Presynaptic Release-Regulating Alpha2 Autoreceptors: Potential Molecular Target for Ellagic Acid Nutraceutical Properties

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.

Guanfacine Normalizes the Overexpression of Presynaptic α-2A Adrenoceptor Signaling and Ameliorates Neuropathic Pain in a Chronic Animal Model of Type 1 Diabetes

“…Additionally, α2-ARs are also present across the dorsal and ventral horn and on the central terminals of nociceptive nerve fibers at the level of the spinal cord [ 25 ]. They also function as auto-receptors on pre-synaptic neurons [ 27 ].…”

Activation of a novel α2AAR-spinophilin-cofilin axis determines the effect of α2 adrenergic drugs on fear memory reconsolidation

“…S10). E189 is a key orthostatic residue and part of an interaction network regulating ligand binding [77], and an α 2A AR antagonist, yohimbine, is predicted to form H-bond with E189 [78]. Our experimental evidence indeed suggests antagonistic features of guanfacine in blocking clonidine-induced α 2A AR cofilin interaction and in attenuating clonidine-induced disruption of fear memory reconsolidation.…”

HPLC Profile, Anticancer, Anti-inflammatory and Antioxidant Activities of Euphorbia inarticulata Ethanolic Extract

“…Additionally, TAC of the ethanolic extract was 46.72 ± 3.86 mg gallic acid equivalent per gram, while the standard drug, ascorbic acid displayed 69.84 ± 3.98 mg gallic acid equivalent per gram. It has been reported that different species of Euphorbia such as Euphorbia hirta Euphorbia wallichii, Euphorbia antisyphilitica possess strong antioxidant potential [44,45]. The antioxidant power of the ethanolic extract might be due to polyphenols such as catechol, syringic acid, gallic acid, ellagic acid, cinnamic acid and caffeic acid as confirmed from HPLC analysis.…”