• BMB Reports
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• v.44 no.5
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• pp.312-316
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• 2011

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its toxic metabolite 1-methyl-4-phenylpyridium ion (MPP$^+$) have been shown to induce Parkinson's disease-like symptoms as well as neurotoxicity in humans and animal species. Recently, we reported that maintenance of redox balance and cellular defense against oxidative damage are primary functions of the novel antioxidant enzyme cytosolic NADP$^+$-dependent isocitrate dehydrogenase (IDPc). In this study, we examined the role of IDPc in cellular defense against MPP$^+$-induced oxidative injury using PC12 cells transfected with IDPc small interfering RNA (siRNA). Our results demonstrate that MPP$^+$-mediated disruption of cellular redox status, oxidative damage to cells, and apoptotic cell death were significantly enhanced by knockdown of IDPc.

• The Korean Journal of Physiology
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• v.30 no.2
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• pp.289-297
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• 1996

Excitatory amino acids (EAA) are thought to play an important role in producing cell death associated with ischemic and traumatic spinal cord injury. The present study was carried out to determine if the response characteristics of spinal sensory neurons in segments adjacent to degeneration sites induced by EAA are altered following these morphological changes. Intraspinal injections of quisqualic acid (QA) produced neuronal degeneration and spinal cavitation of gray matter. The severity of lesions was significantly attenuated by pretreatment with a non-NMDA antagonist NBQX. In extracellular single unit recordings, dorsal horn neurons in QA injected animal showed the increased mechanosensitivity, which included a shift to the left in the stimulus-response relationship, an increased background activity and an increase in the duration of after-discharge responses. Neuronal responses, especially the C-fiber response, to suprathreshold electrical stimulation of sciatic nerve also increased in most cases. These results suggest that altered functional states of neurons may be responsible for sensory abnormalities, e.g. allodynia and hyperalgesia, associated with syringomyolia and spinal cord injury.

• Journal of Korean Neurosurgical Society
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• v.38 no.3
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• pp.215-220
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• 2005

Objective : Many researchers believe that the hypothermia shows neuro-protective effect on brain injury. To understand the molecular mechanism of the hypothermic treatment, this study investigated its effects on the expression of cell death or survival related proteins such as p53, Bcl-2 and Bax in the rat traumatic brain injury[TBI] model. Methods : Twenty rats [Spraque Dawley, $200{\sim}250g$] were subjected to the brain injury of moderate severity [$2.4{\sim}2.6atm$] using the fluid percussion injury device and five rats were received only same surgery as controls. During 30minutes after the brain injury, the hypothermia group was maintained the body temperature around $34^{\circ}C$ while the control group were maintained that of $36^{\circ}C$. Five rats in each group were sacrificed 12h or 24h after brain injury and their brain sections was analyzed for physical damages by H-E stains and the extent of apoptosis by TUNEL assay and immunohistochemical stains. The tissue damage after TBI was mainly observed in the ipsilateral cortex and partly in the hippocampus. Results : Apoptosis was observed by TUNEL assay and the Bax protein was detected in both sample which harvested 12h and 24h after TBI. In the hypothermia treatment group, tissue damage and apoptosis were reduced in HE stains and TUNEL assay. In hypothermia treatment group rat shows more expression of the Bcl-2 protein and shows less expression of the Bax protein, at both 12h and 24h after TBI. Conclusion : These results show that the hypothermia treatment is an effective treatment after TBI, by reducing the apoptotic process. Therefore, it could be suggested that hypothermia has a high therapeutic value for treating tissue damages after TBI.

• Proceedings of the PSK Conference
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• 2002.10a
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• pp.297.3-298
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• 2002

A benzopyranyl derivative. KR32000. synthesized as a plausible KATP opener. has been shown to exert cardioprotective effect in vivo myocardial infarct model. In this study. we investigated whether KR32000 can produce cardioprotective effect against hypoxia- and reactive oxygen species(ROS)-induced injury in heart-derived H9c2 cells. Hypoxic injury was induced by incubating cells in anaerobic chamber (glucose-free. serum-free DMEM. 85% N2. 5% CO2. 10% H2) and oxidative stress was induced by buthionine sulfoximine(BSO). (omitted)

• Proceedings of the Korean Society of Applied Pharmacology
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• 2004.04a
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• pp.3-10
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• 2004

Oxidative stress is a constant threat to all living organisms and an immense repertoire of cellular defense systems is being employed by most pro- and eukaryotic systems to eliminate or to attenuate oxidative stress. Ischemia and reperfusion is characterized by both a significant oxidative stress and characteristic changes in the antioxidant defense. Heme oxigenase-l (HO-l) is up-regulated by various stimuli including oxidative stress so that it is thought to participate in general cellular defense mechanisms against ischemic injury in mammalian cells. Higenamine, an active ingredient of Aconite tuber, has been shown to have antioxidant activity along with inhibitory action of inducible nitric oxide synthase (iNOS) expression in various cells. In the present study, we investigated whether higenamine and related analogs protect cells from oxidative cellular injuries by modulating antioxidant enzymes, such as HO-l, MnSOD etc. R-form of YS-51 was the most potent inducer of HO-l in bovine endothelial cells, which inhibited apoptotic cell death by H$_2$O$_2$. HO-1 induction by YS 51 was mediated by PI3 kinase activation in which PKA- as well as PKG pathway is considered as important regulators. YS-51 also induced Mn-SOD mRNA expression by activating c-jun N-terminal kinase in endothelial cells and Hela cells. In ROS 17/2.1 cells, higenamine and enetiomers of related compounds inhibited iNOS expression by cytokine mixtures. Taken together, higenamine and related compounds can be developed as possible protective agents from oxidative cell injury or death.

• The Journal of Korean Medicine
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• v.27 no.2 s.66
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• pp.1-13
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• 2006

Objectives : Ischemic brain injury is a worldwide problem that often causes irreversible brain damage. Moreover, prevention of ischemic brain injury is more important than anything else, since after-effects of stroke significantly threat the quality of life. Jukryukjichul-hwan (JRH) is an oriental medicinal formula for stroke patients in Korea. This study evaluated neuroprotective effects of methanol extract of JRH on global cerebral ischemia in rats. Changes of the pyramidal neurons, Bax and TUNEL immuno-positive neurons in CA1 hippocampus were observed using immunohistochemistry. Methods : Sprague-Dawley Rats were induced with temporal global cerebral ischemia (TGI) by occluding the bilateral common carotid artery with hypotension, The rats were divided into 3 groups. We treated one group with methanol extract of JRH after operation, another group before and after the operation. We observed Bax expressions inducing apoptosis of neurons and TUNEL-positive Pyramidal Neurons as an index of survival and apoptosis of pyramidal neurons in CA1 Hippocampus. Results : JRH treatment before and after TGI inhibited Bax expression in CA1 hippocampus. JRH treatment before and after TGI reduced the cell death of pyramidal neurons in CA1 hippocampus. JRH treatment after TGI reduced the cell death of pyramidal neurons in CA1 hippocampus. JRH treatment before and after TGI reduced TUNEL-positive cells in CA1 hippocampus. Conclusion : These results suggest that JRH has a neuroprotective effect (by anti-apoptosis) against cerebral ischemia.

• The Journal of Internal Korean Medicine
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• v.21 no.1
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• pp.46-54
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• 2000

Objectives : Talmyung-san(TMS) has been used for treatment of brain diseases in Chinese traditional medicine. However, little is known about the mechanism by which TMS rescues brain cells from ischemic damages. To elucidate the protective mechanisms of TMS, we execute experiments. Methods : The effects of TMS on ischemia/reperfusion-induced cytotoxicity and generation of nitric oxide(NO) are investigated in primary neonatal myocardial cells and A7rS, aortic smooth muscle cell line. Results : Ischemia/reperfusion itself induces severe myocardial cell death in vitro. However, treatment of the cells with TMS significantly reduces both ischemia/reperfusion-induced myocardial cell death and LDH release. In addition, pretreatment of TMS before reperfusion recovers the lose of beating rates alter ischemia/reperfusion. For a while, the water extract of TMS stimulates myocardial cells to produce NO in a dose dependent manner and it protects the damage of ischemia/reperfusion-induced myocardial cells. Furthermore, the protective effects of the water extract of TMS is mimicked by treatment of sodium nitroprusside, an exogenous NO donor. NG-monomethyl-L-arginine (NGMMA), a specific inhibitor of nitric oxide synthase(NOS), significantly blocks the protective effects of TMS on the cells after ischemia/reperfusion. In addition, on ischemia the water extract of TMS induce NO in A7r5 cell. Conclusions : Taken together, we suggest that the protective effects of TMS against ischemia/reperfusion-induced myocardial damages may be mediated by NO production of myocardial and vascular smooth muscle cell during ischemic condition.

• The Korean Journal of Physiology and Pharmacology
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• v.5 no.5
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• pp.381-388
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• 2001

This work describes the pharmacological inhibition by KR 31378 and its acetyl metabolite, KR 31612, of the apoptotic cell death induced by $H_2O_2$ in the A7r5 cells. Exposure of A7r5 cells to $H_2O_2$ (0.5 mM) induced a concentration-dependent cytotoxicity in association with oligonucleosomal DNA fragmentation. $H_2O_2-induced$ cell death was potently suppressed by KR 31378, KR 31612, ${\alpha}-tocopherol$ or trolox. Additionally, the apoptotic death of A7r5 cells (DNA ladders on electrophoresis) was also strongly suppressed by KR 31378 and KR 31612, but to a less degree by ${\alpha}-tocopherol$ and trolox. As a mechanistic study, incubation with $H_2O_2$ markedly showed a decreased Bcl-2 level and, in contrast, increased Bax protein and cytochrome C release, which were significantly and concentration-dependently reversed by KR 31378 and KR 31612 as well as by ${\alpha}-tocopherol$ and trolox. KR 31378 and ${\alpha}-tocopherol$ significantly reduced lipid peroxidation in accordance with reduced intracellular ROS and peroxyl radical. These results suggest that KR 31378 has a therapeutic potential against the apoptotic injury via mediation of anti- oxidative stress.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.82.2-83
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• 2003

Beta-amyloid peptide (A${\beta}$) is considered to be responsible for the pathogenesis of the Alzheimer's disease. Several lines of evidence support that A${\beta}$-amyloid-induced cytotoxicity is mediated through the generation of reactive oxygen species (ROS). Agents that are able to scavenge excess ROS may be useful as protecting or reducing agents for development or progress of AD. Green tea extract has been known to have antioxidant property. Our previous studies also demonstrate that green tea extract protected ischemia/reperfusion-induced brain injury by reduction of cell death through scavenging of oxidative damages of macromolecules. (omitted)

• Journal of Physiology & Pathology in Korean Medicine
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• v.20 no.6
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• pp.1459-1466
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• 2006

The water extract of Hwansodan has been traditionally used for treatment of ischemic brain damage in oriental medicine. However, little is known about the mechanism by which the water extract of Hwansodan rescues cells from neurodegenerative disease. PC12 pheochromocytoma cells have been used extensively as a model for studying the cellular and molecular mechanisms of neuronal cell damages. Under deprivation of growth factor and ischemic injury, PC12 cells spontaneously undergoes apoptotic cell death. Serum and glucose deprivation markedly decreased the viability of PC12 cells, which was characterized with apparent apoptotic features such as membrane blebbing as well as fragmentation of genomic DNA and nuclei. However, the aqueous extract of Hwansodan significantly reduced serum and glucose deprivation-induced cell death and apoptotic characteristics through reduction of intracellular peroxide generation. Pretreatment of Hwansodan also ingibited the activation of caspase-3, in turn, degradation of ICAD/DFF45 was completely abolished in serum and glucose deprivated cells. Furthermore, pretreatment of Hwansodan obviously increased heme oxygenase 1 (HO-1) expression in PC12 cells. Taken together, the data suggest that the protective effects of Hwansodan against serum and glucose deprivation induced oxidative injuries may be achieved through the scavenging of reactive oxygene species accompanying with HO-1 induction.