• The Korean Journal of Physiology and Pharmacology
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• 제13권3호
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• pp.257-263
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• 2009

This study aimed to investigate whether selective serotonin reuptake inhibitors (SSRIs) attenuate brain injury and facilitate recovery following photothrombotic cortical ischemia in mice. Male ICR mice were anesthetized and systemically administered Rose Bengal. Permanent focal ischemia was induced in the medial frontal and somatosensory cortices by irradiating the skull with cold light laser. The animals were treated with fluoxetine or sertraline once a day for 14 d starting 1 h after ischemic insult. Treatment with fluoxetine and sertraline significantly reduced the infarct size. The Evans blue extravasation indices of the fluoxetine- and sertraline-treated groups were significantly lower than that of the vehicle group. Treatment with fluoxetine and sertraline shifted the lower limit of the mean arterial blood pressure for cerebral blood flow autoregulation toward normal, and significantly increased the expression of heme oxygenase-1 (HO-1) and hypoxia-inducible factor-1 ${\alpha}$ (HIF-1 ${\alpha}$) proteins in the ischemic region. These results suggest that SSRIs, such as fluoxetine and sertraline, facilitate recovery following photothrombotic cortical ischemia via enhancement of HO-1 and HIF-1 ${\alpha}$ proteins expression, thereby providing a benefit in therapy of cerebral ischemia.

• 대한한의학회지
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• 제23권4호
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• pp.161-168
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• 2002

Objectives: Hwangryunhaedok-tang (Huang-lian-jie-du-tang, HRHDT, 黃連解毒湯) is a traditional Korean herbal medicine that is formulated with Coptidis Rhizoma, Phellodendri Cortex, Scutellariae Radix and Gardeniae Fructus. HRHDT is cold (寒) and bitter (苦) in nature and has general properties of clearing heat and detoxifying (淸熱解毒), strengthening the stomach and settling the liver (健胃平肝), and reducing inflammation, fever and swelling. This formula can prevent and treat artherosclerosis, hyperplasia of the endothelium, cerebral fluid circulation, cerebral vascular deterioration through aging, impairment of neurotransmitters, or disruption of the functioning of the cerebral cortex following infection or trauma. The purpose of the study reported here was to determine the neuroprotective effect of HRHDT on global ischemia induced by 4-vessel occlusion in Wistar rats. Methods: HRHDT extract was lyophilized after extraction with 85% methanol and 100% water. Rats were induced to 10 minutes of forebrain ischemia by 4-vessel occlusion (4-VO) and reperfused again. HRHDT was administered with a dose of 100 mg/kg, and 500 mg/kg of 85% methanol extracts and 100 mg/kg of 100% water extracts, respectively, at 0 min and 90 min after 4-VO. Rats were killed at 7 days after ischemia and the number of CA1 pyramidal neurons was counted in hippocampal sections stained with cresyl violet. Results: Body temperature of animals showed no significant difference between saline-treated groups and HRHDT extracts-treated groups until 5 hours of reperfusion. This result indicated that neuroprotective effects of HRHDT extracts were not due to hypothermic effects. The administration of HRHDT showed a significant neuroprotective effect on hippocampal CA1 neurons at 7 days after ischemia compared to the saline-treated group (P<0.001). HRHDT methanol extracts of 100 mg/kg, 500 mg/kg and HRHDT water extracts of 100 mg/kg showed 88.5%, 98.3% and 95.1 % neuroprotection, respectively. Conclusions: The results of this study demonstrate that administration of HRHDT is highly effective in reducing neuronal damage in response to transient global cerebral ischemia. HRHDT may involve many mechanisms that might account for its high degree of efficacy. A number of factors including free radicals, glutamate, calcium overload, NO, and various cytokines have been proposed to have an important role in causing neuronal death after short periods of global ischemia. Further studies are needed to know the neuroprotective mechanisms of HRHDT.

• Journal of Chest Surgery
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• 제29권3호
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• pp.255-262
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• 1996

본 연구는 횐 쥐의 적출심장을 이용한 질식사심장의 기능평가로서,기도압박에 의한 질식으로 심정 지가 일어난 후, 10분 지나서 심장을 적출하고 체외관류장치에 연결하여, 80cmH20높이에서 37C의 Krebs-Henseleit용액을 적출 심장에 관류시켜, 그 기능을 평가하여 다음과 같은 결과를 얻었다. Sprague-Dawley계 흰 쥐를, 제 1군(10마리)은 대조군, 제2군(10마리)은 위스콘신대학용액 저장군, 제3 군(10마리)은 스탠포드심정 지용액-생 리식 염수 저장군, 제4군(10마리)은 질식사군으로 분류하여 실험을 시행하였다. 자연 제세동시간은, 모든 군에서 대조군보다 길었으며, 제2군에 비 해서 제3군과 제4군의 제 세동시간도 길었다(p < 0.05). 좌심실내압은, 관류 15분, 30분, 45분에서, 대조군 및 제2군에 비하여 제3 군이 모두 낮았으며,제4군은 관류 15분에, 대조군과 제2군의 15분에 비하여 낮았고, 관류 30분과45분 에는 대조군에 비하여 낮았다(p < 0.05). 관류 15분, 30분, 45분에 측정한 심박동수와 좌심실내압을 곱한 간은, 제3군에서 대조군과 제2군에 비하여 모두 낮았으며, 제4군에서는 대조군에 비하여 모두 낮았고, 제4군의 15분값은 제2군의 15분값에 舟漫\ulcorner\ulcorner낮았다(p<0.05).관류45분에 측정한심근의 수축예비 력은, 대조군과 비교하여 제3군과 제4군이 모두 낮았으며, 제3군은 제2군에 비하여도 낮았다(p < 0.05). 이상의 결과로 보아,질식사로 사망한 조기 적출심장의 기능은, 허혈손상이 없는 대조군과 위스콘신 대학용액에 저장한 심장의 기능에 비하여 그 성적이 불리하나,스탠포드심정지용액-생리식염수 저장군 의 심기능 평가 결과와는 유의한 차이가 없어, 공여심장으로서의 심기능은 비교적 만족할 만한 것으로 볼 수 있다.

• 동의생리병리학회지
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• 제23권3호
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• pp.645-661
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• 2009

The water extract of Dohongsamul-Tang(DHSMT) has been traditionally used to stroke and brain injuries in Oriental Medicine. The present study was designed to investigate the effects of DHSMT on the gene expression profile of cerebral infarction by cDNA microarray in photothrombotic ischemia mouse model. Photothrombotic ischemia was induced in stereotactically held male BALB/c mice using rose bengal and cold light. MRI was performed 24 hours after inducing photothrombosis using 1.5 T MRI and 47 mm surface coil to obtain T2-weighted, and contrast-enhanced images. After MRI test, animal was sacrificed and the brain sections were stained for hematoxylin and eosin and immunohistochemistry. MRI and histological analysis revealed that lesion of thrombotic ischemia was well induced in the cortex with the evidence of biological courses of infarction. The target area of thrombotic infarction was 1 mm anterior to bregma and 3 mm lateral to midline with 2 mm in diameter, which were decreased by administration of DHSMT. To assess gene expression pattern of cerebral infarction, mRNA was isolated and reacted with microarray chip(Agilant's DNA Microarray 44K). Scatter and MA plot analysis were performed to clustering of each functional genes. M value [M=log2(R/G), A={log2(R ${\times}$ G)}/2] was between -0.5 and +0.5 with 40% difference. After pretreatment with DHSMT, the expression levels of mRNA of many genes involved in various signaling pathway such as apoptosis, cell cycle, cell proliferation, response to oxidative stress, immune response, angiogenesis, and inflammatory cytokine were markedly inhibited in photothrombotic ischemia lesion compared to the control group. These results suggest that DHSMT prevent ischemic death of brain on photothrombotic ischemia model of mice through modulation of gene expression at the transcriptional level.

• 한국임상수의학회지
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• 제19권3호
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• pp.299-302
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• 2002

Selectin은 조직 염증반응의 초기화에 관여하는 결합 단백질이며, 맥관내피에서 백혈구의 rolling과 tethering을 매개한다. 따라서 selectin inhibitor를 이용하여, 이들 selectin의 수용체인 sLex 에 대한 block을 유도함으로서 염증반응의 초기화를 억제할 수 있다는 가정하에, 본 연구에서는 장기이식 후 reperfusion에서 발생하는 손상에 대한 selectin inhibitor의 효과를 알아보았다. Beagle 견을 사용하여 신장이식을 실시하였다 공여 신장은 60분의 warm ischemia를 유도한 후 UW solution으로 관류하고 24시간동안 냉장보관하여 자가이식하였으며, 반대쪽 신장은 적출하였다. 술 후 7일동안 혈청 creatinine치를 측정하였다 2차실험으로, 12마리의 Beagle견을 사용하여 4시간의 reperfusion 후 조직학적 변화와 myeloperoxidase의 활성을 조사하였다. 각 실험의 대조군은 생리 식염수를,비교군은 TBC1269 (selectin inhibitor)를 신장 적출 전과 신장이식 수술 후 reperfusion 직전에 각각 투여하였다. 혈청 creatinine은 신장이식후 급격히 증가 하였으나, 두군 사이에 유의적인 차이는 없었다. 신장피질의 백혈구 침윤은, 4시간 reperfusion후 생리식염수를 투여받은 군에서 2배의 유의적인 증가를 보였다. 그러나, TBC 1269로 처리한 군에서는 백혈구의 침윤이 유의적인 억제를 보였으며, 허혈에의한 조직학적 변화도 유의적으로 적었다. 개의 신장이식 수술에서 Selectin의 차단은 warm renal ischemia에서 기인된 손상을 개선하지는 못하나, 백혈구의 침윤을 억제하므로 delayed graft function과 관련된 술 후 염증반응의 초기화를 억제하는 효과가 있는 것으로 사료된다.

• The Korean Journal of Physiology and Pharmacology
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• 제22권1호
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• pp.101-110
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• 2018

In this study, we aimed to investigate the neuroprotective effects of caffeic acid phenethyl ester (CAPE), an active component of propolis purified from honeybee hives, on photothrombotic cortical ischemic injury in mice. Permanent focal ischemia was achieved in the medial frontal and somatosensory cortices of anesthetized male C57BL/6 mice by irradiation of the skull with cold light laser in combination with systemic administration of rose bengal. The animals were treated with CAPE (0.5-5 mg/kg, i.p.) twice 1 and 6 h after ischemic insult. CAPE significantly reduced the infarct size as well as the expression of tumor necrosis $factor-{\alpha}$, hypoxiainducible $factor-1{\alpha}$ monocyte chemoattractant protein-1, $interleukin-1{\alpha}$, and indoleamine 2,3-dioxygenase in the cerebral cortex ipsilateral to the photothrombosis. Moreover, it induced an increase in heme oxygenase-1 immunoreactivity and interleukin-10 expression. These results suggest that CAPE exerts a remarkable neuroprotective effect on ischemic brain injury via its anti-inflammatory properties, thereby providing a benefit to the therapy of cerebral infarction.

• Journal of Chest Surgery
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• 제33권8호
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• pp.605-612
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• 2000

Background: Ischemic preconditioning enhances the tolerance of myocardium against ischemia/reperfusion injury, with the enhancement of the recovery of post-ischemic myocardial function. This study was disigned to assess whether the protective effect of ischemic preconditioning could provide one additional hour of myocardial preservation in four hour myocardial ischemia in a rate heart. Material and method: Fourty four Spargue-Dawley rats, weighing 300~450gm, were divided into four groups. Group 1(n=7) and group 3(n=12) were subjected to 30 minutes of aerobic Langendorff perfusion without ischemic preconditioning and then preserved in saline solution at 2~4$^{\circ}C$ for 4 hours and 5 respectively. Group 2(n=7) and group 4(n=18) were perfused in the same way for 20 minutes, followed by 3 minutes of global mormothermic ischemia and 10 minutes of perfusion and then preserved in the same cold saline solution for 4 hours and 5 hours respectively. Heart rate, left ventricular developed pressure(LVDP), and coronary flow were measured at 15 minutes during perfusion as baseline. Spontaneous defibrillation time was measured after reperfusion. Heart rate, LVDP, and coronary flow were also recorded at 15 minutes, 30 minutes, and 45 minutes during reperfusion. Samples of the apical left ventricular wall were studied using a transmission electron microscope. Result: Time of spontaneous defibrillation(TSD) was significantly longer in group 4 than in group 1(p<0.001), and TSD in group 1 was significantly longer in comparision to that of group 2(p<0.05). Heart rate at 45 minutes was significantly higher in group 1 than in group 4(p<0.05). Heart rate at 15 min was significantly higher in group 2 than in group 1(p<0.001) and in group 4 than in group 3(p<0.05). Left ventricular developed pressure(LVDP) at 30 minutes and 45 minutes was higher in group 1 than in group 4(p<0.01), LVDP at 45 minutes was higher in group 4 than in group 3(p<0.05). Rate-pressure product(RPP) at 30 minutes and 45 minutes was higher in group 1 than in group 4(p<0.05). RPP at 15 minutes was higher in group 2 than in group 1(p<0.01). RPP at 30 minutes and 45 minutes was higher in group 4 than in group 3(p<0.05). Group 2 showed relatively less sarcoplasmic edema and less nuclear chromatin clearance than group 1. Group 4 showed less myocardial cell damage than group 3, group 4 showed less myocardial cell damage than group 3, group 4 showed more myocardial cell edema than group 1. Conclusion: Ischemic preconditioning enhanced the recovery of postischemic myocardial function after 4 hours and 5 hours preservation. However, it was not demonstrated that ischemic preconditioning could definitely provide one additional hour of myocardial preservation in four hour myocardial ischemia in a rat heart.

• 한국임상수의학회지
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• 제26권5호
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• pp.445-449
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• 2009

이식분야에서 University of Wisconsin (UW)용액과 Histidine-Tryptophan Ketoglutarate (HTK)용액은 장기 보존액으로 주로 이용되고 있다. 바이오 장기 동물모델인 미니돼지를 이용하여 신장 저온보존에서 발생하는 허혈손상을 비교함으로써 각 보존액의 효용성을 검토하고자 하였다. 이 연구에서는 12마리의 미니돼지가 이용되었으며, 각 6마리씩 무작위로 선별하여 UW군(n = 6)과 HTK군(n = 6) 두 군으로 나누었다. 미니돼지의 신장을 적출, 세척, 각각 저온 보관(0, 24, 48, 72시간, $4^{\circ}C$) 후에 조직학적 평가를 실시하였다. 저온보관시간이 증가할수록 신장의 손상이 증가하였다. 저온보관 24시간까지는 UW와 HTK용액의 저온보관 효과는 유사하였지만, 48시간 이후에는 HTK 용액의 저온보관손상이 증가하였다. 따라서, 미니돼지 신장의 저온 보존액은 UW 용액이 효과적이며 특히 장기간 보존에 적합한 용액으로 사료된다.

• Journal of Chest Surgery
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• 제49권4호
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• pp.232-241
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• 2016

Background: Paraplegia is a devastating complication following operations on the thoracoabdominal aorta. We investigated whether histidine-tryptophan-ketoglutarate (HTK) solution could reduce the extent of ischemia/reperfusion (IR) spinal cord injuries in a rat model using a direct delivery method. Methods: Twenty-four Sprague-Dawley male rats were randomly divided into four groups. The sham group (n=6) underwent a sham operation, the IR group (n=6) underwent only an aortic occlusion, the saline infusion group (saline group, n=6) underwent an aortic occlusion and direct infusion of cold saline into the occluded aortic segment, and the HTK infusion group (HTK group, n=6) underwent an aortic occlusion and direct infusion of cold HTK solution into the occluded aortic segment. An IR spinal cord injury was induced by transabdominal clamping of the aorta distally to the left renal artery and proximally to the aortic bifurcation for 60 minutes. A neurological evaluation of locomotor function was performed using the modified Tarlov score after 48 hours of reperfusion. The spinal cord was harvested for histopathological and immunohistochemical examinations. Results: The spinal cord IR model using direct drug delivery in rats was highly reproducible. The Tarlov score was 4.0 in the sham group, $1.17{\pm}0.75$ in the IR group, $1.33{\pm}1.03$ in the saline group, and $2.67{\pm}0.81$ in the HTK group (p=0.04). The histopathological analysis of the HTK group showed reduced neuronal cell death. Conclusion: Direct infusion of cold HTK solution into the occluded aortic segment may reduce the extent of spinal cord injuries in an IR model in rats.

• Journal of Chest Surgery
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• 제30권2호
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• pp.119-124
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• 1997

저자들은 흰쥐의 적출된 심장을 이용하여 Verapamil이 허혈성 심근에 대하여 심근보호효과가 있는지를 관찰하였다 흰쥐의 적출된 심장은 허혈상태에서 심근온도가 $25^{\circ}C$가 되게 유지하였다. 24마리의 흰쥐로부터 적출된 심장을 Krebs-Henseleit완충액을 사용하여 30분간의 비작업성 역관류로 안정시킨 후 $25^{\circ}C$의 심정지액 (St. Thomas' Hospital Cardioplegic Solution)에 60분 동안 저장하였다. 허혈성 심정지를 유도하기 전에 적출된 심장을 저온의 심정지액으로 처리한 군을 대조군(n=12)으로 하고, Verapamil 이 첨가된 저온의 심정지액으로 처리한 군을 실험군(n=12)으로 하였다. 60분 동안의 허혈성 심정지후 심정지전에 측정했던 혈역학적 및 생화학적 지표인 심박동수, 좌심실압, +dpfdt max, 관상관류량과 CPK치를 재관류후 30분에 재측정하여 심정지전과 비교하여 심기능 회복 정도를 관찰하였다. Verapamil이 첨가된 저온의 심정지액을 사용한 실험군이 심박동수, 좌심실압, +dp/dt max, 관상관류량과 CPK치에서 대조군에 비하여 유의하게 높은 회복율을 나타내었다(p <0.05).