Abstract
Polyphenol ellagic acid (EA) possesses antioxidant, anti-inflammatory, anti-carcinogenic, anti-diabetic and cardio protection activities, making it an interesting multi-targeting profile. EA also controls the central nervous system (CNS), since it was proven to reduce the immobility time of mice in both the forced swimming and the tail-suspension tests, with an efficiency comparable to that of classic antidepressants. Interestingly, the anti-depressant-like effect was almost nulled by the concomitant administration of selective antagonists of the noradrenergic receptors, suggesting the involvement of these cellular targets in the central effects elicited by EA and its derivatives. By in silico and in vitro studies, we discuss how EA engages with human α2A-ARs and α2C-AR catalytic pockets, comparing EA behaviour with that of known agonists and antagonists. Structurally, the hydrophobic residues surrounding the α2A-AR pocket confer specificity on the intermolecular interactions and hence lead to favourable binding of EA in the α2A-AR, with respect to α2C-AR. Moreover, EA seems to better accommodate within α2A-ARs into the TM5 area, close to S200 and S204, which play a crucial role for activation of aminergic GPCRs such as the α2-AR, highlighting its promising role as a partial agonist. Consistently, EA mimics clonidine in inhibiting noradrenaline exocytosis from hippocampal nerve endings in a yohimbine-sensitive fashion that confirms the engagement of naïve α2-ARs in the EA-mediated effect.
Highlights
Pomegranate (Punica granatum L.) is a very ancient edible fruit originating in the Middle East and North Africa, used from the dawn of history as a healing and healthpromoting fruit in traditional medicine [1]
The peculiar structure of ellagic acid (EA), characterized by a hydrophobic core and hydrophilic ends, led to its accommodation in the TM5 area, close to S200 and S204 which play a crucial role for activation of aminergic G protein coupled receptors (GPCRs), such as the α2 -AR
Thermodynamic investigation revealed that EA is well stabilized into the α2A -AR binding site, if compared to the known partial agonist and antagonist
Summary
Pomegranate (Punica granatum L.) is a very ancient edible fruit originating in the Middle East and North Africa, used from the dawn of history as a healing and healthpromoting fruit in traditional medicine [1]. This rustic crop has obtained high popularity as a nutraceuticals source, becoming a high-value crop. It has demonstrated increased importance due to its adaptability to different climatic conditions, its resilience and longevity, and its high drought and salinity resistance [2]. Pomegranate cultivation is widely spread in many tropical and subtropical regions, and about two million tons of fruits are produced annually worldwide [3]. India, Iran, China, Turkey, the United States, Spain, South Africa, Peru, Chile, and Argentina represent the major producers and exporters of this fruit [4]. India, Iran, China, Turkey, the United States, Spain, South Africa, Peru, Chile, and Argentina represent the major producers and exporters of this fruit [4]. 4.0/).
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