The Differential Effects of Resveratrol and trans-ε-Viniferin on the GABA-Induced Current in GABAA Receptor Subtypes Expressed in Xenopus Laevis Oocytes

Abstract

-Purpose:The natural products resveratrol and trans-ε-viniferin have been reported to have many beneficial effects, which include the enhancement of cognition and memory. There have been no studies which have reported the effects of these compounds on the different GABAA receptor subtypes and this study aimed to address this. Methods: The effects of both resveratrol, and its dimer, trans-ε-viniferin, have been investigated on different GABAA receptor subtypes expressed in Xenopus laevis oocytes, using the twoelectrode voltage clamp technique. Results: Resveratrol induced a current of 22 ± 3.53 nA in the α1β2γ2L subtype of the GABAA receptor (but not in the α5β3γ2L and α2β2γ2L subtypes) when applied alone. It also positively modulated the GABA-induced current (IGABA) in α1β2γ2L receptors, in a dose-dependent manner (EC50 58.24 μM). The effects of resveratrol were not sensitive to the benzodiazepine antagonist flumazenil. trans-ε-Viniferin exhibited a different pattern of activity to resveratrol; it alone had no effect on any of the subtypes, but it did negatively modulate the GABA-induced current (IGABA) in all three subtypes. The greatest inhibition was found in the α1β2γ2L subtype (IC50 5.79 μM), with the inhibition in the α2β2γ2L (IC50 of 19.08 μM) and α5β3γ2L (IC50 of 21.05 μM) subtypes being similar. The effects of trans-ε-viniferin in α1β2γ2L and α2β2γ2L receptors were also not sensitive to the benzodiazepine antagonist flumazenil while, in the α5β3γ2L subtype the effect was not sensitive to the inverse agonist L-655,708, indicating different binding sites for this molecule. Conclusions: The results of the present study indicate that both resveratrol and trans-ε-viniferin modulate the GABA-induced current in different ways, and that trans-ε-viniferin may be a lead compound for the discovery of agents which selectively inhibit the GABA-induced current in α1-containing subtypes.

Molecular Targets for Combined Therapeutic Strategies to Limit Glioblastoma Cell Migration and Invasion

“…Resveratrol has been found alter activity in an array of ion channel classes, including the inhibition of Ca 2+ channels involved in pain perception pathways in mice, consistent with an anti-nociceptive effect of systemic treatment (Pan et al, 2017), inhibition of cardiac L-type Ca 2+ currents in rat ventricular myocytes (Zhang et al, 2006), and activation of T-type Ca 2+ channels in a mesothelioma cell line (Marchetti et al, 2016), providing an interesting parallel with the effects of Olea extracts listed above. Resveratrol activated defined subtypes of GABA A receptors containing a1 subunits, expressed in Xenopus oocytes (Groundwater et al, 2015), and blocked the calcium-dependent K + channel, KCa3.1, heterologously expressed in 3T3 fibroblasts (Olivan-Viguera et al, 2013). Withania extract activated mammalian brain GABA A and GABArho receptors recorded by voltage clamp in the Xenopus expression system, evoking currents comparable to those induced by the native neurotransmittter; however, responses were not activated by the isolated components withaferin A and withanolide A, suggesting other active agents are present in the extract (Candelario et al, 2015).…”

A Computational Method for Unveiling the Target Promiscuity of Pharmacologically Active Compounds

“…These results corroborate the previously known effect of resveratrol on ER, [9,10] which could be quantified in this present study.F urthermore,T IGER correctly identified the ability of resveratrol to block GABAinduced ion-channel currents. [11] Thesuggested STS inhibition is in line with the known effects of resveratrol and its metabolites in breast tissue. [12] Importantly,t he predicted modulatory effect on the dopamine receptor system were also confirmed, although TIGER missed the correct target subtype.I nc ell-based functional assays,w eo bserved an antagonistic effect of resveratrol on the human short dopamine receptor (D 2S ,I C 50 = 180 mm AE 0.04 log units, K B = 12 mm), without an effect on the D 4 and D 5 receptor subtypes.…”

Repeated inhalation of sevoflurane inhibits the information transmission of Purkinje cells and delays motor development via the GABAA receptor ε subunit in neonatal mice

“…Increasing the concentration of sevoflurane in the cerebellum may synergize with the endogenous GABA A -R ε subunit, thereby enhancing the inhibitory effect of the endogenous GABA A -R ε subunit on the field potential response of PCs, delaying or inhibiting the transmission of movement information and, consequently, the development of motor function ( 32 ). Sevoflurane increases the excitability of Golgi cells by inhibiting the activity of Na + /K + ATPase, thereby enhancing the paroxysmal inhibition of PCs and increasing the leakage of the GABA A -R ε subunit around PCs, resulting in an increase in the GABA A -R ε subunit concentration in the cerebellum and further increasing the sustained inhibition of information transmission in PCs, affecting motor function and development ( 33 – 35 ). Therefore, an increase in sevoflurane concentration in the cerebellar cortex may excite Golgi cells, increase the release of the GABA A -R ε subunit, increase the concentration of GABA A -R ε subunits around the PCs, and enhance the sustained inhibitory effect on the sensory stimulus-induced responses of PCs and the transmission of motion information, delaying motor function development.…”