Ayo Isola

Introduction Alzheimer’s Disease (AD) is a neurodegenerative condition that represents nearly 70% of dementia cases worldwide¹, totaling over 24 million estimated cases worldwide². AD manifests clinically as gradual personality changes that progress into memory loss, cognitive decline, dementia, and eventual death by infection or a bed ridden-induced blood clot. The prevalence of Alzheimer’s has been predicted to increase in coming years due to a growing elderly population. Amyloid precursor protein (APP) is a membrane protein that undergoes proteolysis to produce  Aβ plaques. The pathology in AD involves a mutated proteolysis process resulting in toxic aggregated Aβ plaques, as well as neurofibrillary tangles. Sildenafil, brand name Viagra, is an FDA approved treatment for erectile dysfunction in males and pulmonary arterial hypertension in both males and females³. Sildenafil is a highly selective inhibitor of the enzyme phosphodiesterase-5 (PDE-5)³. Without the hydrolyzing effects of PDE-5, the levels of cyclic guanosine monophosphate (cGMP) increase and elicit effects such as smooth muscle relaxation and vasodilation³. Several studies have examined the potential of sildenafil administration to slow/reverse the progression of Alzheimer’s disease. Methods Streptozotocin (STZ) was injected into lab rats to decrease the cerebral insulin pathway function, an effect that mimics human AD pathology⁵. In AD, levels of vascular endothelial growth factor (VEGF) decrease, while vascular cell adhesion molecule-1 (VCAM-1), tumor necrosis factor alpha (TNF-a), and oxidative stress markers are increased.¹ HT-22 hippocampal neuronal cells treated with Aβ_25-35 displayed mitochondrial Ca²⁺ overload, decreased ATP concentration, increased ROS generation, and increased mitochondrial permeability transition which led to caspase-9 activation and cell death⁴. Fractional amplitude of low frequency fluctuations (fALFF) was used to measure the resting-state fMRI and assess spontaneous neural activity in brain regions². Human trials assessed the alterations of cerebral blood blow (CBF), cerebral metabolic rate of oxygen consumption (CMRO₂), and cerebrovascular reactivity (CVR) before and after sildenafil administration³. Results The Sildenafil analogue, yonkenafil, improved the cognitive deficits seen in the STZ-AD-rat model⁵. Sildenafil reversed the AD-induced effects on VEGF, VCAM-1, TNF-a, oxidative stress markers and decreased memory latency time in AD rats¹. Sildenafil administration inhibited the mitochondrial-associated changes and cell death caused by Aβ aggregation⁴. fALFF measurements were normalized in AD-rats in response to sildenafil adminstration². A single dose of sildenafil resulted in increased CBF, CMRO₂, and CVR in human AD subjects³. Conclusion Sildenafil-induced phosphodiesterase-5 inhibition produces multiple favorable effects that alleviate symptoms and could potentially make Alzheimer’s diagnosis more manageable in affected patients. The aim of future studies should determine the safety and feasibility of long-term Sildenafil usage as a primary therapeutic agent for Alzheimer’s Disease.

1. Ibrahim M, Haleem M, AbdelWahab S, Abdel-Aziz A. Sildenafil ameliorates Alzheimer disease via the modulation of vascular endothelial growth factor and vascular cell adhesion molecule-1 in rats. Human & Experimental Toxicology. April 2021:596-607. doi:1177/0960327120960775
2. Samudra, N., Motes, M., Lu, H., Sheng, M., Diaz-Arrastia, R., Devous, M., Hart, J., & Womack, K. B. (2019). A Pilot Study of Changes in Medial Temporal Lobe Fractional Amplitude of Low Frequency Fluctuations after Sildenafil Administration in Patients with Alzheimer’s Disease. Journal of Alzheimer’s disease : JAD, 70(1), 163–170. https://doi.org/10.3233/JAD-190128
3. Sheng, M., Lu, H., Liu, P., Li, Y., Ravi, H., Peng, S. L., Diaz-Arrastia, R., Devous, M. D., & Womack, K. B. (2017). Sildenafil Improves Vascular and Metabolic Function in Patients with Alzheimer’s Disease. Journal of Alzheimer’s disease : JAD, 60(4), 1351–1364. https://doi.org/10.3233/JAD-161006
4. Yonghae Son, Koanhoi Kim, Hyok-rae Cho, Sildenafil protects neuronal cells from mitochondrial toxicity induced by β-amyloid peptide via ATP-sensitive K+ channels, Biochemical and Biophysical Research Communications, Volume 500, Issue 2, 2018, Pages 504-510, ISSN 0006-291X, https://doi.org/10.1016/j.bbrc.2018.04.128.
5. Zhu, Zhen Zhang, Xiao-jie Hou, Yong-feng Wang, Jing-yu Yang, Chun-fu Wu, Inhibition of PDE5 attenuates streptozotocin-induced neuroinflammation and tau hyperphosphorylation in a streptozotocin-treated rat model, Brain Research,Volume 1722, 2019, 146344, ISSN 0006-8993 https://doi.org/10.1016/j.brainres.2019.146344.