Cargando…
Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review
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...
Autor principal: | |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
IOS Press
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242821/ https://www.ncbi.nlm.nih.gov/pubmed/32467879 http://dx.doi.org/10.3233/ADR-200166 |
_version_ | 1783537306145128448 |
---|---|
author | Sanders, Owen |
author_facet | Sanders, Owen |
author_sort | Sanders, Owen |
collection | PubMed |
description | 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-γ coactivator 1α (PGC1α) via protein kinase G-mediated cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) phosphorylation and/or Sirtuin-1 activation and PGC1α deacetylation. Via PGC1α signaling, low-dose sildenafil likely suppresses β-secretase 1 expression and amyloid-β (Aβ) 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 Aβ 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-1β, interleukin-6, and tumor necrosis factor-α, decrease neural apoptosis, increase neurogenesis, and reduce tau hyperphosphorylation. All studies that tested Aβ 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 PGC1α 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. |
format | Online Article Text |
id | pubmed-7242821 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | IOS Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-72428212020-05-27 Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review Sanders, Owen J Alzheimers Dis Rep Review 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-γ coactivator 1α (PGC1α) via protein kinase G-mediated cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) phosphorylation and/or Sirtuin-1 activation and PGC1α deacetylation. Via PGC1α signaling, low-dose sildenafil likely suppresses β-secretase 1 expression and amyloid-β (Aβ) 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 Aβ 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-1β, interleukin-6, and tumor necrosis factor-α, decrease neural apoptosis, increase neurogenesis, and reduce tau hyperphosphorylation. All studies that tested Aβ 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 PGC1α 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. IOS Press 2020-04-22 /pmc/articles/PMC7242821/ /pubmed/32467879 http://dx.doi.org/10.3233/ADR-200166 Text en © 2020 – IOS Press and the authors. All rights reserved https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License (https://creativecommons.org/licenses/by-nc/4.0/) , which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Review Sanders, Owen Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review |
title | Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review |
title_full | Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review |
title_fullStr | Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review |
title_full_unstemmed | Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review |
title_short | Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review |
title_sort | sildenafil for the treatment of alzheimer’s disease: a systematic review |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242821/ https://www.ncbi.nlm.nih.gov/pubmed/32467879 http://dx.doi.org/10.3233/ADR-200166 |
work_keys_str_mv | AT sandersowen sildenafilforthetreatmentofalzheimersdiseaseasystematicreview |