TABLE 3.

List of natural products for PDE inhibitors and their impact on cognitive enhancement in clinical research, with a focus on Alzheimer’s disease.

Phytochemical compound	PDE type	Type of compound	Effect
6-gingerol	PDE4D	Polyphenols	Cox-2 expression is inhibited by blocking p38 mitogen-activated protein (map) kinase and nf-b activation (Azam et al., 2014; Furlan and Bren, 2021).
Amentoflavone	PDE3	Biflavonoid	Inhibition of phosphodiesterase (PDE) reduces camp destruction (Dell’Agli et al., 2006; Xiong et al., 2021)
Apigenin	PDE4	Flavonoids	Inhibit the phosphodiesterase enzyme (PDE) (Wang et al., 2018a).
Beta carboline	PDE1	Alkaloid	Beta act as dual inhibitors of AChE and PDEs (Ribaudo et al., 2021).
Caffeine	PDE5	Flavonoids	Caffeine was discovered to be a non-selective PDE inhibitor, inhibiting both cgmp-specific and PDE type 5 PDEs (PDE5) (Prickaerts et al., 2017).
Capsaicin	PDE4D	Polyphenols	Anti-AD (Furlan and Bren, 2021).
Curcumin	PDE4D	Polyphenols	PDEs (enzymes that convert cyclic AMP and cyclic GMP into 5’ AMP and 5’-GMP) were downregulated in response to curcumin therapy (Heckman et al., 2015; Kim and Clifton, 2018; Furlan and Bren, 2021).
Epigallocatechin-3- gallate	PDE4	Polyphenols	EGCG reduced sevoflurane-induced downregulation of camp/CREB and BDNF/trkb signaling (Ding et al., 2017).
Ferulic acid	PDE4B2	Phenolic compound	FA boosted intracellular camp levels while decreasing intracellular Ca2+ levels. FA can decrease PDE4B2 activity, according to the docking data (Huang et al., 2016).
Ginsenoside rg1	PDE	Class of steroid glycosides, and triterpene saponins	The activity of camp-dependent phosphodiesterase (camp-PDE) was dramatically reduced by Rg1, which increased intracellular camp levels (Stancheva and Alova, 1993; Francis et al., 2011; Min Lai et al., 2018; Mohamed et al., 2019).
Glycocoumarin	PDE3 and4	Coumarin	Glycocoumarin is a non-specific phosphodiesterase inhibitor (PDEs) (Sato et al., 2006).
Icariin	PDE5	Flavonoid	Icariin is a putative selective dual-target ache/PDE5 inhibitor that could be used to treat Alzheimer’s disease. Possess significant anti-AD properties in an indifferent of AD mouse models (Mao et al., 2018).
Luteolin	PDE-1, 4 and 5	Flavonoids	Inhibit the phosphodiesterase enzyme (PDE) (Ayoub and Melzig, 2006; Yu et al., 2010).
Physostigmine	PDE	Alkaloid	Substantial camp PDE inhibition (Curley et al., 1984; Pratap et al., 2021).
Quinovic acid	PDE1	Glycosides	Quinovic acid and its few derivatives have an inhibitory effect against the enzyme phosphodiesterase-1 (Mostafa et al., 2006).
Resveratrol	PDE4D	Polyphenols	Resveratrol may involve the regulation of neuronal inflammation and apoptosis via PDE4 subtypes related camp-CREB-BDNF signaling (Wang et al., 2016; Furlan and Bren, 2021).
Sophoflavescenol	PDE4, 5, and 9	Flavonol	Inhibitors that target cGMP (Ribaudo et al., 2021).
Withanolides	PDE4D	Steroids	PDE4D was discovered to be the most potent target for withanolides after molecular docking, molecular dynamics modeling, and free energy calculations (Rathi and Sundar, 2022).