• Korean Journal of Pharmacognosy
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• v.30 no.2
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• pp.211-215
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• 1999

This study was aimed to evaluate an agonistic activity to benzodiazepine receptor of several medicinal plants, which have been used as sedatives in oriental medicine. Methanol extracts of medicinal plants which were used in this study inhibited the binding of $[^3H]Ro15-1788$, a selective benzodiazepine receptor antagonist to benzodiazepine receptor of rat cortices. Inhibitory activity of Cyperus rotundus was observed to be the highest among the tested medicinal plants. Methanol extracts of Cyperus rotundus and Zizypus jujuba inhibited a $[^3H]flunitrazepam$, a selective benzodiazepine receptor agonist, binding to benzodiazepine receptor. GABA significantly enhanced the inhibition of $[3H]flunitrazepam$ binding by Cyperus rotundus and Zizypus jujuba, and these positive GABA shifts supported the strong possibility of agonistic activity to benzodiazepine receptor. From these results, it may be concluded that the substance or substances with neurochemical properties characteristic of a benzodiazepine receptor agonist may be important components and contribute to the sedative property of these medicinal plants.

• Journal of Life Science
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• v.10 no.4
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• pp.374-379
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• 2000

This study was attempted to evaluate an agonistic activity to benzodiazepine receptor of several medicinal pants, which have been used as sedatives in oriental medicine. The activities of the methanol extracts of composite preparation of oriental drugs were compared with those of the simple drugs, furthermore, the active fraction was found out from the simple preparation. Inhibitory effects of composite preparations, Cyperus rotundus/Acorus gramineus, Thuja orientalis/Euphoria longan, Thuja orientalis/Albizzia julibrissin, on the binding of ${[^3H]}$Ro15-1788, a selective benszodiazepine receptor antagonist to benzodiazepine receptor of rat cortices, were observed to be lower than those of corresponding simple preparations. These unexpected results suggest that some components of the composite druge may rather act as an obstacle, not to show the sinergistic effect. The methanol extracts of Cyperus rotundus having the highest activity were fractionated using polar and nonpolar solvents to give ethylacetate and hexane fractions, respectively. The ethylacetate fraction containing relatively polar components exhibited much higher activity than the hexane fraction, which consiste of nonpolar agonist, binding to benzodiazepine receptor. However, in the presence of GABA, this fraction inhibited ${[^3H]}$flunitrazepan binding, and these positive GABA shift supported the strong possibility of agonistic activity to benzodiazepine receptro. As a result, it may be concluded that the substance or substances with neurochemical properties as a benzodiazepine receptor agonist may contribute to the sedative property of Cyperus rotundus.

• Korean Journal of Pharmacognosy
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• v.30 no.3
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• pp.284-289
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• 1999

In order to find active ingradients having an agonistic activity to benzodiazepine receptor from Gastrodia elata Blume (Orchidaceae) which has been used as an anticonvulsant in oriental medicine, one component and some fractions were separated from the butanol extract of the rhizomes of this plant and evaluated for their activities on GABA/benzodiazepine receptor in vitro. As a result, one crude mixture (F4f) obtained from the most active fraction (F4) inhibited significantly the binding of $[^3H]Ro15-1788$, a selective benzodiazepine receptor antagonist, to benzodiazepine receptor of rat cortices. GABA significantly enhanced the inhibition of $[^3H]flunitrazepam$ binding by F4f, and this positive GABA shift supported the strong possibility of the agonistic activity of F4f to benzodiazepine receptor.

• Biomolecules & Therapeutics
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• v.5 no.4
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• pp.325-330
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• 1997

Methanol extract of G. elata inhibited the binding of [/sup 3/H]Rol5-1788, a selective benzodiazepine receptor antagonest, to benzodiazepine receptor of rat cortices. Saturation experiments followed by Scatchard analysis of the results showed that the inhibition of [sub 3/H]Ro15-1788 binding by G. dlata. appeared to be com-petitive. These competitive inhibiton of the butanol fraction was observed to be higher than the methanol extract. Methanol extract of G. efara inhibited a [sub 3/H]flunitrazepam, a selective benzodiazepine receptor agonist, binding to benzodiazepine receptor. GABA significantly enhanced the inhibition of [/sub 3/H]flunitrazepam binding by G. elata, and these "positive GABA shift" supported the strong possibility of agonestic activity to benzodiazepine receptor Butanol fraction was observed to be higher than crude extract by methanol in an agonistic activity to benzodiazepine receptor, furthermore enhanced the binding of [sub 3/H]SR95531 to GABA receptor. Butanol fraction of G. elata significantly diminished the pentylenetetrazole-induced lethality of mice. From these results, it can be concluded that substance or substances with neurochemical properties characteri- stic of a benzodiazepine receptor agonist may be important components, and contribute to the anticonvulsant property of G. elata.

• YAKHAK HOEJI
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• v.36 no.5
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• pp.496-505
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• 1992

The correlation between GABA receptors($GABA_A$ and $GABA_B$ receptor) and benzodiazepine receptor on the saline infusion-induced micturition reflex contraction was studied in the female rat. To investigate the effect of ${\gamma}-aminobutyric$ acid(GABA) on the micturition reflex, exogenous GABA(10 mg/kg) and GABA transaminase inhibitor(aminooxyacetic acid; AOAA $1\;{\mu}g$) were administered intravenously(i.v.) and intracerebroventriculary(i.c.v.), respectively. In result, both GABA and AOAA inhibited the saline induced micturition reflex contraction. This AOAA induced inhibition of micturition reflex was blocked by both bicuculine. $GABA_A$ receptor antagonist, and Ro 15-1788, benzodiazepine receptor antagonist. Muscimol, $GABA_A$ receptor antagonist($0.1\;{\mu}g$ i.c.v., $3\;{\mu}g$ intrathecal; i.t., 1 mg/kg i.v.) and baclofen, $GABA_A$ receptor agonist($1\;{\mu}g$ i.c.v., $3\;{\mu}g$ i.t., 1 mg/kg i.v.) also inhibited the bladder contraction. Pretreatment of bicuculline($1\;{\mu}g$ i.c.v.), but not of 5-aminovaleric acid(AVA, $1\;{\mu}g$ i.c.v.), $GABA_B$ receptor antagonist blocked the central inhibition of muscimol. These inhibitory effects were reversed by Ro15-1788 but were potentiated by flurazepam, benzodiazepine receptor antagonist. On the other hand, the inhibitory effects of baclofen were not affected by Ro 15-1788. Diazepam and flurazepam also inhibited the micturition reflex contraction when they were administered $3\;{\mu}g$ i.c.v., $10\;{\mu}g$ i.t., $10\;{\mu}M$, $30\;{\mu}M$ transurethrally, respectively. In conclusion, these results suggest that the micturition reflex is mediated by $GABA_A$, $GABA_B$ receptor and benzodiazepine receptor. The bezodiazepines increase the receptor binding of GABA to the $GABA_A$ receptor, so that the benzodiiazepines show the synergistic effect on the inhibition of the micturition reflex contraction, but not to the $GABA_B$ receptor.

• Nuclear Medicine and Molecular Imaging
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• v.41 no.2
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• pp.166-171
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• 2007

GABA is primary an inhibitory neurotransmitter that is localized in inhibitory interneurons. GABA is released from presynaptic terminals and functions by binding to GABA receptors. There are two types of GABA receptors, $GABA_{A}-receptor$ that allows chloride to pass through a ligand gated ion channel and $GABA_{B}-receptor$ that uses G-proteins for signaling. The $GABA_{A}$-receptor has a GABA binding site as well as a benzodiazepine binding sites, which modulate $GABA_{A}$-receptor function. Benzodiazepine GABAA receptor imaging can be accomplished by radiolabeling derivates that activates benzodiazepine binding sites. There has been much research on flumazenil (FMZ) labeled with $^{11}C-FMZ$, a benzodiazepine derivate that is a selective, reversible antagonist to GABAA receptors. Recently, $^{18}F-fluoroflumazenil$ (FFMZ) has been developed to overcome $^{11}C's$ short half-life. $^{18}F-FFMZ$ shows high selective affinity and good pharmacodynamics, and is a promising PET agent with better central benzodiazepine receptor imaging capabilities. In an epileptic focus, because the GABA/benzodiazepine receptor amount is decreased, using $^{11}C-FMZ$ PET instead of $^{18}F-FDG$ PET, restrict the foci better and may also help find lesions better than high resolution MR. $GABA_{A}$ receptors are widely distributed in the cerebral cortex, and can be used as an viable neuronal marker. Therefore it can be used as a neuronal cell viability marker in cerebral ischemia. Also, GABA-receptors decrease in areas where neuronal plasticity develops, therefore, $GAB_{A}$ imaging can be used to evaluate plasticity. Besides these usages, GABA receptors are related with psychological diseases, especially depression and schizophrenia as well as cerebral palsy, a motor-related disorder, so further in-depth studies are needed for these areas.

• Journal of Oriental Neuropsychiatry
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• v.15 no.1
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• pp.77-86
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• 2004

Objective : This study was performed to investigate the agonistic activity of Chunmajeongal-tang extract to the $GABA_A/benzodiazepine$ receptor complex. Methods : Male mice and Sprague-Dawley rats were used for this experiment. Chunmajeongal-tang Prescription was extracted with 80% methanol, evaporated in vacuo and dried with freeze dryer. The agonistic activity to the GABA/ benzodiazepine receptor complex and GABA transaminase activity were measured in vitro. Results : Chunmajeongal-tang extract inhibited dose-dependently the binding of [3H]Ro15-1788, an antagonist on GABA/benzodiazepine receptor complex, in rat cerebral cortices, showing $82.4{\pm}4.12%$ inhibition at a dose of 5.0 mg/kg. This extract inhibited dose-dependently the binding of [3H]flunitrazepam, an agonist on GABA/benzodiazepine receptor complex, in rat cerebral cortices, showing $5.6{\pm}1.24%$ inhibition. Furthermore, Chunmajeongal-tang extract inhibited the binding of [3H]flunitrazepam in the presence of GABA/NaCI with $13.2{\pm}0.44%$ inhibition, its inhibitory effect exhibited a positive GABA shift, which means that this extract activates a GABAergic neurotransmission.

• Anxiety and mood
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• v.1 no.1
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• pp.25-30
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• 2005

In the 40 years since the first benzodiazepine was brought into clinical use there has been a substantial growth in understanding the molecular basis of action of these drugs and the role of their receptors in anxiety disorders. Benzodiazepine receptors are present throughout the brain with the highest concentration in cortex, and it potentiate and prolong the synaptic action of the inhibitory neurotransmitter GABA. Central benzodiazepine receptors and $GABA_A$ receptors are part of the same macromolecular complex. Abnormalities of these $GABA_A$-benzodiazepine receptors as a result of drug challenge tests and neuroimaging studies may underlie some anxiety disorders. The role of $GABA_A$-benzodiazepine receptors in the action of benzodiazepine and as a factor in anxiety disorder, in both animal and humans including knock-out and knock in technique, may lead to new anxiolytics that have potentially significant therapeutic gains without unwanted side effects.

• The Korean Journal of Physiology and Pharmacology
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• v.1 no.6
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• pp.769-774
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• 1997

Non-neuronal high affinity binding sites for benzodiazepines have been found in many peripheral tissues including cardiac muscle and vascular smooth muscle, and have been designated as 'peripheral benzodiazepine receptor'. Benzodiazepines have been shown to induce relaxation of the ileal, vesical, and uterine smooth muscles. However, it is still unclear about possible involvement of peripheral benzodiazepine receptor on the contractility of trachealis muscle. This study was performed to investigate the role of the peripheral benzodiazepine receptor on the contractility of canine trachealis muscle. Canine trachealis muscle strips of 15 mm long were suspended in an isolated organ bath containing 1 ml of physiological salt solution maintained at $37^{\circ}C$, and aerated with $95%\;O_2/5%\;CO_2$. Isometric myography was performed, and the results of the experiments were as follows: Ro5-4684, FGIN-1-27 and clonazepam reduced a basal tone of isolated canine trachealis muscle strip concentration dependently, relaxant actions of RoS-4684 and FGIN-1-27 were antagonized by PK11195, a peripheral benzodiazepine receptor antagonist. Flumazenil, a central type antagonist, did not antagonize the relaxant action of Peripheral type agonists. Saturation binding assay of [3H]Ro5-4864 showed a high affinity$(Kd=5.33{\pm}1.27nM,\;Bmax=\;867.3{\pm}147.2\;fmol/mg\;protein)$ binding site on the canine trachealis muscle. Ro 5-4684 suppressed the bethanechol-, 5-hydroxyoyptamine- and histamine- induced contractions. Platelet activating factor (PAF) exerted strong and prolonged contraction in trachealis muscle strip. Strong tonic contraction by PAE was attenuated by Ro 5-4684, but not by WEB 2086, a PAF antagonist. Based on these results, it is concluded that the peripheral benzodiazepine receptor mediates the inhibitory regulation of contractilty of canine trachealis muscle.

• Archives of Pharmacal Research
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• v.28 no.2
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• pp.238-242
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• 2005

Many reports demonstrate that extremely low frequency magnetic fields (ELF MFs, 60 Hz) may be involved in hyperalgesia. In a previous investigation, we suggested that MFs may produce hyperalgesia and such a response may be regulated by the benzodiazepine system. In order to further confirm this effect of MFs, we used diazepam and/or flumazenil with MFs exposure. When testing the pain threshold of rats using hot plate tests, MFs or diazepam ($0.5\;{\mu}g$, i.c.v.; a benzodiazepine receptor agonist) induced hyperalgesic effects with the reduction of latency. These effects were blocked by a pretreatment of flumazenil (1.5 mg/kg, i.p.; a benzodiazepine receptor antagonist). When the rats were exposed simultaneously to MFs and diazepam, the latency tended to decrease without statistical significance. The induction of hyperalgesia by co-exposure to MFs and diazepam was also blocked by flumazenil. However, the pretreatment of GABA receptor antagonists such as bicuculline ($0.1\;{\mu}g$, i.c.v.; a $GABA_A$ antagonist) or phaclofen ($10\;{\mu}g$, i.c.v.; a $GABA_B$ antagonist) did not antagonize the hyperalgesic effect of MFs. These results suggest that the benzodiazepine system may be involved in MFs-induced hyperalgesia.