Phosphodiesterases (PDEs) are a class of enzymes that hydrolyze cyclic phosphodiester bonds, breaking them down into monophosphates and nucleotides. This enzyme widely exists in organisms and participates in the regulation of various physiological processes. Phosphodiesterases (PDEs) enzymes can hydrolyze intracellular second messenger molecules cAMP and cGMP, and regulate the levels of intracellular cAMP and cGMP, thereby regulating intracellular signal transmission. cAMP and cGMP are two important cell signaling molecules, they can participate in a variety of biological processes in cells, including metabolism, cell proliferation, differentiation, apoptosis, and so on. Of these, phosphodiesterase 5 (PDE5), one of the best-studied PDE, specifically targets cGMP normally produced by nitric oxide (NO)-mediated activation of soluble guanylate cyclase. Given the critical role of cGMP produced in various physiological processes through the activation of this cellular signaling pathway, pharmacological inhibition of PDE5 has proven to have diverse therapeutic applications.
Yonkenafil (Tunodafil) is a PDE5 inhibitor for Alzheimer’s disease research.
Yonkenafil (Tunodafil), a novel phosphodiesterase 5 (PDE5) inhibitor, is effective in reducing cerebral infarction, neurological deficits, edema, and neuronal damage in the infarcted area. It may improve cognitive function by modulating neurogenesis and has a potential therapeutic effect on Alzheimer’s disease. Yonkenafil (4-32 mg/kg, i.v. daily for 7 days) improves behavioral outcomes after stroke and reduces cerebral infarct volume. Besides, it inhibits neuronal apoptosis and significantly enhances the expression of BDNF/TrkB and NGF/TrkA synaptic function in the blood-brain. Moreover, it induces a dose-dependent decrease in infarct volume, with an ED50 of 12.27 mg/kg. Secondly, it increases hsp70 expression, decreases apaf-1 expression, and inhibits caspase-3 and caspase-9 cleavage. Importantly, Yonkenafil significantly prevents neuronal damage and increases the number of surviving neurons after stroke. In addition, it prevents the decrease in synaptophysin levels and increases in PSD-95 and nNOS levels.
In conclusion, Yonkenafil (Tunodafil), a novel phosphodiesterase 5 (PDE5) inhibitor, can improve cognitive function by modulating neurogenesis and has potential therapeutic effects on Alzheimer’s disease.
 Wesam S Ahmed, et al. Biomed Pharmacother. 2021 Feb;134:111128.
 Xuemei Chen, et al. Exp Neurol. 2014 Nov;261:267-77.