배양 대뇌피질 신경세포에서 glutamate에 의한 Ca2+/calmodulin-dependent protein kiarse IV의 활성변화

조정숙(Jungsook Cho) 대한약학회 2001 약학회지 Vol.45 No.4

The neuronal cell death induced by excess glutamate (Glu) has been implicated in many acute and chronic neurodegenerative diseases including cerebral ischemia. Glu-induced elevation of intra-cellular Ca2+ plays a critical role in the excitotoxicity partly through the activation of a variety of Ca2+-dependent enzymes. In the present study; we investigated the Glu-induced modulation of Ca2+/calmodulin-dependent protein kinase IV (CaMK IV, a multifunctional enzyme abundantly present in the nuclei of neurons. The exposure of cultured rat cortical neurons to 100μM Glu for 3 min dramatically increased CaMK IV activity up to 4.5-fold of the control-treated enzyme activity The activation was very rapid, reaching peak at 3 min and then declined gradually: Under the same experimental conditions, time-dependent acute and delayed neuronal cell death was observed. Immunoblot analyses using specific antibodies showed that the expressions of CaMK IV and CaMKαwere time-dependently modulated by Glu. Ttken together, These results imply that the modulation of CaMK IV activity by Glu may be involved in the cascade of events resulting in neuronal cell death in cortical cultures.

소전통락편(消栓通絡片)의 항산화 및 신경세포 보호작용

조정숙 東國大學校醫學硏究所 2004 東國醫學 Vol.11 No.1

소전통락편(消栓通絡片, Xiaoshuan TongluoPian)은 어혈을 제거하고 혈액순환을 원활하게 한다고 하여 뇌혈전에 의한 뇌졸중의 후유증을 완화시킬 목적으로 중국에서 사용되고 있는 당의정이다. 본 연구에서는 일차 배양한 횐쥐 대뇌피질 신경세포를 이용하여 소전통락편의 약리작용을 규명함으로써 임상적 활용에 대한 과학적 근거를 제시하고자 하였다. 소전통락편은 배양한 세포를 H₂O₂로 처리하거나 Fe^(2+)와 ascorbic acid로 처리하여 유발되는 산화적 신경세포손상을 농도 의존적으로 억제하였다. 반면, 배양한 세포를 xanthine 및 xanthine oxidase로 처리하여 유발되는 산화적 손상에 대해서는 미약한 정도의 효과를 나타내었다. 또한, 소전통락편은 뇌졸중이나 간질 등의 퇴행성 신경질환에서 흥분성 신경독성을 일으키는 물질로 알려진 glutamate나 N-methyl-D-aspartate (NMDA)에 의해 유발되는 손상도 유의하게 억제하였다. 다음에는, 알쯔하이머병의 중요한 유발요인으로 알려진 β-amyloid (A_{β})의 활성부분으로 처리하여 유발되는 손상에 대한 작용을 연구한 결과, 소전통락편은 A_{β}(25.35)에 의한 신경세포의 손상도 현저하게 억제함을 확인하였다. 뿐만 아니라 이 제제는 흰쥐의 뇌균질액에서 유도한 지질 과산화를 강력하게 억제하였으며, 약간의 라디칼 소거작용을 나타내었다. 이상의 결과로부터 본 연구에서는 소전통락편이 지질 과산화를 억제하여 항산화작용을 나타내며, 대뇌피질 신경세포에서 산화적 스트레스로 유발한 손상과 흥분성 손상 및 A_{β}(25.35)로 유발한 손상을 억제함을 확인함으로써 이 제제의 신경세포 보호 효과를 실험적으로 규명하였다. 이 연구결과는 소전통락편이 중국에서 뇌졸중 치료제로 이용되는 사실에 대한 약리학적인 근거를 제시할 뿐만 아니라, 알쯔하이머병에도 도움을 줄 수 있을 가능성을 제기하는 결과로 사료된다. Xiaoshuan TongluoPian (XTP), which is believed to remove extravasated blood and improve blood circulation, has been used in China to alleviate the sequelae caused by cerebral thrombosis. To characterize pharmacological actions of XTP, the present study evaluated its effects on neuronal cell damage induced in primary cultured rat cortical cells by various oxidative insults, glutamate or N-methyl-Daspartate (NMDA), and B-amyloid fragment (A_(β)(25-35)). XTP was found to inhibit the oxidative neuronal damage induced by H₂O₂or Fe^(2+)/ascorbic acid. In contrast, it had minimal effect on the toxicity induced by xanthindxanthine oxidase. It also attenuated the excitotoxic damage induced by glutamate or NMDA. The NMDA-induced neurotoxicity was more effectively inhibited than the glutamate-induced toxicity. In addition, we found that XTP protected neurons against the (A_(β)(25-35))-induced toxicity. Moreover, XTP exhibited dramatic inhibition of lipid peroxidation in rat brain homogenates and mild 1,1-diphenyl-2-picryIhydrazyl radical scavenging activity. Taken together, these results demonstrate that XTP exerts antioxidant and neuroprotective effects against oxidative, excitotoxic, or A_(β)(25-35)-induced neuronal damage. These findings may provide pharmacological basis for its clinical usage to alleviate the sequelae of stroke. Furthermore, XTP may exert beneficial effects on Alzheimer's disease and other oxidative stress-related neurodegenerative disorders.

Anti-convulsive Effects of Quinoxalinediones Acting at the Glycine Binding Site of the N-methyl-D-aspartate Receptor

Cho, Jungsook 東國大學校醫學硏究所 1997 東國醫學 Vol.4 No.-

NMDA 수용체에 길항작용을 나타내는 많은 약물들은 항경련 효과 및 신경세포 보호효과를 가진다고 알려져 있다. 본 연구에서는 NMDA 수용체의 glycine binding site에 높은 친화력을 갖는 quinoxalinedione 유도체인 6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione(6,7-DCQX) 및 5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione(5-N-6,7-DCQX)의 항경련 작용을 시험하였다. 흰쥐 전뇌에서 얻은 synaptic membrane에 대한 [³H]MK-801 결합실험을 통하여 NMDA 수용체의 활성을 측정한 결과, NMDA, glycine, spermidine의 존재 하에서 [³H]MK-801 결함이 증강되었고, 이는 5-N-6,7-DCQX 및 기존의 glycine site antagonist인 5,7-dichlorokynurenic acid (5,7-DCKA)에 의해 완전히 억제되었다. 5-n-6,7-DCQX는 5,7-DCKA보다 20배 더 강력한 억제를 나타내었다. 반면, glycine site partial agonist인 (+)-HA-966은 예상한 바와 같이 [³H]MK-801 결합중 일부분만을 억제하였다. 생쥐에 NMDA를 투여하여 유발한 경련실험모델에서 복강내 주사에 의해 이들 화합물의 항경련 효과를 측정한 결과, 6,7-DCQX는 (±)-HA-966의 효과와 비슷하였으며, 5-N-6,7-DCQX는 이들보다 10배 이상의 강력한 효과인 16.5mg/kg의 ED? 치를 보였다. 5,7-DCKA는 뇌실내 주사에 의해서만 항경련 효과를 나타내었다. 본 연구를 통하여 quinoxalinedione 유도체인 6,7-DCQX 및 5-N-6,7-DCQX는 NMDA 수용체인 glycine site에 작용하여 길항함으로서 항경련 효과를 나타내며, 특히 5-N-6,7-DCQX는 [³H]MK-801 결합 및 동물을 이용한 경련실험에서 6,7-DCQX나 (±)-HA-966 보다 더 강력한 억제효과를 보임을 관찰하엿다. A variety of N-methyl-D-aspartate (NMDA) receptor antagonists are shown to have anticonvulsive and neuroprotective effects. In the present study two quinoxalinedione derivatives with high binding affinities for the glycine site of the receptor, 6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione(6,7-DCQX) and 5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (5-N-6,7-DCQX), were evaluated as potential anti-convulsants. The [³H]MK-801 binding to the synaptic membranes of rat forebrains was dramatically potentiated by the presence of NMDA, glycine and spermidine. The potentiated binding was inhibited completely by either 5-n-6,7-DCQX or 5,7-dichlorokynurenic acid (5,7-DCKA), a known glycine site antagonist. 5-N-6,7-DCQX was a 20-fold more potent antagonist than 5,7-DCKA. R-(+)-HA-966, a weak partial agonist at the glycine site, exhibited only a partial inhibition as expected. The anti-convulsive activities of 6,7-DCQX, 5-N-6,7-DCQX, and several reference compounds were examined via i.p. administrations in mice using NMDA (i.c.v.)-induced convulsion tests. The effect of 6,7-DCQX was similar to that of (±)-HA-966. In consistency with the results from the binding studies, 5-N-6,7-DCQX showed potent anti-convulsive activity, of which the ED? value was 16.9 mg/kg. 5,7-DCKA exhibited anti-convulsive antivity only with the i.c.v. administration. These results demonstrated that the two quinoxalinediones showed anti-convulsive effects through the antagonism of the NMDA receptor function acting at the glycine binding site, and 5-N-6,7-DCQX showed higher potency than 6,7-DCqx or (±)-HA-966 in both [³H]MK-801 binding studies and convulsion tests in mice.

Functional Roles of Chemokines and Chemokine Receptors in the Central Nervous System

Cho, Jungsook 東國大學校醫學硏究所 2005 東國醫學 Vol.12 No.2

케모카인은 8-14kDa 정도의 작은 화학유인성 단백질로써 림프성 또는 비림프성 조직의 염증 부위로 백혈구를 유입하는데 필수적 역할을 한다고 알려져 있다. 뿐만 아니라, 케모카인과 케모카인 수용체는 중추신경계에서 발생하는 여러 신경염증 및 퇴행성 질환에 있어서도 매우 중요한 신호전달 분자로 인지되고 있다. 신경세포와 별아교세포, 희소돌기아교세포 및 미세아교세포는 정상 상태에서는 물론 병적인 상태의 중추신경계에서 케모카인을 유리하는 주요근원이 되는동시에 유리된 각종 케모카인의 작용점이기도 하다. 본 종설에서는 뇌에서 케모카인과 케모카인 수용체의 발현을 알아보고, 이들이 신경의 이동, 세포의 증식 및 연접 활성에 미치는 생리적 역할을 살펴보았다 . 또한, 다발성 경화증, 알쯔하이머씨병, HIV와 연관된 치매와 뇌허혈 질환 등과 같은 신경염증 및 퇴행성 신경질환에서 케모카인과 그 수용체의 발현 및 역할에 대하여 기술하였다. Chemokines, small (8—14 kDa) secreted chemoattractive proteins, are known to be essential for the recruitment of leukocyte subsets into inflammatory areas of lymphoid and non—lymphoid tissues. Chemokines and chemokine receptors have also been recognized as key signaling molecules in many neuroinflammatory and neurodegenerative diseases of the central nervous system (CNS). Neurons, astrocytes, oligodendrocytes and microglia are the major cellular sources and targets of chemokines produced in the CNS under physiological and pathological conditions. This article describes the expression of chemokines and chemokine receptors in the brain and their possible physiological roles in neuronal migration, cell proliferation and synaptic activity. In addition, functional roles of chemokines and chemokine receptors in the neuroinflammatory and neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease, HIV—associated dementia and cerebral ischemia are also discussed in this review.

신규간호사를 위한 맞춤형 멘토 프로그램(새싹프로그램)의 개발 및 적용 : 일개 대학병원 중환자실을 중심으로

권은옥,조정숙,송경자,최스미,장선주,김주희,박승현,신효연,유미,김정아 대한간호학회 간호행정학회 2009 간호행정학회지 Vol.15 No.4

Purpose: The purpose of this study was to develop specialized mentor program to improve adaptation for new nurses of intensive care unit and to identify the effect of the program on early resignation rate. Methods: The study adopted nonequivalent control group, non synchronized design. Based on the identification of problems and the needs of new nurses, a 6 month specialized mentor program was developed. The program was consisted of three parts; developing knowledge, improving interpersonal relationship and increasing coping competency for emergency situation. Data were collected between July 2006 and 2008 from 37 nurses and the early resignation rate was compared before and after the implementation of the mentoring program. Results: Early resignation rate of the nurses who received the mentor program was significantly lower than that of the nurses who didn't. The resignation rate within 1 year dropped from 44.5% to 8.3%(p=.034). Conclusions: The specialized six month mentoring program was effective in reducing early resignation rate.

4-카바모일옥시메틸-1-아자안트라퀴논 유도체들의 합성 및 세포독성

이희순,이승일,홍승수,조정숙,김영호 충남대학교 약학대학 의약품개발연구소 1998 藥學論文集 Vol.14 No.-

In the course of developing novel antitumor intercalating agents, we synthesized 4-carbamoyloxymethyl-1-azaanthraquinones 7-12. incorporating the latent alkylating functionality. These compounds were designed to explore the effect of substituent on the nitrogen of carbamate. The target compounds were prepared by hetero Diels-Alder reaction as a key step followed by functionalization of benzylic methyl to the desired substituents. Growth inhibitory studies of the azaanthraquinones were conducted in vitro against human cancer cell lne (SNU-354: liver and MCF7: breast) and human epidermoid carcinoma cells that are sensitive (KB-3-1) and multidrug-resistant (KB-V-1). the compounds were less potent than doxorubicin against sensitive cell lines. However, the most active compound 12 was not cross-resisitant with doxorubicin against KB-V-1.