catalase down-regulation and vascular hypertrophy. J Biol activated receptor-␥ coactivator-1␣ in the regenerating Chem 285, 2474-2487. liver. Mol Endocrinol 22, 1596-1605. [82] Li X, Monks B, Ge Q, Birnbaum MJ (2007) Akt/PKB [69] Olmos Y,Sanchez-G´ omez´ FJ, Wild B, Garc´ıa-Quintans N, regulates hepatic metabolism by directly inhibiting PGC- Cabezudo S, Lamas S, Monsalve M (2013) SirT1 regula- 1␣ transcription coactivator. Nature 447, 1012-1016. tion of antioxidant genes is dependent on the formation of [83] Borniquel S, Valle I, Cadenas S, Lamas S, Monsalve a FoxO3a/PGC-1␣ complex. Antioxidants Redox Signal M (2006) Nitric oxide regulates mitochondrial oxidative 19, 1507-1521. stress protection via the transcriptional coactivator PGC- [70] Whitaker RM, Wills LP, Stallons LJ, Schnellmann 1␣. FASEB J 20, 1889-1891. RG (2013) CGMP-selective phosphodiesterase inhibitors [84] Lou L, Urbani J, Ribeiro-Neto F, Altschuler DL (2002) stimulate mitochondrial biogenesis and promote recov- cAMP inhibition of Akt is mediated by activated and phos- ery from acute kidney injury. J Pharmacol Exp Ther 347, phorylated Rap1b. J Biol Chem 277, 32799-32806. 626-634. [85] Lu Y-F, Hawkins RD (2002) Ryanodine receptors con- [71] Perk H, Armagan A, Nazıroglu˘ M, Soyupek S, Hoscan tribute to cGMP-induced late-phase LTP and CREB MB, Sutc¨ u¨ R, Ozorak A, Delibas N (2008) Sildenafil cit- phosphorylation in the hippocampus. J Neurophysiol 88, rate as a phosphodiesterase inhibitor has an antioxidant 1270-1278. effect in the blood of men. J Clin Pharm Ther 33, 635-640. [86] Chen Y, Zhuang S, Cassenaer S, Casteel DE, Gudi T, [72] Sheweita S, Salama B, Hassan M (2015) Erectile dysfunc- Boss GR, Pilz RB (2003) Synergism between calcium and tion drugs and oxidative stress in the liver of male rats. cyclic GMP in cyclic AMP response element-dependent Toxicol Rep 2, 933-938. transcriptional regulation requires cooperation between [73] Nisoli E, Clementi E, Paolucci C, Cozzi V, Tonello C, CREB and C/EBP-beta. Mol Cell Biol 23, 4066-4082. Sciorati C, Bracale R, Valerio A, Francolini M, Moncada [87] Fiorito J, Deng S, Landry DW, Arancio O (2018) Targeting S, Carruba MO (2003) Mitochondrial biogenesis in mam- the NO/cGMP/CREB phosphorylation signaling pathway mals: The role of endogenous nitric oxide. Science 299, in Alzheimer’s disease. In Neurochemical Basis of Brain 896-899. Function and Dysfunction, Heinbockel T, Csoka AB, eds. [74] Gureev AP, Shaforostova EA, Popov VN (2019) Regu- IntechOpen, doi: 10.5772/intechopen.81029 lation of mitochondrial biogenesis as a way for active [88] Ciani E, Guidi S, Bartesaghi R, Contestabile A ␣ longevity: Interaction between the Nrf2 and PGC-1 sig- (2002) Nitric oxide regulates cGMP-dependent cAMP- naling pathways. Front Genet 10, 435. responsive element binding protein phosphorylation and [75] Gutsaeva DR, Carraway MS, Suliman HB, Demchenko Bcl-2 expression in cerebellar neurons: Implication for a IT, Shitara H, Yonekawa H, Piantadosi CA (2008) Tran- survival role of nitric oxide. J Neurochem 82, 1282-1289. sient hypoxia stimulates mitochondrial biogenesis in brain [89] Nagai-Kusuhara A, Nakamura M, Mukuno H, Kanamori subcortex by a neuronal nitric oxide synthase-dependent A, Negi A, Seigel GM (2007) cAMP-responsive ele- mechanism. J Neurosci 28, 2015-2024. ment binding protein mediates a cGMP/protein kinase [76] Banerjee J, Bruckbauer A, Thorpe T, Zemel MB (2019) G-dependent anti-apoptotic signal induced by nitric oxide Biphasic effect of sildenafil on energy sensing is medi- in retinal neuro-glial progenitor cells. Exp Eye Res 84, ated by phosphodiesterases 2 and 3 in adipocytes and 152-162. hepatocytes. Int J Mol Sci 20, E2992. [90] Puzzo D, Vitolo O, Trinchese F, Jacob JP, Palmeri A, [77] Vettel C, Lammle¨ S, Ewens S, Cervirgen C, Emons J, Arancio O (2005) Amyloid- peptide inhibits activation of Ongherth A, Dewenter M, Lindner D, Westermann D, the nitric oxide/cGMP/cAMP-responsive element-binding Nikolaev VO, Lutz S, Zimmermann WH, El-Armouche protein pathway during hippocampal synaptic plasticity. J A (2014) PDE2-mediated cAMP hydrolysis accelerates Neurosci 25, 6887-6897. cardiac fibroblast to myofibroblast conversion and is [91] Lustig Y,Ruas JL, Estall JL, Lo JC, Devarakonda S, Laznik antagonized by exogenous activation of cGMP signaling D, Choi JH, Ono H, Olsen JV,Spiegelman BM (2011) Sep- pathways. Am J Physiol Heart Circ Physiol 306, H1246- aration of the gluconeogenic and mitochondrial functions H1252. of pgc-1␣ through s6 kinase. Genes Dev 25, 1232-1244. [78] Laurent A-C, Bisserier M, Lucas A, Tortosa F, Roumieux [92] Anderson RM, Barger JL, Edwards MG, Braun KH, M, De Regibus´ A, Swiader A, Sainte-Marie Y, Heymes C, O’connor CE, Prolla TA, Weindruch R (2008) Dynamic Vindis C, Lezoualc’h F (2015) Exchange protein directly regulation of PGC-1␣ localization and turnover impli- activated by cAMP 1 promotes autophagy during car- cates mitochondrial adaptation in calorie restriction and diomyocyte hypertrophy. Cardiovasc Res 105, 55-64. the stress response. Aging Cell 7, 101-111. [79] Omar B, Zmuda-Trzebiatowska E, Manganiello V, [93] Dominy JE, Lee Y, Gerhart-Hines Z, Puigserver P (2010) Goransson¨ O, Degerman E (2009) Regulation of AMP- Nutrient-dependent regulation of PGC-1␣’s acetylation activated protein kinase by cAMP in adipocytes: Roles for state and metabolic function through the enzymatic phosphodiesterases, protein kinase B, protein kinase A, activities of Sirt1/GCN5. Biochim Biophys Acta 1804, Epac and lipolysis. Cell Signal 21, 760-766. 1676-1683. [80] Borniquel S, Garc´ıa-Quintans´ N, Valle I, Olmos Y, Wild [94] Gerhart-Hines Z, Rodgers JT, Bare O, Lerin C, Kim SH, B, Mart´ınez-Granero F, Soria E, Lamas S, Monsalve Mostoslavsky R, Alt FW, Wu Z, Puigserver P (2007) O. Sanders / Sildenafil for Alzheimer’s Disease 103
Metabolic control of muscle mitochondrial function and miR-22/SIRT1 pathway: Evidence from the CECSID trial. fatty acid oxidation through SIRT1/PGC-1␣. EMBO J 26, J Clin Endocrinol Metab 101, 1525-1534. 1913-1923. [110] Nisoli E, Tonello C, Cardile A, Cozzi V, Bracale R, [95] Lerin C, Rodgers JT, Kalume DE, Kim SH, Pandey Tedesco L, Falcone S, Valerio A, Cantoni O, Clementi A, Puigserver P (2006) GCN5 acetyltransferase com- E, Moncada S, Carruba MO (2005) Calorie restric- plex controls glucose metabolism through transcriptional tion promotes mitochondrial biogenesis by inducing the repression of PGC-1␣. Cell Metab 3, 429-438. expression of eNOS. Science 310, 314-317. [96] Nemoto S, Fergusson MM, Finkel T (2005) SIRT1 [111] Kitada M, Ogura Y, Koya D (2016) The protective role of functionally interacts with the metabolic regulator and Sirt1 in vascular tissue: Its relationship to vascular aging transcriptional coactivator PGC-1␣. J Biol Chem 280, and atherosclerosis. Aging (Albany NY) 8, 2290-2307. 16456-16460. [112] Ayrapetyan T (2018) Defective NO/cGMP/PKG signaling [97] Jaer¨ S, Handschin C, St-Pierre J, Spiegelman BM (2007) downregulates Sirt1 expression in aged osteoblasts. UC AMP-activated protein kinase (AMPK) action in skeletal San Diego. ProQuest ID: AYRAPETYAN ucsd 0033M muscle via direct phosphorylation of PGC-1␣. Proc Natl 17722. Merritt ID: ark:/13030/m5f819f3. Acad SciUSA104, 12017-12022. [113] Shao H, Xue Q, Zhang F, Luo Y,Zhu H, Zhang X, Zhang H, [98] Garcia D, Shaw RJ (2017) AMPK: Mechanisms of cellular Ding W, Yu B (2014) Spinal SIRT1 activation attenuates energy sensing and restoration of metabolic balance. Mol neuropathic pain in mice. PLoS One 9, e100938. Cell 66, 789-800. [114] Bermudez-Oca´ na˜ DY, Ambriz-Tututi M, Perez-Severiano´ [99] Wan Z, Root-Mccaig J, Castellani L, Kemp BE, Steinberg F, Granados-Soto V (2006) Pharmacological evidence for GR, Wright DC (2014) Evidence for the role of AMPK the participation of NO-cyclic GMP-PKG-K+ channel in regulating PGC-1 alpha expression and mitochondrial pathway in the antiallodynic action of resveratrol. Phar- proteins in mouse epididymal adipose tissue. Obesity 22, macol Biochem Behav 84, 535-542. 730-738. [115] Jia H, Guo Z, Yao Y (2019) PDE5 inhibitor protects the [100] Leick L, Fentz J, Biensø RS, Knudsen JG, Jeppesen J, mitochondrial function of hypoxic myocardial cells. Exp Kiens B, Wojtaszewski JFP, Pilegaard H (2010) PGC-1␣ Ther Med 17, 199-204. is required for AICAR-induced expression of GLUT4 and [116] Li N, Yuan Y,Li S, Zeng C, Yu W, Shen M, Zhang R, Li C, mitochondrial proteins in mouse skeletal muscle. Am J Zhang Y, Wang H (2016) Pde5 inhibitors protect against Physiol Endocrinol Metab 299, E456-E465. post-infarction heart failure. Front Biosci (Landmark Ed) [101] Tang BL (2016) Sirt1 and the mitochondria. Mol Cells 39, 21, 1194-1210. 87-95. [117] Domek-łopacinska´ KU, Strosznajder JB (2010) Cyclic [102] Barger PM, Browning AC, Garner AN, Kelly DP (2001) GMP and nitric oxide synthase in aging and Alzheimer’s p38 mitogen-activated protein kinase activates peroxi- disease. Mol Neurobiol 41, 129-137. some proliferator-activated receptor ␣: A potential role [118] Alsop DC, Casement M, De Bazelaire C, Fong T, Press in the cardiac metabolic stress response. J Biol Chem 276, DZ (2008) Hippocampal hyperperfusion in Alzheimer’s 44495-44501. disease. Neuroimage 42, 1267-1274. [103] Teyssier C (2005) Activation of nuclear receptor coac- [119] Uazzi MAG, Amaja MIS, Caretti A, Bianciardi P, tivator PGC-1 by arginine methylation. Genes Dev 19, Ronchi R, Fantacci M, Guazzi M, Samaja M (2008) 1466-1473. Phosphodiesterase-5 inhibition abolishes neuron apop- [104] Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, tosis induced by chronic hypoxia independently of Puigserver P (2005) Nutrient control of glucose homeosta- hypoxia-inducible factor-1␣ signaling. Exp Biol Med 233, sis through a complex of PGC-1␣ and SIRT1. Nature 434, 1222-1230. 113-118. [120] Wang L, Zhang ZG, Zhang RL, Chopp M (2005) [105] Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Activation of the PI3-K/Akt pathway mediates cGMP Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, enhanced-neurogenesis in the adult progenitor cells Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J derived from the subventricular zone. J Cereb Blood Flow (2006) Resveratrol improves mitochondrial function and Metab 25, 1150-1158. protects against metabolic disease by activating SIRT1 and [121] Dias Fiuza Ferreira E, Valerio´ Romanini C, Cypriano PE, PGC-1␣. Cell 127, 1109-1122. Weffort de Oliveira RM, Milani H (2013) Sildenafil pro- [106] Gurd BJ (2011) Deacetylation of PGC-1a by SIRT1: vides sustained neuroprotection in the absence of learning Importance for skeletal muscle function andexercise- recovery following the 4-vessel occlusion/internal carotid induced mitochondrial biogenesis. Appl Physiol Nutr artery model of chronic cerebral hypoperfusion in middle- Metab 36, 589-597. aged rats. Brain Res Bull 90, 58-65. [107] Amat R, Planavila A, Chen SL, Iglesias R, Giralt M, Vil- [122] Zhang R, Wang Y, Zhang L, Zhang Z, Tsang W, Lu M, larroya F (2009) SIRT1 controls the transcription of the Zhang L, Chopp M (2002) Sildenafil (Viagra) induces neu- PGC-1a gene in skeletal muscle through PGC-1a auto- rogenesis and promotes functional recovery after stroke in regulatory loop and interaction with MyoD. J Biol Chem rats. Stroke 33, 2675-2680. 284, 21872-21880. [123] Zhang RL, Chopp M, Roberts C, Wei M, Wang X, Liu X, [108] Shalwala M, Zhu S-G, Das A, Salloum FN, Xi L, Lu M, Zhang ZG (2012) Sildenafil enhances neurogenesis Kukreja RC (2014) Sirtuin 1 (SIRT1) activation medi- and oligodendrogenesis in ischemic brain of middle-aged ates sildenafil induced delayed cardioprotection against mouse. PLoS One 7, e48141. ischemia-reperfusion injury in mice. PLoS One 9, e86977. [124] Zemel MB, Kolterman O, Rinella M, Vuppalanchi R, [109] Fiore D, Gianfrilli D, Giannetta E, Galea N, Panio G, Flores O, Barritt AS, Siddiqui M, Chalasani N (2019) Ran- di Dato C, Pofi R, Pozza C, Sbardella E, Carbone I, domized controlled trial of a leucine-metformin-sildenafil Naro F, Lenzi A, Venneri MA, Isidori AM (2016) PDE5 combination (NS-0200) on weight and metabolic param- inhibition ameliorates visceral adiposity targeting the eters. Obesity 27, 59-67. 104 O. Sanders / Sildenafil for Alzheimer’s Disease
[125] Ramirez CE, Nian H, Yu C, Gamboa JL, Luther JM, angioplasty and inhibits platelet aggregation via activation Brown NJ, Shibao CA (2015) Treatment with sildenafil of cGMP-dependent protein kinase. Sci Rep 9, 1-12. improves insulin sensitivity in prediabetes: A randomized, [140] Son Y,Kim K, Cho HR (2018) Sildenafil protects neuronal controlled trial. J Clin Endocrinol Metab 100, 4533-4540. cells from mitochondrial toxicity induced by -amyloid [126] Aversa A, Vitale C, Volterrani M, Fabbri A, Spera G, Fini peptide via ATP-sensitive K+ channels. Biochem Biophys M, Rosano GMC (2008) Chronic administration of Silde- Res Commun 500, 504-510. nafil improves markers of endothelial function in men with [141] Sung SK, Woo JS, Kim YH, Son DW, Lee SW, Song Type 2 diabetes. Diabet Med 25, 37-44. GS (2016) Sildenafil ameliorates advanced glycation end [127] Sheng M, Lu H, Liu P, Li Y, Ravi H, Peng SL, Diaz- products-induced mitochondrial dysfunction in HT-22 Arrastia R, Devous MD, Womack KB (2017) Sildenafil hippocampal neuronal cells. J Korean Neurosurg Soc 59, improves vascular and metabolic function in patients with 259-268. Alzheimer’s disease. J Alzheimers Dis 60, 1351-1364. [142] Perrone L, Grant WB (2015) Observational and ecolog- [128] Grome JJ, Harper AM (1983) The effects of serotonin on ical studies of dietary advanced glycation end products local cerebral blood flow. J Cereb Blood Flow Metab 3, in national diets and Alzheimer’s disease incidence and 71-77. prevalence. J Alzheimers Dis 45, 965-979. [129] Geday J, Hermansen F, Rosenberg R, Smith DF (2005) [143] Devan BD, Sierra-Mercado D, Jimenez M, Bowker JL, Serotonin modulation of cerebral blood flow measured Duffy KB, Spangler EL, Ingram DK (2004) Phospho- with positron emission tomography (PET) in humans. diesterase inhibition by sildenafil citrate attenuates the Synapse 55, 224-229. learning impairment induced by blockade of cholinergic [130] Steiner JA, Carneiro AMD, Wright J, Matthies HJG, muscarinic receptors in rats. Pharmacol Biochem Behav Prasad HC, Nicki CK, Dostmann WR, Buchanan 79, 691-699. CC, Corbin JD, Francis SH, Blakely RD (2009) [144] Puzzo D, Staniszewski A, XianDeng S, Privitera L, Leznik cGMP-dependent protein kinase i␣ associates with the E, Liu S, Zhang H, Feng Y, Palmeri A, Landry DW, Aran- antidepressant-sensitive serotonin transporter and dictates cio O (2009) Phosphodiesterase 5 inhibition improves rapid modulation of serotonin uptake. Mol Brain 2, 26. synaptic function, memory, and amyloid- load in an [131] Wong A, Zhang YW, Jeschke GR, Turk BE, Rudnick G Alzheimer’s disease mouse model. J Neurosci 29, 8075- (2012) Cyclic GMP-dependent stimulation of serotonin 8086. transport does not involve direct transporter phosphoryla- [145] Zhu L, Yang JY, Xue X, Dong YX, Miao FR, Wang tion by cGMP-dependent protein kinase. J Biol Chem 287, YF, Xue H, Wu CF (2015) A novel phosphodiesterase- 36051-36058. 5 Inhibitor: Yonkenafil modulates neurogenesis, gliosis to [132] Zhang YW, Gesmonde J, Ramamoorthy S, Rudnick G improve cognitive function and ameliorates amyloid bur- (2007) Serotonin transporter phosphorylation by cGMP- den in an APP/PS1 transgenic mice model. Mech Ageing dependent protein kinase is altered by a mutation Dev 150, 34-45. associated with obsessive-compulsive disorder. J Neurosci [146] Jin F, Gong Q-HH, Xu Y-SS, Wang L-NN, Jin H, 27, 10878-10886. Li F, Li L-SS, Ma Y-MM, Shi J-SS (2014) Icariin, a [133] Nurnberg HG, Seidman SN, Gelenberg AJ, Fava M, Rosen phoshphodiesterase-5 inhibitor, improves learning and R, Shabsigh R (2002) Depression, antidepressant thera- memory in APP/PS1 transgenic mice by stimulation of pies, and erectile dysfunction: Clinical trials of sildenafil NO/cGMP signalling. Int J Neuropsychopharmacol 17, citrate (Viagra®) in treated and untreated patients with 871-881. depression. Urology 60, 58-66. [147] Zhang J, Guo J, Zhao X, Chen Z, Wang G, Liu A, Wang [134] Socała K, Nieoczym D, Pierog´ M, Szuster-Ciesielska A, Q, Zhou W, Xu Y, Wang C (2013) Phosphodiesterase- Wyska E, Wlaz´ P (2016) Antidepressant-like activity of 5 inhibitor sildenafil prevents neuroinflammation, lowers sildenafil following acute and subchronic treatment in the beta-amyloid levels and improves cognitive performance forced swim test in mice: Effects of restraint stress and in APP/PS1 transgenic mice. Behav Brain Res 250, 230- monoamine depletion. Metab Brain Dis 31, 1095-1104. 237. [135] Cheitlin MD, Hutter AM, Brindis RG, Ganz P, Kaul S, [148] Cuadrado-Tejedor M, Hervias I, Ricobaraza A, Puerta E, Russell RO, Zusman RM, Forrester JS, Douglas PS, Faxon Perez-Rold´ an´ JM, Garc´ıa-Barroso C, Franco R, Aguirre N, DP, Fisher JD, Gibbons RJ, Halperin JL, Hochman JS, Garc´ıa-Osta A (2011) Sildenafil restores cognitive func- Kaul S, Weintraub WS, Winters WL, Wolk MJ (1999) tion without affecting -amyloid burden in a mouse model Use of sildenafil (Viagra) in patients with cardiovascular of Alzheimer’s disease. Br J Pharmacol 164, 2029-2041. disease. Circulation 99, 168-177. [149] Puzzo D, Loreto C, Giunta S, Musumeci G, Frasca [136] Kontaras K, Varnavas V,Kyriakides ZS (2008) Does silde- G, Podda MV, Arancio O, Palmeri A (2014) Effect of nafil cause myocardial infarction or sudden cardiac death? phosphodiesterase-5 inhibition on apoptosis and beta amy- Am J Cardiovasc Drugs 8, 1-7. loid load in aged mice. Neurobiol Aging 35, 520-531. [137] Andersson DP, Trolle Lagerros Y, Grotta A, Bellocco R, [150] Orejana L, Barros-Minones˜ L, Jordan J, Cedazo-Minguez Lehtihet M, Holzmann MJ (2017) Association between A, Tordera RM, Aguirre N, Puerta E (2015) Sildenafil treatment for erectile dysfunction and death or cardio- decreases BACE1 and cathepsin B levels and reduces APP vascular outcomes after myocardial infarction. Heart 103, amyloidogenic processing in the SAMP8 mouse. J Geron- 1264-1270. tol Ser A Biol Sci Med Sci 70, 675-685. [138] Balarini CM, Leal MA, Gomes IBS, Pereira TMC, Gava [151] Orejana L, Barros-Minones˜ L, Aguirre N, Puerta E (2013) AL, Meyrelles SS, Vasquez EC (2013) Sildenafil restores Implication of JNK pathway on tau pathology and cog- endothelial function in the apolipoprotein E knockout nitive decline in a senescence-accelerated mouse model. mouse. J Transl Med 11,3. Exp Gerontol 48, 565-571. [139] Yang HM, Jin S, Jang H, Kim JY, Lee JE, Kim J, Kim [152] Samudra N, Motes M, Lu H, Sheng M, Diaz-Arrastia R, HS (2019) Sildenafil reduces neointimal hyperplasia after Devous M, Hart J, Womack KB (2019) A pilot study of O. Sanders / Sildenafil for Alzheimer’s Disease 105
changes in medial temporal lobe fractional amplitude of JR (2018) Memory and brain amyloid and tau effects of low frequency fluctuations after sildenafil administration a bioavailable form of curcumin in non-demented adults: in patients with Alzheimer’s disease. J Alzheimers Dis 70, A double-blind, placebo-controlled 18-month trial. Am J 163-170. Geriatr Psychiatry 26, 266-277. [153] Melov S, Adlard PA, Morten K, Johnson F, Golden TR, [167] Shoghi-Jadid K, Small GW, Agdeppa ED, Kepe V, Ercoli Hinerfeld D, Schilling B, Mavros C, Masters CL, Volitakis LM, Siddarth P, Read S, Satyamurthy N, Petric A, Huang I, Li Q-X, Laughton K, Hubbard A, Cherny RA, Gibson SC, Barrio JR (2002) Localization of neurofibrillary tan- B, Bush AI (2007) Mitochondrial oxidative stress causes gles and beta-amyloid plaques in the brains of living hyperphosphorylation of tau. PLoS One 2, e536. patients with Alzheimer disease. Am J Geriatr Psychiatry [154] Gerhart-Hines Z, Dominy JE, Blattler¨ SM, Jedrychowski 10, 24-35. MP, Banks AS, Lim JH, Chim H, Gygi SP, Puigserver P [168] Xu F, Ge Y, Lu H (2009) Noninvasive quantification of (2011) The cAMP/PKA pathway rapidly activates SIRT1 whole-brain cerebral metabolic rate of oxygen (CMRO2) to promote fatty acid oxidation independently of changes by MRI. Magn Reson Med 62, 141-148. in NAD +. Mol Cell 44, 851-863. [169] Liu P, Xu F, Lu H (2013) Test-retest reproducibility of a [155] Wang R, Li JJ, Diao S, Kwak YD, Liu L, Zhi L, Bueler¨ rapid method to measure brain oxygen metabolism. Magn H, Bhat NR, Williams RW, Park EA, Liao FF (2013) Reson Med 69, 675-681. Metabolic stress modulates Alzheimer’s -secretase gene [170] de Leon MJ, Convit A, Wolf OT, Tarshish CY, transcription via SIRT1-PPAR␥-PGC-1 in neurons. Cell DeSanti S, Rusinek H, Tsui W, Kandil E, Scherer Metab 17, 685-694. AJ, Roche A, Imossi A, Thorn E, Bobinski M, [156] Han B, Jiang W, Liu H, Wang J, Zheng K, Cui P, Feng Y, Caraos C, Lesbre P, Schlyer D, Poirier J, Reisberg Dang C, Bu Y,Wang QM, Ju Z, Hao J (2020) Upregulation B, Fowler J (2001) Prediction of cognitive decline in of neuronal PGC-1␣ ameliorates cognitive impairment normal elderly subjects with 2-[(18)F]fluoro-2-deoxy-D- induced by chronic cerebral hypoperfusion. Theranostics glucose/poitron-emission tomography (FDG/PET). Proc 10, 2832-2848. Natl Acad SciUSA98, 10966-10971. [157] Meskini N, Nemoz´ G, Okyayuz-Baklouti I, Lagarde M, [171] De Leon MJ, Mosconi L, Blennow K, DeSanti S, Prigent AF (1994) Phosphodiesterase inhibitory profile Zinkowski R, Mehta PD, Pratico D, Tsui W, Saint Louis of some related xanthine derivatives pharmacologically LA, Sobanska L, Brys M, Li Y, Rich K, Rinne J, Rusinek active on the peripheral microcirculation. Biochem Phar- H (2007) Imaging and CSF studies in the preclinical diag- macol 47, 781-788. nosis of Alzheimer’s disease. Ann N Y Acad Sci 1097, [158] Rother M, Erkinjuntti T, Roessner M, Kittner B, Marcus- 114-145. son J, Karlsson I (1998) Propentofylline in the treatment [172] Mosconi L, De Santi S, Li J, Tsui WH, Li Y, Boppana of Alzheimer’s disease and vascular dementia: A review M, Laska E, Rusinek H, de Leon MJ (2008) Hippocampal of phase III trials. Dement Geriatr Cogn Disord 9, 36-43. hypometabolism predicts cognitive decline from normal [159] Frampton MA, Harvey RJ, Kirchner V (2003) Propento- aging. Neurobiol Aging 29, 676-692. fylline for dementia. Cochrane Database Syst Rev, [173] Mosconi L, Mistur R, Switalski R, Tsui WH, Glodzik L, CD002853. Li Y, Pirraglia E, De Santi S, Reisberg B, Wisniewski T, [160] Rother M (1999) A 72-week, placebo-controlled study De Leon MJ (2009) FDG-PET changes in brain glucose assessing propentofylline’s safety, efficacy, and impact on metabolism from normal cognition to pathologically ver- disease progression in patients with Alzheimer’s disease. ified Alzheimer’s disease. Eur J Nucl Med Mol Imaging Eur Neuropsychopharmacol 9, 319. 36, 811-822. [161] Kittner B, De Deyn PP, Erkinjuntti T (2000) Investigat- [174] Mosconi L, Pupi A, De Leon MJ (2008) Brain glu- ing the natural course and treatment of vascular dementia cose hypometabolism and oxidative stress in preclinical and Alzheimer’s disease. Parallel study populations in two Alzheimer’s disease. Ann N Y Acad Sci 1147, 180-195. randomized, placebo-controlled trials. Ann N Y Acad Sci [175] Cojocaru IM, Cojocaru M, Miu G, Sapira V (2011) Study 903, 535-541. of interleukin-6 production in Alzheimer’s disease. Rom J [162] Kittner B (1999) Using a combined randomized Intern Med 49, 55-58. start/withdrawal design to assess propentofylline’s effects [176] Cacabelos R, Alvarez XA, Fernandez-Novoa´ L, Franco on disease progression in Alzheimer’s disease and vascular A, Mangues R, Pellicer A, Nishimura T (1994) Brain dementia: Results of clinical studies. Eur Neuropsy- interleukin-1 beta in Alzheimer’s disease and vascu- chopharmacol 9, 320. lar dementia. Methods Find Exp Clin Pharmacol 16, [163] Rother M (1999) Long-term effects of propentofylline 141-151. in patients with Alzheimer’s disease: Safety, efficacy, [177] Cheng X, He P, Lee T, Yao H, Li R, Shen Y (2014) High and impact on disease progession. J Am Geriatr Soc activities of BACE1 in brains with mild cognitive impair- 47, s2. ment. Am J Pathol 184, 141-147. [164] Rother M (1999) Propentofylline versus placebo in [178] Chang R, Yee K-L, Sumbria RK (2017) Tumor necrosis patients with Alzheimer’s disease: A 72-week study exam- factor ␣ Inhibition for Alzheimer’s disease. J Cent Nerv ining safety, efficacy, and impact on disease progression. Syst Dis 9, 1179573517709278. Neurology 52, 172. [179] Diniz BS, Teixeira AL, Ojopi EB, Talib LL, Mendonc¸a [165] Heckman PRA, Blokland A, Prickaerts J (2017) From VA, Gattaz WF, Forlenza OV (2011) Higher serum age-related cognitive decline to Alzheimer’s disease: A sTNFR1 level predicts conversion from mild cognitive translational overview of the potential role for phosphodi- impairment to Alzheimer’s disease. J Alzheimers Dis 22, esterases. Adv Neurobiol 17, 135-168. 1305-1311. [166] Small GW, Siddarth P, Li Z, Miller KJ, Ercoli L, Emerson [180] Lourenco M V,Clarke JR, Frozza RL, Bomfim TR, Forny- ND, Martinez J, Wong KP, Liu J, Merrill DA, Chen ST, Germano L, Batista AF, Sathler LB, Brito-Moreira J, Henning SM, Satyamurthy N, Huang SC, Heber D, Barrio Amaral OB, Silva CA, Freitas-Correa L, Esp´ırito-Santo 106 O. Sanders / Sildenafil for Alzheimer’s Disease
S, Campello-Costa P, Houzel J-C, Klein WL, Holscher [182] Wu Y-Y, Hsu J-L, Wang H-C, Wu S-J, Hong C-J, Cheng C, Carvalheira JB, Silva AM, Velloso LA, Munoz DP, IH-J (2015) Alterations of the neuroinflammatory markers Ferreira ST, De Felice FG (2013) TNF-␣ mediates PKR- IL-6 and TRAIL in Alzheimer’s disease. Dement Geriatr dependent memory impairment and brain IRS-1 inhibition Cogn Dis Extra 5, 424-434. induced by Alzheimer’s -amyloid oligomers in mice and [183] Zengi O, Karakas A, Ergun U, Senes M, Inan L, Yucel D monkeys. Cell Metab 18, 831-843. (2011) Urinary 8-hydroxy-2’-deoxyguanosine level and [181] Montgomery SL, Mastrangelo MA, Habib D, Narrow WC, plasma paraoxonase 1 activity with Alzheimer’s disease. Knowlden SA, Wright TW, Bowers WJ (2011) Ablation of Clin Chem Lab Med 50, 529-534. TNF-RI/RII expression in Alzheimer’s disease mice leads to an unexpected enhancement of pathology. Am J Pathol 179, 2053-2070.