Effects of Cholecystokinin Octapeptide on Neuronal Activities in the Rat Nucleus Tractus Solitarius

Hyewhon Rhim,Chan-Woong Park 대한생리학회-대한약리학회 2000 The Korean Journal of Physiology & Pharmacology Vol.4 No.4

<P> Cholecystokinin (CCK) is a gastrointestinal hormone which plays an important role in satiety and gastric motility. It is also widely distributed throughout the central nervous system, where it appears to be involved in the central control of anxiety, feeding behavior and nociception. Two distinct CCK receptor types, CCK<SUB>A</SUB> and CCK<SUB>B</SUB>, have been found in the brain. Both CCK receptors coexist in the rat nucleus tractus solitarius (NTS), which is the primary center for the coordination of peripheral and central activities related to gastrointestinal, cardiovascular and respiratory functions. <P> In order to study ionic actions of CCK on each type of receptor, we investigated the effects of CCK-8S on neurons located in the NTS of the rat using whole-cell patch-clamp recordings in brainstem slices. Application of CCK-8S, under current clamp, produced a membrane depolarization accompanied by action potential firing. This CCK-evoked excitation was dose-dependent (10 nM∼10μM) and observed in more than 60% of NTS neurons. Under voltage clamp conditions, CCK-8S induced an inward current with a notably increased spontaneous excitatory synaptic activity. However, CCK-8S did not significantly change the amplitude of pharmacologically isolated and evoked EPSP(C)s. Using selective CCK<SUB>A</SUB> and CCK<SUB>B</SUB> receptor antagonists, we observed two different effects of CCK-8S, which suggest CCK<SUB>A</SUB> receptor-mediated inhibitory and CCK<SUB>B</SUB> receptor-mediated excitatory effects in the NTS. These results may help to explain the ability of CCK to modulate gastrointestinal and other reflex systems in the NTS.

진세노사이드에 의한 신경계 이온 통로와 수용체 조절이 신경계 보호 작용과의 연계성에 대하여

임혜원(Hyewhon Rhim),김동현(Dong-Hyun Kim),나승열(Seung-Yeol Nah) 고려인삼학회 2007 최신고려인삼연구 Vol.- No.-

말초 및 중추신경계에서 칼슘채널 및 NMDA 매개 채널의 억제제로의 진세노사이드 Rg₃의 효과

임혜원(Hyewhon Rhim) 고려인삼학회 2003 Journal of Ginseng Research Vol.27 No.3

Alternative medicines such as herbal products are increasingly being used for preventive and therapeutic purposes. Ginseng is the best known and most popular herbal medicine used worldwide. In spite of some beneficial effects of ginseng on the nervous system, little scientific evidence shows at the cellular level. In the present study, I have examined the direct modulation of ginseng total saponins and individual ginsenosides on the activation of Ca2+ channels and NMDA-gated channels in cultured rat dorsal root ganglion (DRG) and hippocampal neurons, respectively. In DRG neurons, application of ginseng total saponins suppressed high-voltage-activated Ca2+ channel currents and ginsenoside Rg3,<br/> among the 11 ginsenosides tested, produced the strongest inhibition on Ca2+ channel currents. Occlusion experiments using selective Ca2+ channel blockers revealed that ginsenoside Rg3 could modulate L-, N-, and P/Q-type currents. In addition, ginsenoside Rg3 also proved to be an active component of ginseng actions on NMDA receptors in cultured hippocampal neurons. Application of ginsenoside Rg3 suppressed NMDA-induced [Ca2+]i increase an d-gated channels using fura-2-based digital imaging and patch-clamp techniques, respectively. These results suggest that the modulation of Ca2+ channels and NMDA receptors by ginsenoside Rg3 could be part of the pharmacological basis of ginseng actions in the<br/> peripheral and central nervous systems.

Synthesis and SAR of N-Chlorophenyl Substituted Piperrazinylethyl-aminomethylpyrazoles as 5-HT3A Inhibitors

이병환,In Sung Choi,Hyewhon Rhim,Kyung Il Choi,나승열,Ghilsoo Nam 대한화학회 2009 Bulletin of the Korean Chemical Society Vol.30 No.11

The 5-HT3A receptors are one of ligand-gated ion channels and are known to be involved in visceral pain, anxiety, or anticancer agent-induced nausea and vomiting. In present study, we designed novel skeletons based on the developed 5-HT3 receptor antagonists and evaluated their effects on 5-HT3A receptor channel currents (I5-HT) of a series of pyrazole derivatives having N-chlorophenylpiperazine functionality (6-9). We found that most of N-p-chlorophenyl substituted piperazinyl-pyrazole derivatives (7b, 7c, 7e and 7h) exhibited the high potency for the inhibition of I5-HT, whereas the compound without chloride (6) or with m-chlorophenyl group (a serious of 8 and 9) showed the low potency. These results indicate that p-chlorophenyl group is might play an important role for increasing the inhibitory potency on I5-HT.

The Serotonin-6 Receptor as a Novel Therapeutic Target

Yun, Hyung-Mun,Rhim, Hyewhon The Korean Society for Brain and Neural Science 2011 Experimental Neurobiology Vol.20 No.4

<P>Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter that is found in both the central and peripheral nervous systems. 5-HT mediates its diverse physiological responses through 7 different 5-HT receptor families: 5-HT<SUB>1</SUB>, 5-HT<SUB>2</SUB>, 5-HT<SUB>3</SUB>, 5-HT<SUB>4</SUB>, 5-HT<SUB>5</SUB>, 5-HT<SUB>6</SUB>, and 5-HT<SUB>7</SUB> receptors. Among them, the 5-HT<SUB>6</SUB> receptor (5-HT<SUB>6</SUB>R) is the most recently cloned serotonin receptor and plays important roles in the central nervous system (CNS) and in the etiology of neurological diseases. Compared to other 5-HT receptors, the 5-HT<SUB>6</SUB>R has been considered as an attractive CNS therapeutic target because it is expressed exclusively in the CNS and has no known isoforms. This review evaluates in detail the role of the 5-HT<SUB>6</SUB>R in the physiology and pathophysiology of the CNS and the potential usefulness of 5-HT<SUB>6</SUB>R ligands in the development of therapeutic strategies for the treatment of CNS disorders. Preclinical studies provide support for the use of 5-HT<SUB>6</SUB>R ligands as promising medications to treat the cognitive dysfunction associated with Alzheimer's disease, obesity, depression, and anxiety.</P>

Synthesis and Inhibition Effects on 5-HT6 Receptor of Benzothiazole Derivatives

Faisal Hayat,Euna Yoo,Hyewhon Rhim,박혜영 대한화학회 2013 Bulletin of the Korean Chemical Society Vol.34 No.2

A novel series of aryl sulfonylpiperazine derivatives (5-15) were synthesized as 5-HT6 ligands. In vitro assay was evaluated by measuring the 5-HT-induced Ca2+ increases using HeLa cell line expressing the cloned human 5-HT6 receptor, and the compound 13 showed potent 5-HT6 receptor antagonistic effect with IC50 value of 3.9 μM. Compound 13 also showed good selectivity on the 5-HT6 over 5-HT4 and 5-HT7 receptors.

Effects of amyloid-β peptides on voltage-gated L-type CaV1.2 and CaV1.3 Ca2+ channels

Kim, Sunoh,Rhim, Hyewhon Springer-Verlag 2011 Molecules and cells Vol.32 No.3

Therapeutic implication of autophagy in neurodegenerative diseases

( Md. Ataur Rahman ),( Hyewhon Rhim ) 생화학분자생물학회(구 한국생화학분자생물학회) 2017 BMB Reports Vol.50 No.7

Autophagy, a catabolic process necessary for the maintenance of intracellular homeostasis, has recently been the focus of numerous human diseases and conditions, such as aging, cancer, development, immunity, longevity, and neurode-generation. However, the continued presence of autophagy is essential for cell survival and dysfunctional autophagy is thought to speed up the progression of neurodegeneration. The actual molecular mechanism behind the progression of dysfunctional autophagy is not yet fully understood. Emerging evidence suggests that basal autophagy is necessary for the removal of misfolded, aggregated proteins and damaged cellular organelles through lysosomal mediated degradation. Physiologically, neurodegenerative disorders are related to the accumulation of amyloid β peptide and α -synuclein protein aggregation, as seen in patients with Alzheimer`s disease and Parkinson`s disease, respectively. Even though autophagy could impact several facets of human biology and disease, it generally functions as a clearance for toxic proteins in the brain, which contributes novel insight into the pathophy-siological understanding of neurodegenerative disorders. In particular, several studies demonstrate that natural compounds or small molecule autophagy enhancer stimuli are essential in the clearance of amyloid β and α-synuclein deposits. Therefore, this review briefly deliberates on the recent implications of autophagy in neurodegenerative disorder control, and emphasizes the opportunities and potential therapeutic application of applied autophagy. [BMB Reports 2017; 50(7): 345-354]

Gintonin stimulates autophagic flux in primary cortical astrocytes

Md. Ataur Rahman,황홍익,나승열,Hyewhon Rhim 고려인삼학회 2020 Journal of Ginseng Research Vol.44 No.1

Background: Gintonin (GT), a novel ginseng-derived exogenous ligand of lysophosphatidic acid (LPA)receptors, has been shown to induce cell proliferation and migration in the hippocampus, regulatecalcium-dependent ion channels in the astrocytes, and reduce b-amyloid plaque in the brain. However,whether GT influences autophagy in cortical astrocytes is not yet investigated. Methods: We examined the effect of GT on autophagy in primary cortical astrocytes using immunoblotand immunocytochemistry assays. Suppression of specific proteins was performed via siRNA. LC3 punctawas determined using confocal microscopy. Results: GT strongly upregulated autophagy marker LC3 by a concentration- as well as time-dependentmanner via G proteinecoupled LPA receptors. GT-induced autophagy was further confirmed by theformation of LC3 puncta. Interestingly, on pretreatment with an mammalian target of rapamycin (mTOR)inhibitor, rapamycin, GT further enhanced LC3-II and LC3 puncta expression. However, GT-inducedautophagy was significantly attenuated by inhibition of autophagy by 3-methyladenine and knockdownBeclin-1, Atg5, and Atg7 gene expression. Importantly, when pretreated with a lysosomotropicagent, E-64d/peps A or bafilomycin A1, GT significantly increased the levels of LC3-II along with theformation of LC3 puncta. In addition, GT treatment enhanced autophagic flux, which led to an increase inlysosome-associated membrane protein 1 and degradation of ubiquitinated p62/SQSTM1. Conclusion: GT induces autophagy via mTOR-mediated pathway and elevates autophagic flux. This studydemonstrates that GT can be used as an autophagy-inducing agent in cortical astrocytes.

Synthesis and Inhibition Effects on 5-HT₆ Receptor of Benzothiazole Derivatives

Hayat, Faisal,Yoo, Euna,Rhim, Hyewhon,ParkChoo, Hea-Young Korean Chemical Society 2013 Bulletin of the Korean Chemical Society Vol.34 No.2

A novel series of aryl sulfonylpiperazine derivatives (5-15) were synthesized as 5-$HT_6$ ligands. In vitro assay was evaluated by measuring the 5-HT-induced $Ca^{2+}$ increases using HeLa cell line expressing the cloned human 5-$HT_6$ receptor, and the compound 13 showed potent 5-$HT_6$ receptor antagonistic effect with $IC_{50}$ value of 3.9 ${\mu}M$. Compound 13 also showed good selectivity on the 5-$HT_6$ over 5-$HT_4$ and 5-$HT_7$ receptors.