GABA_A receptor modulation by terpenoids from Sideritis extracts

Abstract

ScopeGABAA receptors are modulated by Sideritis extracts. The aim of this study was to identify single substances from Sideritis extracts responsible for GABAA receptor modulation.Methods and resultsSingle volatile substances identified by GC have been tested in two expression systems, Xenopus oocytes and human embryonic kidney cells. Some of these substances, especially carvacrol, were highly potent on GABAA receptors composed of α1β2 and α1β2γ2 subunits. All effects measured were independent from the presence of the γ2 subunit. As Sideritis extracts contain a high amount of terpenes, 13 terpenes with similar structure elements were tested in the same way. Following a prescreening on α1β2 GABAA receptors, a high-throughput method was used for identification of the most effective terpenoid substances on GABA-affinity of α1β2γ2 receptors expressed in transfected cell lines. Isopulegol, pinocarveol, verbenol, and myrtenol were the most potent modifiers of GABAA receptor function.ConclusionComparing the chemical structures, the action of terpenes on GABAA receptors is most probably due to the presence of hydroxyl groups and a bicyclic character of the substances tested. We propose an allosteric modulation independent from the γ2 subunit and similar to the action of alcohols and anesthetics.

Kazakh Ziziphora Species as Sources of Bioactive Substances

“…bungeana [201] trans-Sabinene hydrate (64) Z. clinopodioides subsp. rigida (0.1%) [21] Antiviral (HSV-1) [282] Moderate repellent (against tick Amblyomma americanum) [305] Z. tenuior [94] Anti-inflammatory (in carrageenan-induced edema and inhibition of hyperalgesia induced by L-glutamate and prostaglandin E2 in rats) [311]; anti-inflammatory (through inhibition of the expression of TNF-α and IL-6 in LPS-stimulated RAW 264.7 cells) [312]; antiinflammatory (in cigarette smoke-induced ALI in mice through inhibiting NF-κB activation) [313] Cytotoxic (human amelanotic melanoma cell line C32, renal cell adenocarcinoma ACHN, hormone-dependent prostate carcinoma LNCaP) [314]; induction of apoptosis (variety of human leukaemia cells) [315][316][317] Hypocholesterolemic (through inhibition of HMG-CoA reductase and conversion of lanosterol to cholesterol) [318,319] Protective effect against t-BOOH induced mutagenesis [194] Review on some effects on cardiovascular system [221] Sedative and anxiolytic [320]; antidepressant [321]; GABAA receptor modulation [322] OH Z. clinopodioides subsp. rigida [21] Z. tenuior [94] p-Menth-3-en-8-ol (65)…”

“…rigida [21] Z. clinopodioides subsp. rigida (12.5%) [21] Z. tenuior (53.97%) [179] Linalool ( Anti-inflammatory (in carrageenan-induced edema and inhibition of hyperalgesia induced by L-glutamate and prostaglandin E 2 in rats) [311]; anti-inflammatory (through inhibition of the expression of TNF-α and IL-6 in LPS-stimulated RAW 264.7 cells) [312]; anti-inflammatory (in cigarette smoke-induced ALI in mice through inhibiting NF-κB activation) [313] Cytotoxic (human amelanotic melanoma cell line C32, renal cell adenocarcinoma ACHN, hormone-dependent prostate carcinoma LNCaP) [314]; induction of apoptosis (variety of human leukaemia cells) [315][316][317] Hypocholesterolemic (through inhibition of HMG-CoA reductase and conversion of lanosterol to cholesterol) [318,319] Protective effect against t-BOOH induced mutagenesis [194] Review on some effects on cardiovascular system [221] Sedative and anxiolytic [320]; antidepressant [321]; GABA A receptor modulation [322] Analgesic activity reviewed [199] Review on metabolism and toxicity [200] Molecules 2016, 21, 826 20 of 53 [296]; antioxidant [273,[297][298][299] Review on some effects on cardiovascular system [221] Gastroprotective effects in the acute and chronic ulcer models in rats [300] Positive allosteric modulator of the GABAA receptors in primary cultures of mouse cortical neurons [301] Anti-hyperglycemic and anti-hyperlipidemic activity in high fat-induced type 2 diabetic C57BL/6J mice [302] and protective effect in nephropathy [303] Analgesic activity reviewed [199] Review on metabolism and toxicity [200]; general review on thyme and 62 [304] cis-Sabinene hydrate …”

“…Antifungal [187,350,352], antimicrobial activity [306] Antiviral activity against influenza A⁄PR⁄8 virus subtype H1N1 [231] Enhancement of GABA modulation [353] Anticancer (melanoma cells) [343] Insecticidal (against L. serricorne) [351] Inhibition of the acetic acid-induced writhing and formalin-induced nociception in mice [354] Analgesic activity reviewed [199] Review on metabolism and toxicity [200] OH 1,8-Cineol (72) Z. clinopodioides (5.4%-21.6%) [185] Antimicrobial activity (MDR resistant bacteria) [355] Hypocholesterolemic (through inhibition of HMG-CoA reductase and conversion of squalene to lanosterol [319] Analgesic activity reviewed [199] Review on some effects on cardiovascular system [221] Review on metabolism and toxicity [200] O [273,297,299] Anti-inflammatory (inhibition of NO production in LPS-stimulated RAW-264.7 macrophages) [223]; anti-inflammatory effect by reducing the production of IL-1β and prostanoids, possibly through the induction of IL-10 release [364] Anti-genotoxic [287] Anxiolytic, GABA A receptor modulation [322,365] Bronchodilatory effect in guinea pigs [366] Antinociceptive activity in mice in the acetic acid-induced abdominal constriction, formalin and hot-plate tests [367] Acetyl-and butyrylcholinesterase inhibitory activity [269,368] Analgesic activity reviewed [199] Review on anti-inflammatory, antioxidant, and immunological effects [292] Review on some effects on cardiovascular system [221] General reviews on 73 [369,370] [184...…”

“…cumaldehyde) (78) Z. clinopodioides subsp. rigida (0.8%) [21] Tyrosinase inhibitory activity [377] Suppression of melanin formation in cultured murine B16-F10 melanoma cells [378] O H Z. clinopodioides (0.12%-0.24%) [15] Z. tenuior [94] Anthelmintic Haemonchus contortus [371] Anti-inflammatory effect through inhibition of edema induced by carrageenan, histamine, serotonin or PGE2 [372] Anxiolytic-like effect probably through acting on the GABAergic system [373,374] O O Antibacterial (multi-drug resistant E. coli) [329] Insecticidal activity (against Lasioderma serricorne) [351] GABAA receptor modulation [322] Repellent activity against Anopheles gambiae [375] Anti-ischemic and anti-inflammatory activity [376] OH trans-Verbenol (77) Z. clinopodioides subsp. rigida (0.1%) [21] Antibacterial (multi-drug resistant E. coli) [329] GABAA receptor modulation [322] OH Cuminyl aldehyde (syn.…”

“…Antibacterial (multi-drug resistant E. coli) [329] Insecticidal activity (against Lasioderma serricorne) [351] GABAA receptor modulation [322] Repellent activity against Anopheles gambiae [375] Anti-ischemic and anti-inflammatory activity [376] OH trans-Verbenol (77) Z. clinopodioides subsp. rigida (0.1%) [21] Antibacterial (multi-drug resistant E. coli) [329] GABAA receptor modulation [322] OH Cuminyl aldehyde (syn.…”