Inhibition of phosphodiesterase: A novel therapeutic target for the treatment of mild cognitive impairment and Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is the most common form of dementia and is ranked as the 6th leading cause of death in the US. The prevalence of AD and dementia is steadily increasing and expected cases in USA is 14.8 million by 2050. Neuroinflammation and gradual neurodegeneration occurs in Alzheimer’s disease. However, existing medications has limitation to completely abolish, delay, or prevent disease progression. Phosphodiesterases (PDEs) are large family of enzymes to hydrolyze the 3’-phosphodiester links in cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in signal-transduction pathways for generation of 5’-cyclic nucleotides. It plays vital role to orchestrate several pharmacological activities for proper cell functioning and regulating the levels of cAMP and cGMP. Several evidence has suggested that abnormal cAMP signaling is linked to cognitive problems in neurodegenerative disorders like AD. Therefore, the PDE family has become a widely accepted and multipotential therapeutic target for neurodegenerative diseases. Notably, modulation of cAMP/cGMP by phytonutrients has a huge potential for the management of AD. Natural compounds have been known to inhibit phosphodiesterase by targeting key enzymes of cGMP synthesis pathway, however, the mechanism of action and their therapeutic efficacy has not been explored extensively. Currently, few PDE inhibitors such as Vinpocetine and Nicergoline have been used for treatment of central nervous system (CNS) disorders. Considering the role of flavonoids to inhibit PDE, this review discussed the therapeutic potential of natural compounds with PDE inhibitory activity for the treatment of AD and related dementia.

Resveratrol alleviates amyloid β‐induced neuronal apoptosis, inflammation, and oxidative and endoplasmic reticulum stress by circ_0050263/miR‐361‐3p/PDE4A axis during Alzheimer's disease

“…Importantly, miR‐361‐3p inhibition reversed Aβ‐evoked neuronal apoptosis, inflammatory reaction, and oxidative stress, which was related to SNHG1/miR‐361‐3p/ZNF217 axis (Gao et al, 2020). PDE4A is a subtype of PDE4, PDE4 belongs to the PDE family that hydrolyzes key second messengers, cyclic AMP (cAMP), and cyclic GMP (cGMP), in signal‐transduction pathways, cAMP signaling aberrant is associated with cognitive dysfunction in AD neurodegenerative disorder, moreover, the inhibitor of PDE has been shown to have neuroprotective and anti‐inflammatory activity, and can improve cognitive impairment in AD (Bhat et al, 2020; Sheng et al, 2022). PDE4 is a widely accepted and multipotential therapeutic target for AD (Gurney et al, 2015).…”

Exploring the Molecular Targets for the Antidepressant and Antisuicidal Effects of Ketamine Enantiomers by Using Network Pharmacology and Molecular Docking

“…Another interesting finding of the bioinformatic analysis is that 3′,5′-cyclic nucleotide phosphodiesterases (PDE) may be molecular targets of ketamine enantiomers. PDEs are classified into 11 subtypes based on sequence homology and structural and enzymatic features mainly related to sensitivity to modulators [ 39 ]. These enzymes are responsible for the hydrolysis of the intracellular second messengers cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP), which are essential for synaptic plasticity, learning, and memory [ 40 ].…”

Microorganism-Derived Molecules as Enzyme Inhibitors to Target Alzheimer’s Diseases Pathways

“…PDEs are essential for controlling cell functioning and adjusting the levels of cAMP and cGMP. Abnormal cAMP signaling is related to AD [56]. NADPH oxidase is the main enzyme causing the creation of damaging free radicals that lead to oxidative stress-a general cause in the pathology of neurodegenerative disorders such as AD [57].…”