• 대한의생명과학회지
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• 제14권2호
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• pp.69-76
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• 2008

${\gamma}$-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system, and its actions are mediated by subtypes of GABA receptors named as $GABA_A$, $GABA_B,\;and\;GABA_C,\;GABA_A$, receptor consisting of ${\alpha},\;{\beta},\;{\gamma}\;and\;{\delta}$ subunits is a heterooligomeric ligand-gated chloride channel. This study was performed to investigate regulation of $GABA_A$ receptor by protein kinase C(PKC). Ion currents were recorded using gramicidine-perforated patch and whole cell patch clamp. mRNA encoding the subunits of PKC expressed in major pelvic ganglion (MPG) neurons was detected by using RT-PCR. The GABA-induced inward current was increased by PKC activators and decreased by PKC inhibitors, respectively. These effects were not associated with intracellular $Ca^{2+}$ and GAG (1-oleoyl-2-acetyl-sn-glycerol), a membrane permeable diacylglycerol (DAG) analogue. These results mean that the subfamily of PKC participating in activation of $GABA_A$ receptor would be an atypical PKC (aPKC). Among theses, ${\xi}$ isoform of aPKC was detected by RT-PCR. Taking together, we suggest that excitable $GABA_A$ receptor in sympathetic MPG neuron seemed to be regulated by aPKC, particular in ${\xi}$ isoform. The regulatory roles of PKC on excitatory $GABA_A$ receptors in sympathetic neurons of MPG may be an important factor to control the functional activity of various pelvic organs such as bowel movement, micturition and erection.

• Natural Product Sciences
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• 제19권2호
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• pp.179-185
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• 2013

Polygalae radix (PR) has traditionally been used as a sedative and anti-stress agent in oriental countries for a long time. PR which contains many ingredients is especially rich in saponins. This study was performed to investigate whether ethanol extract of PR enhances pentobarbital-induced sleep behaviors. In addition, possible mechanisms also were investigated. PR inhibited locomotor activity in mice. PR increased sleep rate and sleep time by concomitant administration with sub-hypnotic dose of pentobarbital (28 mg/kg). PR prolonged total sleeping time, and shortened sleep latency induced by pentobarbital (42 mg/kg). In addition, PR increased intracellular chloride concentration in primary cultured neuronal cells. The expression level of glutamic acid decarboxylase (GAD) were increased, and ${\gamma}$-aminobutyric acid $(GABA)_A$ receptors subunits were modulated by PR, especially increasing ${\gamma}$-subunit expression. In conclusion, PR augments penobarbital-induced sleep behaviors through activation of $GABA_A$ receptors and chloride channel complex.

• 대한불안의학회지
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• 제2권2호
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• pp.79-85
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• 2006

Anxiety and anxiety disorders are related to many neurotransmitters, such as norepinephrine, serotonine, dopamine, glutamate, and Gamma-aminobutyric acid (GABA). GABA, the main inhibitory neurotransmitter of the CNS, is known to counterbalance the action of the excitatory neurotransmitters and control anxiety. GABA acts on 3 GABA receptor subtypes, $GABA_A$, $GABA_B$, and $GABA_C$. $GABA_A$ and $GABA_c$ receptors are oligomeric transmembrane glycoproteins composed of 5 subunits that are arranged around a central chloride channel. $GABA_B$ receptor comprises two 7-transmembraneis-spanning proteins that are coupled to either calcium or potassium channel via G proteins. This article highlights neurobiological interactions between anxiety and GABA system.

• Biomolecules & Therapeutics
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• 제25권2호
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• pp.105-111
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• 2017

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 ${\gamma}-aminobutyric$ 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 ${\delta}-waves$ and the decrease in ${\alpha}-waves$. On the other hand, RA (0.1, 1.0 and $10{\mu}g/ml$) increased intracellular $Cl^-$ influx in the primary cultured hypothalamic cells of rats. RA (p.o.) increased the protein expression of glutamic acid decarboxylase ($GAD_{65/67}$) and $GABA_A$ receptors subunits except ${\beta}1$ subunit. In conclusion, RA augmented pentobarbital-induced sleeping behaviors through $GABA_A-ergic$ transmission. Thus, it is suggested that RA may be useful for the treatment of insomnia.

• Natural Product Sciences
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• 제21권3호
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• pp.219-225
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• 2015

In the previous experiments, we reported that ethanol extract of Gastrodiae Rhizoma, the dried tuber of Gastrodia ElataBlume (Orchidaceae) increased pentobarbital-induced sleeping behaviors. These experiments were undertaken to know whether 4-hydroxybenzaldehyde (4-HBD), is one of the major compounds of Gastrodiae Rhizoma increases pentobarbital-induced sleeping behaviors and changes sleep architectures via activating GABA_A-ergic systems in rodents. 4-HBD decreased locomotor activity in mice. 4-HBD increased total sleep time, and decreased of sleep onset by pentobarbital (28 mg/kg and 40 mg/kg). 4-HBD showed synergistic effects with muscimol (a GABA_A receptor agonist), shortening sleep onset and enhancing sleep time on pentobarbital-induced sleeping behaviors. On the other hand, 4-HBD (200 mg/kg, p.o.) itself significantly inhibited the counts of sleepwake cycles, and prolonged total sleep time and non-rapid eye movement (NREM) in rats. Moreover, 4-HBD increased intracellular Cl⁻ levels in the primary cultured cerebellar cells. The protein levels of glutamic acid decarboxylase (GAD) and GABA_A receptors subunits were over-expressed by 4-HBD. Consequently, these results demonstrate that 4-HBD increased NREM sleep as well as sleeping behaviors via the activation of GABA_A-ergic systems in rodents.

• The Korean Journal of Pain
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• 제28권1호
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• pp.4-10
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• 2015

Etifoxine (etafenoxine, $Stresam^{(R)}$) is a non-benzodiazepine anxiolytic with an anticonvulsant effect. It was developed in the 1960s for anxiety disorders and is currently being studied for its ability to promote peripheral nerve healing and to treat chemotherapy-induced pain. In addition to being mediated by $GABA_A{\alpha}2$ receptors like benzodiazepines, etifoxine appears to produce anxiolytic effects directly by binding to ${\beta}2$ or ${\beta}3$ subunits of the $GABA_A$ receptor complex. It also modulates $GABA_A$ receptors indirectly via stimulation of neurosteroid production after etifoxine binds to the 18 kDa translocator protein (TSPO) of the outer mitochondrial membrane in the central and peripheral nervous systems, previously known as the peripheral benzodiazepine receptor (PBR). Therefore, the effects of etifoxine are not completely reversed by the benzodiazepine antagonist flumazenil. Etifoxine is used for various emotional and bodily reactions followed by anxiety. It is contraindicated in situations such as shock, severely impaired liver or kidney function, and severe respiratory failure. The average dosage is 150 mg per day for no more than 12 weeks. The most common adverse effect is drowsiness at the initial stage. It does not usually cause any withdrawal syndromes. In conclusion, etifoxine shows less adverse effects of anterograde amnesia, sedation, impaired psychomotor performance, and withdrawal syndromes than those of benzodiazepines. It potentiates $GABA_A$ receptor-function by a direct allosteric effect and by an indirect mechanism involving the activation of TSPO. It seems promising that non-benzodiazepine anxiolytics including etifoxine will replenish shortcomings of benzodiazepines and selective serotonin reuptake inhibitors according to animated studies related to TSPO.

• Biomolecules & Therapeutics
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• 제22권4호
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• pp.314-320
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• 2014

This study was investigated to know whether pachymic acid (PA), one of the predominant triterpenoids in Poria cocos (Hoelen) has the sedative-hypnotic effects, and underlying mechanisms are mediated via ${\gamma}$-aminobutyric acid (GABA)-ergic systems. Oral administration of PA markedly suppressed locomotion activity in mice. This compound also prolonged sleeping time, and reduced sleep latency showing synergic effects with muscimol (0.2 mg/kg) in shortening sleep onset and enhancing sleep time induced by pentobarbital, both at the hypnotic (40 mg/kg) and sub-hypnotic (28 mg/kg) doses. Additionally, PA elevated intracellular chloride levels in hypothalamic primary cultured neuronal cells of rats. Moreover, Western blotting quantitative results showed that PA increased the amount of protein level expression of $GAD_{65/67}$ over a broader range of doses. PA increased ${\alpha}$- and ${\beta}$-subunits protein levels, but decreased ${\gamma}$-subunit protein levels in $GABA_A$ receptors. The present experiment provides evidence for the hypnotic effects as PA enhanced pentobarbital-induced sleeping behaviors via $GABA_A$-ergic mechanisms in rodents. Taken together, it is proposed that PA may be useful for the treatment of sleep disturbed subjects with insomnia.

• Journal of Ginseng Research
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• 제34권4호
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• pp.304-313
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• 2010

This study was undertaken to discover the effects and possible mechanisms of the effect of red ginseng extract (RGE) on spontaneous sleep. The effects of a low dose (10 mg/kg) and a high dose (200 mg/kg) of RGE were compared in rats. After recovery from a surgical operation enabling electroencephalograms recordings, rats were administered RGE orally. RGE was administered orally for 1 day or once per day for 5 days in either 10 or 200 mg/kg doses. Polygraphic signs were recorded for 12 h after oral administration of RGE. Both treatment with a large dose (200 mg/kg) of RGE for one day and treatment with either a large or a small dose for 5 days reduced the number of sleep.wake cycles. Daily treatment with RGE (either 10 or 200 mg/kg) for 5 days augmented NREM and total sleep, but reduced wakefulness. Delta wave activity recorded during non-REM (NREM) sleep and REM sleep was increased after one treatment with RGE (either 10 or 200 mg/kg). Delta wave activity during NREM was enhanced after daily treatment with RGE (either 10 or 200 mg/kg) for 5 days. Both alpha and beta subunits of the $\gamma$-aminobutyric acid $(GABA)_A$ receptor were significantly over-expressed in the hypothalamus of the RGE-treated groups. Moreover, the expression of glutamic acid decarboxylase was also increased in the hypothalamus. These results demonstrate that RGE may regulate spontaneous sleep via $GABA_A$ergic systems.

• The Korean Journal of Physiology and Pharmacology
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• 제17권2호
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• pp.175-180
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• 2013

Resveratrol is a phytoalexin found in grapes, red wine, and berries. Resveratrol has been known to have many beneficial health effects, such as anti-cancer, neuroprotective, anti-inflammatory, and life-prolonging effects. However, relatively little is known about the effects of resveratrol on the regulation of ligand-gated ion channels. We have previously reported that resveratrol regulates subsets of homomeric ligand-gated ion channels such as those of 5-$HT_{3A}$ receptors. The ${\gamma}$-aminobutyric $acid_C$($GABA_C$) receptor is mainly expressed in retinal bipolar cells and plays an important role in visual processing. In the present study, we examined the effects of resveratrol on the channel activity of homomeric $GABA_C$ receptor expressed in Xenopus oocytes injected with cRNA encoding human $GABA_C$ ${\rho}$ subunits. Our data show that the application of GABA elicits an inward peak current ($I_{GABA}$) in oocytes that express the $GABA_C$ receptor. Resveratrol treatment had no effect on oocytes injected with $H_2O$ or with $GABA_C$ receptor cRNA. Co-treatment with resveratrol and GABA inhibited $I_{GABA}$ in oocytes with $GABA_C$ receptors. The inhibition of $I_{GABA}$ by resveratrol was in a reversible and concentration-dependent manner. The $IC_{50}$ of resveratrol was $28.9{\pm}2.8{\mu}M$ in oocytes expressing $GABA_C$ receptor. The inhibition of $I_{GABA}$ by resveratrol was in voltage-independent and non-competitive manner. These results indicate that resveratrol might regulate $GABA_C$ receptor expression and that this regulation might be one of the pharmacological actions of resveratrol on the nervous system.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 2008년도 Proceedings of the Convention
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• pp.119-142
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• 2008

Zizyphi Spinosi Semen (ZSS) has been widely used for the treatment of anxiety and insomnia in Korea and China. This experiment was performed to know whether sanjoinine A, one of major alkaloid compounds of ZSS has anxiolytic and hypnotic effects through the GABAergic systems. Our results showed that administration of sanjoinine A increased open arm entries and spent time in open arm in the elevated plus-maze and increased head dips in hole board test. Different from traditional anxiolytic, diazepam, sanjoinine A itself did not decrease locomotor activity and strength level in mice. Furthermore, Sanjoinine A (0.5-2.0 mg/kg) prolonged sleeping time and reduced sleeping latency induced by pentobarbital in a dose-dependent manner similar to muscimol, a $GABA_A$ receptor agonist. Sanjoinine A (0.25-1.0 mg/kg) also increased sleeping rate and sleeping time in the combined administration at the sub-hypnotic dose of pentobarbital and showed synergic effects with muscimol in potentiating sleeping onset and enhancing sleeping time induced by pentobarbital. However, sanjoinine A itself did not induce sleeping at the higher dose. In addition, both of sanjoinine A and pentobarbital increased chloride influx in primary cultured cerebellar granule cells. Sanjoinine A decreased the $GABA_A$ receptor ${\alpha}$-subunit expression and increased ${\gamma}$-subunit expression, and had no effects on abundance of ${\beta}$-subunit in primary cultured cerebellar granule cells, showing different expression of subunits from pentobarbital. In conclusion, sanjoinine A shows anxiolytic-like effects and augments pentabarbital-induced sleeping behaviors through the modification of GABAergic systems. [This work was supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD) (The Regional Research Universities Program/Center for Healthcare Technology Development)].