Allosteric positive interaction of thymol with the GABA-A receptor in primary cultures of mouse cortical neurons

GARCÍA DANIEL A.; BUJONS JORDI; SUÑOL CRISTINA

Innsbruck - Austria

Congreso; 20th Biennal Meeting International Society of Neurochemistry and European Society of Neurochemistry; 2005

International Society of Neurochemistry and European Society of Neurochemistry

Thymol is a naturally occurring phenolic monoterpene widely known as anti-microbial agent. It has also antioxidant properties, which give reason for its utilization as anaesthetic stabilizer in halothane prepararations. Studies on its mechanism of neuroactive action came quite recently. An enhanced activity of GABAA receptor (GABAA-R)-operated Cl- channels as well as an incremented affinity of the binding of [3H]flunitrazepam to the GABAA-R was lately reported, suggesting a possible behaviour as GABAA-R agonist/modulator. In the present work, we investigated more deeply the pharmacological action of thymol on native GABAA-R by determining its effects on benzodiazepine binding, on muscimol binding and on the chloride channel, using primary cultures of cortical neurones, which express functional GABAA-Rs. Two thymol structural analogues (menthol and cymene) were also analyzed. Thymol produced an increment on [3H]flunitrazepam binding and induced Cl- influx in the absence of GABA. Likewise, it increased the Cl- uptake induced by GABA 5 mM. Different GABA antagonists inhibited these effects of thymol. Furthermore, thymol was unable to displace to [3H]muscimol of its receptor site. Thus, the obtained results would indicate a positive modulation of GABAA-R performed by thymol through an eventual action on a different site to that recognized by GABA. Thymol (0-1 mM) had no effect on cellular viability. Menthol and cymene did not show significant effects on the [3H]flunitrazepam binding. Finally, a pharmacophore model of thymol activity on GABAA-R was also analysed.