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A Systematic Review Portland State University PDXScholar OHSU-PSU School of Public Health Faculty Publications and Presentations OHSU-PSU School of Public Health 2020 Sildenafil for the rT eatment of Alzheimer’s Disease: A Systematic Review Owen Sanders Portland State University, [email protected] Follow this and additional works at: https://pdxscholar.library.pdx.edu/sph_facpub Part of the Medicine and Health Sciences Commons Let us know how access to this document benefits ou.y 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 A␤42 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
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