The role of Phosphodiesterase-1 and its natural product inhibitors in Alzheimer’s disease: A review

Abstract

Phosphodiesterase-1 (PDE1) is a versatile enzyme that has surprisingly received considerable attention as a possible therapeutic target in Alzheimer’s disease (AD) because it maintains the homeostasis of 3ʹ,5ʹ-cyclic adenosine monophosphate (cAMP) and 3ʹ,5ʹ-cyclic guanosine monophosphate (cGMP) in the brain. 3ʹ,5ʹ-cyclic adenosine monophosphate and 3ʹ,5ʹ-cyclic guanosine monophosphate are the two key second messengers that regulate a broad range of intracellular processes and neurocognitive functions, specifically memory and cognition, associated with Alzheimer’s disease. However, the lack of available selective drugs on the market poses challenges to identifying the beneficial effects of natural products. The present review focuses on Phosphodiesterase-1 and its isoforms, splicing variants, location, distribution, and function; the role of Phosphodiesterase-1 inhibitors in Alzheimer’s disease; and the use of vinpocetine and natural products as specific Phosphodiesterase-1 inhibitors. Moreover, it aims to provide ongoing updates, identify research gaps, and present future perspectives. This review indicates the potential role of Phosphodiesterase-1 inhibitors in the treatment of neurodegenerative disorders, such as Alzheimer’s disease. Certain clinical trials on the alleviation of Alzheimer’s disease in patients are still in progress. Among de novo outcomes, the employment of Phosphodiesterase-1 inhibitors to treat Alzheimer’s disease is an important advancement given the absence of particular therapies in the pipeline for this highly prevalent disease. To sum up, Phosphodiesterase-1 inhibition has been specifically proposed as a critical therapeutic approach for Alzheimer’s disease. This study provides a comprehensive review on the biological and pharmacological aspects of Phosphodiesterase-1, its role on the Alzheimer’s diseases and its significance as Alzheimer’s disease therapeutic target in drug discovery from natural products. This review will help clinical trials and scientific research exploring new entities for the treatment and prevention of Alzheimer’s disease.

Development of White Cabbage, Coffee, and Red Onion Extracts as Natural Phosphodiesterase-4B (PDE4B) Inhibitors for Cognitive Dysfunction: In Vitro and In Silico Studies

“…A deficiency of neurotrophic protein can raise the risk of neuronal loss, which can cause damage and death to brain neurons. This loss of neurons impairs brain function physiologically and results in cognitive issues, including memory loss [ 1 ]. However, the compounds present in white cabbage, coffee, and red onion extracts have the ability to block PDE4B and reverse memory loss.…”

“…Cognitive dysfunction is a serious health issue worldwide; this condition is primarily caused by Alzheimer's disease (AD), which is characterized by the aggregation of amyloid- β plaques and neurofibrillary tangles of hyperphosphorylated tau proteins [ 1 ]. In 2020, dementia was estimated to affect 55 million individuals globally [ 2 ].…”

“…In 2020, dementia was estimated to affect 55 million individuals globally [ 2 ]. The declining concentrations of cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), and brain-derived neurotrophic factor (BDNF) in the hippocampus have been observed to be attributed to AD development [ 1 ]. The exploration of nootropics or cognitive enhancers, known as “smart drugs,” is catching intrigue on a daily basis.…”

Potentiality of Coffee (Coffea robusta) and its Bioactive Compounds in Memory Function: A Review

“…50 Coffee and its bioactive compounds deliver antioxidant and anti-inflammatory activities, which help to reduce cognitive decline. 54 The antioxidative effect of C. robusta is chiefly linked with its polyphenols because they have scavenging free radicals capability in the biological system. 55 Marucci et al 56 have investigated, acetylcholine (ACh), a muscarinic agonist, is hydrolytically broken down by two cholinesterases, AChE and BChE, in the brain (cerebral cortex and hippocampus regions).…”

Virtual Screening-Accelerated Discovery of a Phosphodiesterase 9 Inhibitor with Neuroprotective Effects in the Kainate Toxicity In Vitro Model

“…11 PDE5 is among the most studied families in the brain, 12,13 but very recent reports are also supporting the role of PDE1 and PDE7 inhibitors in Alzheimer's disease (AD) and neurodegeneration. 14,15 More in general, brain bioavailable PDE inhibitors activating cGMP signaling are being investigated as potential therapeutic strategies against AD. 11,16 PDE9 is endowed with high affinity for cGMP (K m = 70 nM) and the highest selectivity over cAMP (K m = 230 μM).…”