• Biomolecules & Therapeutics
• /
• 제3권4호
• /
• pp.322-326
• /
• 1995

General pharmacology of LB20304, a quinolone antibiotic, were examined in terms of general behaviour, cardiovascular, and central nervous system. LB20304 at oral dose of 2,000 mg/kg did not induce significant behavioural changes in mice. In contrast with ciprofloxacin, LB20304 at dose of 20 mg/kg, iv. did not show any observable effects on the blood pressure in rats. Displacement of [$^3$H]muscimol binding to the rat brain synaptic membranes was measured. LB20304 was shown to be about five times less potent than ciprofloxacin in specific GABA receptor binding. Drug interaction between LB20304 and 4-biphenyl acetic acid, an active metabolite of fenbufen, was assessed in mice by measuring convulsion and/or subsequent death. A single oral pretreatment with 4-BPA at 400 mg/kg increased the incidence of convulsion and death after oral administration of ciprofloxacin at the doses of 25, 50, and 100 from zero of five to three of five, two of five, and four of five, respectively, whereas LB20304 alone or combination with 4-BPA caused neither convulsions nor death at the doses of 12.5, 25, 50, and 100 mg/kg, respectively. Quinolones-induced epileptogenic activities were assessed by a direct intracerebral injection of test articles. The CD$_{50}$ values (nmole) are as follows; 169.47, 35.36, 105.29, and 88.67 for LB20304, ciprofloxacin, of loxacin, and lomefloxacin, respectively. From these data, LB 20304 at therapeutic doses seems to be much more safe than any other quinolones tested.d.

• Journal of Yeungnam Medical Science
• /
• 제16권1호
• /
• pp.25-33
• /
• 1999

세계적으로 그 처방률이 높은 약물들 중 하나인 benzodiazepine계 약물은, 강력한 불안해소작용, 항경련작용, 최면작용 및 근이완작용을 가지고 있다. Benzodiazepine계 약물의 약리작용기전과 관련하여 불안장애의 병인에서 각종 신경전달계의 역할은 밝혀지고 있다. Benzodiazepine 약물은 편도체와 같은 변연계, 우측 시상하부 및 raphe nuclei에서 GALA성 신경전달을 조절함으로써 불안해소 작용을 나타내는 것으로 보고되었으며, 공포와 스트레스로 인해 유발되는 행동에 있어서 편도체의 역할은 이미 여러 보고를 통해 시사된 바 있다. 본 종설에서는 GABA성 신경전달 조절작용이 있다고 보고된 내인성 benzodiazepine 수용체 배위자의 불안 및 스트레스 반응의 인지 조절작용 및 기억 형성과정 조절작용 등에 관한 연구결과들을 종합하여 본 결과 내인성 benzodiazepine 수용체 배위자들이 불쾌한 학습과정에 동반되는 스트레스와 불안의 정도에 영향을 미침으로써 기억 형성과정을 조절한다는 생각을 뒷받침해 주었다. 또한 각종 행동 검사후 나타나는 뇌조직의 benzodiazepine 유사 물질의 부위별(편도체, 해마, 중격) 농도 감소는 행동 검사에 수반되는 스트레스 및 불안 정도에 비례하므로, 이러한 물질의 감소는 스트레스 및 불안에 대한 변연계의 일반적인 반응으로 생각된다. 부가적으로 이러한 결과는 변연계의 $GABA_A$/benzodiazepine 수용체 복합체는 생체의 스트레스 및 불안반응의 생리, 생화학적 면에서 중추적인 역할을 한다는 생각을 할 수 있게 하는 결과라 할 수 있다.

• Natural Product Sciences
• /
• 제15권3호
• /
• pp.115-120
• /
• 2009

Woohwangcheongsimwon (WHCSW) is a traditional oriental medicinal fomula which has been clinically used for treating strokes, palpitation, loss of consciousness and anxiety. The purpose of this study was to characterize the putative anxiolytic properties of WHCSW using an elevated plus-maze (EPM) and hole-board test. Control mice were orally treated with an equal volume of vehicle (10% Tween 80 solution), and positive control mice were treated with diazepam (1 mg/kg, i.p.). In the EPM test, WHCSW significantly increased the percentage of time-spent in the open arms (200 mg/kg, P < 0.05) and the percentage of open arm entries (200 and 400 mg/kg, P < 0.05). WHCSW also significantly increased the number of head-dips in the hole-board test (200 mg/kg, P < 0.05). In addition, the anxiolytic properties of WHCSW examined in the EPM test were inhibited by flumazenil (10 mg/kg, i.p.), a GABA$_A$ antagonist. However, no changes in spontaneous locomotor activity or myorelaxant effects were observed versus 10% Tween 80 controls. These results suggested that WHCSW is an effective anxiolytic agent, and that its anxiolytic effects are mediated via GABA$_A$ receptors.

• Animal cells and systems
• /
• 제1권3호
• /
• pp.467-473
• /
• 1997

Taurine (2-aminoethanesulfonic acid), one of bioactive amino acid in the mammalian brain, is known to exert inhibitory effects on neurons via GABA receptor. In the present study, we examined effects of taurine on glutamateinduced neurotoxicity on hippocampal neuron cell culture using cell counting method and lactate dehydrogenase (LDH) assay. After 10 d of culture, cells were stimulated with appropriate drugs. Only 43% of cultured neuronal cells survived at one day after stimulation with 500 uM L-glutamate for 10 min. Survival rate was enhanced by 82% in the presence of 10 mM taurine. LDH activity from the culture supernatant incubated with a combination of L-glutamate and taurine was less than half of that with L-glutamate alone. In the next series of experiments, interleukin-6 (IL-6) mRNA expression in cultured astrocytes was investigated using reverse tanscription-PCR (RT-PCR). IL-6 mRNA was detected in the astrocytes stimulated with L-glutamate in a dose-dependent manner, while not detected in the unstimulated control astrocytes. The expression of IL-6 mRNA caused by 10 mM glutamate was inhibited by taurine, but not by GABA. These findings demonstrated a neuroprotective action of taurine against glutamate-induced toxicity.

• Journal of Ginseng Research
• /
• 제36권4호
• /
• pp.403-410
• /
• 2012

The current inquiry was conducted to assess the change in sleep architecture after long periods of administration to determine whether ginseng can be used in the therapy of sleeplessness. Following post-surgical recovery, red ginseng extract (RGE, 200 mg/kg) was orally administrated to rats for 9 d. Data were gathered on the 1st, 5th, and 9th day, and an electroencephalogram was recorded 24 h after RGE administration. Polygraphic signs of unobstructed sleep-wake activities were simultaneously recorded with sleep-wake recording electrodes from 11:00 a.m. to 5:00 p.m. for 6 h. Rodents were generally tamed to freely moving polygraphic recording conditions. Although the 1st and 5th day of RGE treatment showed no effect on power densities in nonrapid eye movement (NREM) and rapid eye movement (REM) sleep, the 9th day of RGE administration showed augmented ${\alpha}$-wave (8.0 to 13.0 Hz) power densities in NREM and REM sleep. RGE increased total sleep and NREM sleep. The total percentage of wakefulness was only decreased on the 9th day, and the number of sleep-wake cycles was reduced after the repeated administration of RGE. Thus, the repeated administration of RGE increased NREM sleep in rats. The ${\alpha}$-wave activities in the cortical electroencephalograms were increased in sleep architecture by RGE. Moreover, the levels of both ${\alpha}$- and ${\beta}$-subunits of the ${\gamma}$-aminobutyric acid $(GABA)_A$ receptor were reduced in the hypothalamus of the RGE-treated groups. The level of glutamic acid decarboxylase was over-expressed in the hypothalamus. These results demonstrate that RGE increases NREM sleep via $GABA_A$ergic systems.

• Journal of Veterinary Science
• /
• 제25권5호
• /
• pp.63.1-63.12
• /
• 2024

Importance: Glutamic acid decarboxylase 67 (GAD67) is a gamma-aminobutyric acid (GABA) synthesis enzyme associated with the function of other neurotransmitter receptors, such as the N-methyl-D-aspartate (NMDA) receptor and cannabinoid receptor 1. However, the role of GAD67 in the development of different abused drug-induced reward behaviors remains unknown. In order to elucidate the mechanisms of substance use disorder, it is crucial to study changes in biomarkers within the brain's reward circuit induced by drug use. Objective: The study was designed to examine the effects of the downregulation of GAD67 expression in the dorsal striatum on reward behavior development. Methods: We evaluated the effects of GAD67 knockdown on depression-like behavior and anxiety using the forced swim test and elevated plus maze test in a mouse model. We further determined the effects of GAD67 knockdown on ketamine- and JWH-018-induced conditioned place preference (CPP). Results: Knockdown of GAD67 in the dorsal striatum of mice increased depression-like behavior, but it decreased anxiety. Moreover, the CPP score on the NMDA receptor antagonist ketamine was increased by GAD67 knockdown, whereas the administration of JWH-018, a cannabinoid receptor agonist, did not affect the CPP score in the GAD67 knockdown mice group compared with the control group. Conclusions and Relevance: These results suggest that striatal GAD67 reduces GABAergic neuronal activity and may cause ketamine-induced NMDA receptor inhibition. Consequently, GAD67 downregulation induces vulnerability to the drug reward behavior of ketamine.

• Biomolecules & Therapeutics
• /
• 제27권6호
• /
• pp.584-590
• /
• 2019

Luteolin, a widespread flavonoid, has been known to have neuroprotective activity against various neurologic diseases such as epilepsy, and Alzheimer's disease. However, little information is available regarding the hypnotic effect of luteolin. In this study, we evaluated the hypnotic effect of luteolin and its underlying mechanism. In pentobarbital-induced sleeping mice model, luteolin (1, and 3 mg/kg, p.o.) decreased sleep latency and increased the total sleep time. Through electroencephalogram (EEG) and electromyogram (EMG) recording, we demonstrated that luteolin increased non-rapid eye movement (NREM) sleep time and decreased wake time. To evaluate the underlying mechanism, we examined the effects of various pharmacological antagonists on the hypnotic effect of luteolin. The hypnotic effect of 3 mg/kg of luteolin was not affected by flumazenil, a GABAA receptorbenzodiazepine (GABAAR-BDZ) binding site antagonist, and bicuculine, a GABAAR-GABA binding site antagonist. On the other hand, the hypnotic effect of 3 mg/kg of luteolin was almost completely blocked by caffeine, an antagonist for both adenosine A1 and A2A receptor (A1R and A2AR), 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), an A1R antagonist, and SCH-58261, an A2AR antagonist. From the binding affinity assay, we have found that luteolin significantly binds to not only A1R but also A2AR with $IC_{50}$ of 1.19, $0.84{\mu}g/kg$, respectively. However, luteolin did not bind to either BDZ-receptor or GABAAR. From these results, it has been suggested that luteolin has hypnotic efficacy through A1R and A2AR binding.

• Natural Product Sciences
• /
• 제26권1호
• /
• pp.1-9
• /
• 2020

Flavonoids are mainly contained in the vegetables and medicinal herbs. Until now, over 5,000 kinds of flavonoid have been identified and their biological activities have been reported. Among them, we are interested in oroxylin A and spinosin because of their specific structures having bulky group at C-6 of ring A. Oroxylin A is contained in the Scutellaria baicalensis and exhibits cognitive enhancing activity as a GABA_A receptor antagonist, which is different from those of mainly contained in the S. baicalenis, baicalein or wogonin. Spinosin is isolated from Zizyphus jujuba var. spinosa and mainly studied as a hypnotic or anxiolytic agent because of traditional knowledge about its original herb. As far as we know, the cognitive function of spinosin was first identified by our group. In this review, we discuss how such flavonoids exert their pharmacological activities associated with cognitive function based on the receptor binding study and behavioral studies. Traditional knowledge and reverse pharmacology may be addressed in the research field of phytochemical pharmacology and useful to unveil the secret of phytochemicals.

• 생명과학회지
• /
• 제29권5호
• /
• pp.564-569
• /
• 2019

최근 알코올 소비량이 증가함에 따라 과량의 에탄올을 섭취하는 경우 또한 늘어나고 있다. 이런 과도한 에탄올 섭취는 ${\gamma}$-aminobutyric acid (GABA) 수용체의 활성화와 glutamate 수용체의 활성 억제를 통해 신경계를 교란시켜 단기 기억 형성을 방해 한다. 알코올에 의한 인지기능의 저하는 알코올성 black out을 유도할 수 있으며, 반복될 경우 알코올성 치매로 이어질 수 있기 때문에 black out을 예방하는 치료제의 개발이 필요하다. 따라서 본 연구자는 해당 연구를 통하여 Cassia obtusifolia seeds 에탄올 추출물(COE)이 가진 black out 예방제로써의 가능성을 평가하였다. 본 연구에서는 에탄올에 의해 유도된 기억 장애에 대한 COE의 효과를 확인하였다. 실험 동물의 기억력을 측정하기 위하여 수동 회피 실험과 Y자 미로 실험을 수행하였고, 마우스 해마 절편을 사용하여 에탄올이 기억의 형성과 관련하여 장기 강화(long term potentiation; LTP)에 어떠한 영향을 끼치는지 전기생리학을 통해 확인하였다. 또한 ${\alpha}$-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid 수용체 길항제인 NBQX ($50{\mu}M$)를 사용하여 에탄올에 의한 인지기능 장애와 관련이 있다고 알려진 N-Methyl-D-aspartate (NMDA) 매개 field 흥분성 시냅스 후 전위를 측정하였다. 결과적으로, COE는 에탄올에 의한 기억력의 손상을 방지하였고, 해마 절편에서 에탄올에 의해 감소된 LTP와 NMDA 매개 흥분성 시냅스 후 전위를 대조군과 비슷한 수준까지 회복시켰다.

• 생명과학회지
• /
• 제25권5호
• /
• pp.594-600
• /
• 2015

단백질-단백질 결합은 다양한 세포내 반응 조절에서 중요한 역할을 한다. Postsynaptic density-95/disks large/ zonula occludens-1 (PDZ) 도메인은 널리 알려진 단백질-단백질 결합 매개 도메인 중 하나이다. PDZ 도메인은 결합 단백질의 카르복실(C)-말단의 특정 motif와 결합한다. Multi-PDZ domain protein 1 (MUPP1)은 13개 PDZ 도메인을 가지는 단백질로서 다양한 구조단백질 및 신호단백질에 대한 scaffold로 작용한다고 알려져 있지만 MUPP1의 세포 내 기능은 아직 명확히 밝혀지지 않았다. 본 연구에서 MUPP1의 PDZ 도메인과 결합하는 단백질을 규명하기 위하여 효모 two-hybrid 방법을 이용하였고 muskelin이 MUPP1과 결합하는 것을 확인하였다. Muskelin은 GAB_AA 수용체(GABA_AR)의 α1 subunit와 결합하며 수용체의 endocytosis와 분해에 관여하는 것으로 알려져 있다. Muskelin은 MUPP1의 3번째 PDZ 도메인과 결합하지만, 다른 PDZ 도메인과는 결합하지 않았다. 또한 MUPP1과의 결합에 muskelin의 C-말단부위가 필수적임을 효모 two-hybrid 방법으로 확인하였다. HEK-293T 세포에 MUPP1과 muskelin을 동시에 발현하여 면역 침강한 결과 두 단백질은 같이 면역 침강하였다. 반면에 C-말단 결손 muskelin은 MUPP1과 같이 면역 침강하지 않았다. 또한 muskelin과 MUPP1은 세포내의 같은 위치에서 발현하였다. 이러한 결과들은, muskelin과의 결합을 통해, MUPP1 혹은 MUPP1과 결합하는 단백질이 GABA_AR의 세포내이동과 회전(turnover)을 조절할 가능성을 시사한다.