Biomol Ther (Seoul)  
Rosmarinic Acid Potentiates Pentobarbital-Induced Sleep Behaviors and Non-Rapid Eye Movement (NREM) Sleep through the Activation of GABAA-ergic Systems
Yeong Ok Kwon, Jin Tae Hong and Ki-Wan Oh*
College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju 28644, Republic of Korea
E-mail: kiwan@chungbuk.ac.kr
Tel: +82-43-261-2827, Fax: +82-43-268-2732
Received: February 18, 2016; Revised: March 16, 2016; Accepted: May 11, 2016; Published online: August 1, 2016.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
It has been known that RA, one of major constituents of Perilla frutescens which has been used as a traditional folk remedy for sedation in oriental countries, shows the anxiolytic-like and sedative effects. This study was performed to know whether RA may enhance pentobarbital-induced sleep through γ-aminobutyric acid (GABA)A-ergic systems in rodents. RA (0.5, 1.0 and 2.0 mg/ kg, p.o.) reduced the locomotor activity in mice. RA decreased sleep latency and increased the total sleep time in pentobarbital (42 mg/kg, i.p.)-induced sleeping mice. RA also increased sleeping time and number of falling sleep mice after treatment with sub-hypnotic pentobarbital (28 mg/kg, i.p.). In electroencephalogram (EEG) recording, RA (2.0 mg/kg) not only decreased the counts of sleep/wake cycles and REM sleep, but also increased the total and NREM sleep in rats. The power density of NREM sleep showed the increase in δ-waves and the decrease in α-waves. On the other hand, RA (0.1, 1.0 and 10 μg/ml) increased intracellular Cl- influx in the primary cultured hypothalamic cells of rats. RA (p.o.) increased the protein expression of glutamic acid decarboxylase (GAD65/67) and GABAA receptors subunits except β1 subunit. In conclusion, RA augmented pentobarbital-induced sleeping behaviors through GABAA-ergic transmission. Thus, it is suggested that RA may be useful for the treatment of insomnia.
Keywords: Rosmarinic acid, Electroencephalogram, γ-Aminobutyric acid A receptors subunits, Glutamic acid decarboxylase, Pentobarbital-induced sleep, Insomnia


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