(+)- And (−)-borneol: efficacious positive modulators of GABA action at human recombinant α1β2γ2L GABAA receptors
Introduction
Monoterpenes are the primary components of plant essential oils and the effects of many medicinal herbs have been attributed to them [1], [2], [3], [4], [5], [6]. (+)-Borneol (Fig. 1) is a bicyclic monoterpene present in the essential oils of numerous medicinal plants, including valerian (Valeriana officinalis), chamomile (Matricaria chamomilla) and lavender (Lavandula officinalis). Extracts of these plants are used traditionally to relieve anxiety, restlessness and insomnia [7], [8], [9], [10]. Valerian extracts and essential oil demonstrate significant sedative activity in animal and human studies, providing equivalent sedation to conventional sedative and hypnotic agents [11], while also increasing sleep depth [12]. (+)-Borneol and its structural analogue camphor (Fig. 1) are used for analgesia and anaesthesia in traditional Chinese and Japanese medicine [13].
While many possible mechanisms for the actions of sedative herbal medicines have been proposed, these herbs have been primarily linked with functions associated with the neurotransmitter GABA [14], [15], [16], [17], [18]. GABA is the predominant inhibitory transmitter in the mammalian central nervous system, present in 40% of all mammalian CNS neurons. GABAA and GABAC receptors are ligand-gated chloride channels that mediate an inhibitory effect by increasing the chloride influx into neurons, inducing membrane hyperpolarisation and neuronal inhibition [19]. GABAA receptors comprise of five protein subunits chosen from α1–6, β1–4, γ1–3, δ, ɛ, π and θ, with α1β2γ2 being the most common arrangement in the mammalian brain [20]. Stimulation of GABAA receptors by GABA (and added positive modulators, such as benzodiazepines and barbiturates) produces anxiolysis, sedation, anaesthesia and myorelaxation [21], akin to the effects of these sedative herbs. Valerian extracts have been previously shown to prevent GABA re-uptake [18], bind at the GABA and benzodiazepine sites of the GABAA receptor [22] and facilitate GABA transport to the brain [23]. Additionally, lavender essential oil mildly potentiates the effects of GABA at GABAA receptors [24]. Thus, traditional sedative herbs like valerian and lavender most likely contain GABAergic compounds. Determining their structure and activity could result in new drug leads for the treatment of anxiety and insomnia.
(+)-Borneol produces mild sedation in mice when inhaled; yet, its isomer isoborneol increases locomotion [25] which may indicate divergent actions at GABAA receptors, despite their structural similarity. Previous research indicates some monoterpenes, including citronellol and α-pinene, produce positive modulation of GABA at α1β1 GABAA receptors [24], suggesting (+)-borneol and analogues (Fig. 1) may also act via GABAA receptors to contribute to the traditionally acknowledged sedative and anxiolytic effects of valerian.
The present study compares the effects of bicyclic monoterpenes found in essential oils, particularly (+)- and (−)-borneol, on GABA-induced chloride currents at α1β2γ2L GABAA receptors expressed in Xenopus laevis oocytes using two-electrode voltage-clamp electrophysiology.
Section snippets
Materials
Human α1, β2 and γ2L cDNAs subcloned in pcDM8 (Stratagene, La Jolla, CA, USA) were kindly provided by Dr. Paul Whiting, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, UK). GABAA receptor mRNA (α1β2γ2L) were the kind gifts of Ms. Shelley Huang and Ms. Belinda Hall (The University of Sydney, Sydney, Australia). GABA, (+)-borneol, (−)-borneol, isoborneol, (−)-bornyl acetate, zinc sulfate, and dimethyl sulfoxide (DMSO) were obtained from Sigma–Aldrich (St. Louis, MO, USA). Camphor was
Expression of functional α1β2γ2L GABAA receptors
GABA-sensitive channels were produced via injection of α1, β2, γ2L (GABAA) cRNAs in X. laevis oocytes. At a holding potential of −60 mV, the injected oocytes responded to bath applied GABA with an inward current response. Current traces are shown in Fig. 2. Incorporation of the γ2L subunit was confirmed via insensitivity to Zn2+ ions. GABA-evoked currents were concentration-dependent, exhibiting comparable pharmacological profiles to those previously described, with GABA EC50 (32.9 μM; 95% CI:
Discussion
Many studies have shown that traditional herbal extracts have GABAergic effects, such as sedation and anxiolysis. Furthermore, a range of reports have shown that some monoterpenes present within the essential oils of such herbal medicines have modulatory activity with GABA at several GABAA receptor subtypes, but these monoterpenes had not been tested at α1β2γ2L receptors, thought to comprise 40% of GABA receptors in the mammalian CNS [20]. The current study demonstrates that a number of
Acknowledgements
We thank Dr. Paul Whiting, Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, UK, for human α1, β2 and γ2L cDNAs; Dr. Hue Tran, Mr. Kong Li and Ms. Suzanne Habjan for technical assistance; and National Health and Medical Research Council of Australia for financial support.
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