Pharmacological actions of thymol and an analogue at GABA_B autoreceptors

Abstract

GABAB autoreceptors inhibit release of GABA from GABAergic nerve terminals. Agonists of these receptors (e.g. baclofen) inhibit, whereas antagonists (e.g. (+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid; Sch 50911) enhance release of the transmitter. The actions of thymol (2-isopropyl-5-methylphenol) and the structurally related compound 2-tert-butyl-4-methylphenol, (4MP) on the release of [(3) H]-GABA were examined in rat neocortical slices where the GABAergic nerves had been preloaded with [(3) H]-GABA and subsequently stimulated electrically on two occasions (S1 and S2 ). Test agents, baclofen and Sch 50911 were added to the superfusion medium prior to the second period of stimulation (S2 ). Stimulation-induced overflow (SIO) of [(3) H]-GABA as a consequence of these stimulations (SIO1 and SIO2 ) were calculated and the effects of agents determined by comparing the SIO2 /SIO1 ratio in the presence of each agent with that in control tissue. Thymol potentiated the release of [(3) H]-GABA (EC50 170 μmol/L), an action reversed by baclofen (2 μmol/L). Baclofen alone had little effect on GABA release. Release of [(3) H]-GABA was inhibited by 4MP (IC50 3 μmol/L) and this effect was blocked by Sch 50911 (10 μmol/L). Alone, Sch 50911 markedly potentiated the release of GABA. These results imply that 4MP is an agonist of GABAB autoreceptors; however, further studies are needed to confirm that thymol is indeed a GABAB autoreceptor antagonist. Of interest are structural differences in these agents. Thymol has a propyl group in the ortho position relative to the phenolic hydroxyl, whereas in 4MP this is a butyl group and the methyl group moves from position 5 to 4. Whether one or both of these changes was responsible for the above actions is unknown.

Antidepressant-Like Effect of Lippia sidoides CHAM (Verbenaceae) Essential Oil and Its Major Compound Thymol in Mice

“…This effect can be explained because the PMT is specific to benzodiazepine-like drugs, not to SSRIs. TML has been described as a GABA A agonist opening Cl-channels, resembling the anesthetic agent propofol (2,6-isopropyl-phenol) [51]. These findings confirm the effects of LSEO and TML in the PMT, which is more specific for anxiolytic drugs that act by activating the GABA A receptor, such as benzodiazepines.…”

Pharmacological Properties and Molecular Mechanisms of Thymol: Prospects for Its Therapeutic Potential and Pharmaceutical Development

“…Thymol (2.7 mM) (IC 50 = 0.34 mM) inhibited the peak amplitude in compound action potentials (CAP) in frog sciatic nerves (Kawasaki et al, 2013). Thymol (200 μM) potentiated the release of (3H)-GABA (EC 50 = 170 μM/L) probably by its antagonistic effect on GABA b autoreceptors in rat neocortical slices (Parker et al, 2014). Thymol (0–400 mg/L) was shown to trigger cytotoxicity in N2a neuroblastoma cells (Aydin et al, 2016).…”

Antinociceptive activity of Thyme (Thymus vulgaris L.) and interactions with neurotropics and analgesics

“…It has been previously demonstrated that different phytochemical compounds in medicinal plants interact with GABAergic system to induce xenobiotics hypnotic effect (Chu et al, 2007;Nogueira, Vassilieff, 2000). Carvacrol has been identified as a potent GABA B agonist and thymol is a positive allosteric modulator of the GABA(A) receptor (García et al, 2006;Parker et al, 2014). In addition to possible synergistic interaction, potentiation of pharmacological properties of diazepam and pentobarbital may be the consequence of pharmacokinetic interference, through inhibition of their metabolic pathways.…”