• Biomolecules & Therapeutics
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• v.28 no.6
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• pp.512-518
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• 2020

Stroke is a leading cause of long-term disability in ischemic survivors who are suffering from motor, cognitive, and memory impairment. Previously, we have reported suppressing LPA₅ activity with its specific antagonist can attenuate acute brain injuries after ischemic stroke. However, it is unclear whether suppressing LPA₅ activity can also attenuate chronic brain injuries after ischemic stroke. Here, we explored whether effects of LPA₅ antagonist, TCLPA5, could persist a longer time after brain ischemic stroke using a mouse model challenged with tMCAO. TCLPA5 was administered to mice every day for 3 days, starting from the time immediately after reperfusion. TCLPA5 administration improved neurological function up to 21 days after tMCAO challenge. It also reduced brain tissue loss and cell apoptosis in mice at 21 days after tMCAO challenge. Such long-term neuroprotection of TCLPA5 was associated with enhanced neurogenesis and angiogenesis in post-ischemic brain, along with upregulated expression levels of vascular endothelial growth factor. Collectively, results of the current study indicates that suppressing LPA₅ activity can provide long-term neuroprotection to mice with brain ischemic stroke.

• Biomolecules & Therapeutics
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• v.32 no.3
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• pp.319-328
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• 2024

Lysophosphatidic acid receptor 1 (LPA₁) plays a critical role in brain injury following a transient brain ischemic stroke. However, its role in permanent brain ischemic stroke remains unknown. To address this, we investigated whether LPA₁ could contribute to brain injury of mice challenged by permanent middle cerebral artery occlusion (pMCAO). A selective LPA₁ antagonist (AM152) was used as a pharmacological tool for this investigation. When AM152 was given to pMCAO-challenged mice one hour after occlusion, pMCAO-induced brain damage such as brain infarction, functional neurological deficits, apoptosis, and blood-brain barrier disruption was significantly attenuated. Histological analyses demonstrated that AM152 administration attenuated microglial activation and proliferation in injured brain after pMCAO challenge. AM152 administration also attenuated abnormal neuroinflammatory responses by decreasing expression levels of pro-inflammatory cytokines while increasing expression levels of anti-inflammatory cytokines in the injured brain. As underlying effector pathways, NF-κB, MAPKs (ERK1/2, p38, and JNKs), and PI3K/Akt were found to be involved in LPA₁-dependent pathogenesis. Collectively, these results demonstrate that LPA₁ can contribute to brain injury by permanent ischemic stroke, along with relevant pathogenic events in an injured brain.

• The Journal of Korean Medicine
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• v.21 no.1
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• pp.91-98
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• 2000

The water extract of Seongpungtang(SPT) has commonly been used for treatment of ischemic brain damage in Oriental traditional medicine. However, little is known about the mechanism by which the water extract of SPT rescues brain cells from ischemic damage. To elucidate the protective mechanism of ischemic induced cytotoxicity, the regulation of Lipopolysaccharide (LPS) and PMA (phobol-12-myristate-13-acetate) induced iNOS expression in microglial cells was investigated. LPS and PMA treatment for 48 hr in microglial cells markedly induced nitric oxide (NO), but treatment of the cells with the water extract of SPT decreased nitrite formation. In addition, LPS and PMA treatment for 48 hr induced severe cell death in microglial cells. However treatment of the cells with the water extract of SPT did not induce significant changes compared to the control cells. Furthermore, NO production was markedly decreased by treatment of nuclear factor kappa B(NF-kB) inhibitor, pyrrolidine dithiocarbamate(PDTC). According to the above results, it is suggested that the protective effects of the water extract of SPT against ischemic brain damage may be mediated by regulation of iNOS during ischemic condition.

• The Journal of Pediatrics of Korean Medicine
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• v.25 no.1
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• pp.40-48
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• 2011

Objectives: The purpose of this study is to evaluate the effect of Gonjadaesungchimjoongbang on spatial learning abilities and memories in ischemic brain injury. Methods: Rats were separated into three groups; (1) Normal, (2) Saline medication after ischemic brain injuries (control), (3) Gonjadaesungchimjoongbang medication after ischemic brain injuries (experiment). Ischemic brain injuries was induced by MCA occlusion and reperfusion. Morris water maze test was conducted for spatial learning and memory tests. Then, the change of BDNF in the hippocampus($7^{th}$, $14^{th}$ day) was examined by immunohistoche- mistry. Results: In Morris water maze test, spatial learning abilities and memory functioning were considerably increased in the experiment group as oppose to control group on $7^{th}$ and $14^{th}$ day(p<0.01). Moreover, immunohistochemistric response of BDNF in the hippocampus indicated that the more increased immune reaction was found in the experiment group as oppose to the control group on $7^{th}$ and $14^{th}$ day. Conclusions: Gonjadaesungchimjoongbang can improve the learning abilities and memories in ischemic brain injury.

• Nuclear Medicine and Molecular Imaging
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• v.41 no.2
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• pp.91-96
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• 2007

The measurement of pathologically low levels of tissue $pO_2$ is an important diagnostic goal for determining the prognosis of many clinically important diseases including cardiovascular insufficiency, stroke and cancer. The target tissues nowaday have mostly been tumors or the myocardium, with less attention centered on the brain. Radiolabelled nitroimidazole or derivatives may be useful in identifying the hypoxic cells in cerebrovascular disease or traumatic brain injury, and hypoxic-ischemic encephalopathy. In acute stroke, the target of therapy is the severely hypoxic but salvageable tissue. $^{18}F-MISO$ PET and $^{99}mTc-EC-metronidazole$ SPECT in patients with acute ischemic stroke identified hypoxic tissues and ischemic penumbra, and predicted its outcome. A study using $^{123}I-IAZA$ in patient with closed head injury detected the hypoxic tissues after head injury. Up till now these radiopharmaceuticals have drawbacks due to its relatively low concentration with hypoxic tissues associated with/without low blood-brain barrier permeability and the necessity to wait a long time to achieve acceptable target to background ratios for imaging in acute ischemic stroke. It is needed to develop new hypoxic marker exhibiting more rapid localization in the hypoxic region in the brain. And then, the hypoxic brain imaging with imidazoles or non-imidazoles may be very useful in detecting the hypoxic tissues, determining therapeutic strategies and developing therapeutic drugs in several neurological disease, especially, in acute ischemic stroke.

• Biomolecules & Therapeutics
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• v.30 no.1
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• pp.55-63
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• 2022

Oleanolic acid (OA), a natural pentacyclic triterpenoid, has been reported to exert protective effects against several neurological diseases through its anti-oxidative and anti-inflammatory activities. The goal of the present study was to evaluate the therapeutic potential of OA against acute and chronic brain injuries after ischemic stroke using a mouse model of transient middle cerebral artery occlusion (tMCAO, MCAO/reperfusion). OA administration immediately after reperfusion significantly attenuated acute brain injuries including brain infarction, functional neurological deficits, and neuronal apoptosis. Moreover, delayed administration of OA (at 3 h after reperfusion) attenuated brain infarction and improved functional neurological deficits during the acute phase. Such neuroprotective effects were associated with attenuation of microglial activation and lipid peroxidation in the injured brain after the tMCAO challenge. OA also attenuated NLRP3 inflammasome activation in activated microglia during the acute phase. In addition, daily administration of OA for 7 days starting from either immediately after reperfusion or 1 day after reperfusion significantly improved functional neurological deficits and attenuated brain tissue loss up to 21 days after the tMCAO challenge; these findings supported therapeutic effects of OA against ischemic stroke-induced chronic brain injury. Together, these findings showed that OA exerted neuroprotective effects against both acute and chronic brain injuries after tMCAO challenge, suggesting that OA is a potential therapeutic agent to treat ischemic stroke.

• Proceedings of the Korean Society of Developmental Biology Conference
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• 2003.10a
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• pp.71-71
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• 2003

Human umbilical cord blood cells(HUCBC) are rich in mesenchymal progenitor cells, endothelial cell precursors and hematopoietic cells. HUCBC have been used as a source of transplantable stem and progenitor cells. However, little is known about survival and development of HUCBC transplantation in the CNS. Estrogen has a neuroprotective potential against oxidative stress-induced cell death so has an effect on reducing infarct size of ischemic brain. We investigated the potential use of HUCBC as donor cells and tested whether estrogen mediates intravenously infused HUCBC enter and survive in ischemic brain. PKH26 labeled mononuclear fraction of HUCBC were injected into the tail vein of ischemic OVX rat brain with or without $17\beta$-estradiol valerate(EV). Under fluorescence microscopy, labeled cells were observed in the brain section. Significantly more cells were found in the ischemic brain than in the non-ischemic brain. HUCBC transplanted into ischemic brain could migrate and survive. Some of cells have shown neuronal like cells in hippocampus, striatum and cortex tissues. These result suggest that estrogen reduces ischemic damage and increases the migration of human umbilical cord blood cells. This Study was supported by the Korea Science and Engineering Foundation(KOSEF) though the Biohealth Products Research Center(BPRC), Inje University, Korea.

• Journal of Korean Medicine Rehabilitation
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• v.18 no.2
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• pp.45-60
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• 2008

Objectives : Sopung-tang(Shufeng-tang) is a famous herbal prescription that treated ischemic brain injury. This study was designed to evaluate the effects of Sopung-tang(Shufeng-tang) on congnition and motor function recovery after ischemic brain injury in rats. Methods : Male rats were divided into 4 groups. Those rats caused ischemic brain injury by occlusion of MCA as Longa method. Control group I was per os normal saline for 7 days after ischemic brain injury. Control group II was per os normal saline for 14 days after ischemic brain injury. Experimental group I(Ex I) was taken with Sopung-tang(Shufeng-tang) for 7 days after ischemic brain injury. Experimental group II(Ex II) was taken with Sopung-tang(Shufeng-tang) for 14 days after ischemic brain injury. The author carried out neurological, cognitive motor behavior tests and histological assessment. Neurological motor behavior tests consist of limb placement test, beam-walking test and horizontal wire test. Morris water maze test was used for cognitive motor behavior test. In the histological assessment test, TTC(2,3,5-triphenylteterazolium chloride) staining, Hematoxylin & Eosin staining and immunohistochemical staining were experimented. Results : 1. In neurological motor behavior tests, motor function recovery was significantly increased in the experimental groups as compared with control groups(p<0.05). Especially Ex II was significantly increased as compared with Ex I(p<0.05). 2. In Morris water maze test, congnitive motor function recovery was significantly increased in the experimental groups as compared with control group(p<0.05). Especially Ex II was significantly increased as compared with Ex I(p<0.05). 3. In the immunohistochemical staining for the expression of BDNF in hippocampus, more immune reaction was investigated in the experimental groups as compared with control groups. Especially most immune reaction was experimented in the EX II. Conclusions : According to the above results, Sopung-tang(Shufeng-tang) can treat on the congnition and motor function recovery after ischemic brain injury in rats. And it is effective method in expression of BDNF in hippocampus.

• The Journal of Korean Medicine
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• v.24 no.3
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• pp.72-83
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• 2003

Objective : The goal of the present study was to investigate the protective effect of Gamiheechum-tang (Jiaweixiqian-tang; GHCT) on brain tissue damage from chemical or ischemic insults. Methods : Levels of cultured cortical neuron death caused by toxic chemicals were measured by LDH release assay. Neuroprotective effects of GHCT on brain tissues were examined in vivo by ischemic model of middle cerebral artery (MCA) occlusion. Results : Animal groups treated with GBCT showed significantly decreased hypertension, and reduced levels of aldosterone, dopamine, and epinephrine in the plasma. GHCT treatments ($l0-200\mu\textrm{g}/ml$) significantly decreased cultured cortical neuron death mediated by AMPA, kainate, BSO, or Fe2+ when measured by LDH release assay. Yet, cell death mediated by NMDA was effectively protected by GHCT at the highest concentration examined ($200\mu\textrm{g}/ml$). In the in vivo experiment examining brain damage by MCA occlusion, affected brain areas by ischemic damage and edema were significantly less in animal groups administered with GHCT compared to the non-treated control group. Neurological examinations of forelimbs and hindlimbs showed that GHCT treatment improved animals' recovery from ischemic injury. Moreover, the extent of injury in cortical and hippocampal pyramidal neurons in ischemic rats was much reduced by GHCT, whose morphological features were similarly observed in non-ischemic animals. Conclusion : The present data suggest that GBCT may play an important role in protecting brain tissues from chemical or ischemic injuries.

• The Journal of Internal Korean Medicine
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• v.21 no.2
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• pp.341-348
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• 2000

I have treated one ischemic stroke patient in acute stage with Seonghyangjeonggi-san, and observed remarkable reduction of the size ischemic portion in brain CT, notable improved motor power of patient. So I report this case of stroke patint. The ischemic penumbra, simply stated, is the part of the brain that is sandwiched brain regions committed to die and those that receive enough blood to communicate. Therefore, it is ischemic brain tissue that has just enough to communicte and function. The life expectancy of the penumbrais short. Although the penumbra is an elegant concept, in practice, it has been a difficult one to exploit. Up to now, a lot of research worker have tried to develop the method to make a accurate diagnosis. and then we know that PET and Xenon CT is available for the diagnosis for the ischemic penumbra. But those are not perfect to diagnose of penumbra. The case in my case report was confirmed as ischemic penumbra with CT. I know that CT is not prefect to diagnose penumbra, but I just want to raise the interest in penumbra of oriental medicine researcher and my report will be benificial to the penumbra researcher.