• Biomedical Science Letters
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• v.12 no.2
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• pp.81-89
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• 2006

The ischemia-responsive 94 gene (irp94) encoding a 94 kDa endoplasmic reticulum resident protein was investigated its molecular properties associated with unfoled protein responses. First, the expression of irp94 mRNA was tested after the reperfusion of the transient forebrain ischemia induction at the central nervous system in three Mongolian gerbils. Second, irp94 expression in PC12 cells, which are derived from transplantable rat pheochromocytoma cultured in the DMEM media, was tested at transcriptional and translational levels. The half life of irp94 mRNA was also determined In PC12 cells. Last, the changes of irp94 mRNA expression were investigated by the addition of various ER stress inducible chemicals (A23187, BFA, tunicamycin, DTT and $H_2O_2$) and proteasome inhibitors, and heat shock. High level expression of irp94 mRNA was detected after 3 hours reperfusion in the both sites of the cerebral cortex and hippocampus of the gerbil brain. The main regulation of irp94 mRNA expression in PC 12 cells was determined at the transcriptional level. The half life of irp94 mRNA in PC12 cells was approximately 5 hours after the initial translation. The remarkable expression of irp94 mRNA was detected by the treatment of tunicamycin, which blocks glycosylation of newly synthesized polypeptides, and $H_2O_2$, which induces apoptosis. When PC12 cells were treated with the cytosol proteasome inhibitors such as ALLN (N-acetyl-leucyl-norleucinal) and MG 132 (methylguanidine), irp94 mRNA expression was increased. These results indicate that expression of irp94 was induced by ER stress including oxidation condition and glycosylation blocking in proteins. Expression of irp94 was increased when the cells were chased after heat shock, suggesting that irp94 may be involved in recovery rather than protection against ER stresses. In addition, irp94 expression was remarkably increased when cytosol proteasomes were inhibited by ALLN and MG 132, suggesting that irp94 plays an important role for maintaining the ERAD (endoplasmic reticulum associated degradation) function.

• Journal of Trauma and Injury
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• v.19 no.1
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• pp.14-20
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• 2006

Purpose: Although hypothermia has been used in many clinical situations, such as post cardiopulmonary resuscitation, stroke, traumatic brain injury, septic shock, and hemorrhagic shock, the mechanism by which it works has not been clearly elucidated. We aimed to evaluate the effect of hypothermia on the plasma nitric oxide (NO) concentration, lung iNOS expression, and histologic changes in intestinal ischemia-reperfusion (IR). Method: Male Sprague-Dawley rats were randomly divided into the hypothermia group (HT, n=8, $27{\sim}30^{\circ}C$) and the normothermia group (NT, n=8, $36{\sim}37^{\circ}C$). They underwent 30 min of intestinal ischemia by clamping the superior mesenteric artery, which was followed by 1.5 h of reperfusion. They were then sacrificed. The acute lung injury (ALI) score, the plasma NO concentration, and lung iNOS gene expression were measured. Results: Compared with the HT group, the NT group showed severe infiltrations of inflammatrory cells, alveolar hemorrhages, and interstitial hypertrophies in lung tissues. There were significant differences in the ALI scores between the NT and the HT groups ($8.7{\pm}1.5/HPF$ in NT vs $5.8{\pm}1.2/HPF$ in HT, p=0.008). Although the plasma NO concentration was slightly lower in the HT group, there was no significant difference between the two groups ($0.80{\pm}0.24{\mu}mol/L$ in NT vs $0.75{\pm}0.30{\mu}mol/L$ in HT, p=0.917). Lung iNOS gene expression was stronger in the NT group than in the HT group. The band density of the expression of iNOS in lung tissues was significantly increased in the NT group compared to the HT group ($5.54{\pm}2.75$ in NT vs$0.08{\pm}0.52$ in HT, p=0.002). Conclusions: This study showed that hypothermia in intestinal IR reduces inflammatory responses, ALI scores, and iNOS gene expression in lung tissues. There was no significant effect of hypothermia on the plasma NO concentration.

• International Journal of Molecular Medicine
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• v.44 no.3
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• pp.939-948
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• 2019

Chemokine C-X3-C motif ligand 1 (CX3CL1) and its sole receptor, CX3CR1, are known to be involved in neuronal damage/death following brain ischemia. In the present study, time-dependent expression changes of CX3CL1 and CX3CR1 proteins were investigated in the hippocampal CA1 field following 5 min of transient global cerebral ischemia (tgCI) in gerbils. To induce tgCI in gerbils, bilateral common carotid arteries were occluded for 5 min using aneurysm clips. Expression changes of CX3CL1 and CX3CR1 proteins were assessed at 1, 2 and 5 days after tgCI using western blotting and immunohistochemistry. CX3CL1 immunoreactivity was strong in the CA1 pyramidal cells of animals in the sham operation group. Weak CX3CL1 immunoreactivity was detected at 6 h after tgCI, recovered at 1 day after tgCI and disappeared from 5 days after tgCI. CX3CR1 immunoreactivity was very weak in CA1 pyramidal cells of the sham animals. CX3CR1 immunoreactivity in CA1 pyramidal cells was significantly increased at 1 days after tgCI and gradually decreased thereafter. On the other hand, CX3CR1 immunoreactivity was significantly increased in microglia from 5 days after tgCI. These results showed that CX3CL1 and CX3CR1 protein expression levels in pyramidal cells and microglia in the hippocampal CA1 field following tgCI were changed, indicating that tgCI-induced expression changes of CX3CL1 and CX3CR1 proteins might be closely associated with tgCI-induced delayed neuronal death and microglial activation.

• Clinical and Experimental Pediatrics
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• v.59 no.11
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• pp.440-445
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• 2016

Purpose: This study aimed to identify prognostic factors of neurological outcomes, including developmental delay, cerebral palsy and epilepsy in late-preterm and term infants with perinatal asphyxia. Methods: All late-preterm and term infants with perinatal asphyxia or hypoxic-ischemic insults who admitted the neonatal intensive care unit of Inje University Sanggye Paik Hospital between 2006 and 2014 and were followed up for at least 2 years were included in this retrospective study. Abnormal neurological outcomes were defined as cerebral palsy, developmental delay and epilepsy. Results: Of the 114 infants with perinatal asphyxia, 31 were lost to follow-up. Of the remaining 83 infants, 10 died, 56 had normal outcomes, and 17 had abnormal outcomes: 14 epilepsy (82.4%), 13 cerebral palsy (76.5%), 16 developmental delay (94.1%). Abnormal outcomes were significantly more frequent in infants with later onset seizure, clinical seizure, poor electroencephalography (EEG) background activity, lower Apgar score at 1 and 5 minutes and abnormal brain imaging (P<0.05). Infants with and without epilepsy showed significant differences in EEG background activity, clinical and electrographic seizures on EEG, Apgar score at 5 minutes and brain imaging findings. Conclusion: We should apply with long-term video EEG or amplitude integrated EEG in order to detect and management subtle clinical or electrographic seizures in neonates with perinatal asphyxia. Also, long-term, prospective studies with large number of patients are needed to evaluate more exact prognostic factors in neonates with perinatal asphyxia.

• Journal of Korean Neurosurgical Society
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• v.53 no.3
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• pp.139-144
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• 2013

Objective : Transient anterograde amnesia is occasionally observed in a number of conditions, including migraine, focal ischemia, venous flow abnormalities, and after general anesthesia. The inhalation anesthetic, isoflurane, is known to induce transient anterograde amnesia. We examined the involvement of brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B (TrkB) in the underlying mechanisms of the isoflurane-induced transient anterograde amnesia. Methods : Adult male Sprague-Dawley rats were divided into three groups : the control group, the 10 minutes after recovery from isoflurane anesthesia group, and the 2 hours after recovery from isoflurane anesthesia group (n=8 in each group). The rats in the isoflurane-exposed groups were anesthetized with 1.2% isoflurane in 75% nitrous oxide and 25% oxygen for 2 hours in a Plexiglas anesthetizing chamber. Short-term memory was determined using the step-down avoidance task. BDNF and TrkB expressions in the hippocampus were evaluated by immunofluorescence staining and western blot analysis. Results : Latency in the step-down avoidance task was decreased 10 minutes after recovery from isoflurane anesthesia, whereas it recovered to the control level 2 hours after isoflurane anesthesia. The expressions of BDNF and TrkB in the hippocampus were decreased immediately after isoflurane anesthesia but were increased 2 hours after isoflurane anesthesia. Conclusion : In this study, isoflurane anesthesia induced transient anterograde amnesia, and the expressions of BDNF and TrkB in the hippocampus might be involved in the underlying mechanisms of this transient anterograde amnesia.

• Biomolecules & Therapeutics
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• v.8 no.2
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• pp.160-166
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• 2000

The present study examined influence of various ischemic duration on extent of focal ischemic brain injury induced by middle cerebral artery occlusion (MCAO) in rats. The MCAO was produced by insertion of a 17 mm silicone-coated 4-0 nylon surgical thread to the origin of MCA through the internal carotid artery for 30, 60, 90, 120 min (transient) or 24 hr (permanent) in male Sprague-Dawley rats under isoflurane anesthesia. Reperfusion in transient MCAO models was achieved by pulling the thread out of the internal carotid artery. Only rats showing neurological deficits characterized by left hemiparesis and/or circling to the left, were included in cerebral ischemic groups. The rats were sacrificed 24 hr after MCAO and seven serial coronal slices of the brain were stained with 2,3,5-triphenyltetrazolium chloride. Infarct size was measured using a computerized image analyzer. Ischemic damage was common in the frontoparietal cortex (somatosensory area) and the lateral segment of the striatum while damage to the medial segment of the striatum depended on the duration of the occlusion. In the 30-min MCAO grouts, however, infarcted region was primarily confined to the striatum and it was difficult to clearly delineate the region since there was mixed population of live and dead cells in the nucleus. Infarct volume was generally increased depending on the duration of MCAO, showing the most severe damage in the permanent MCAO group. However, there was no significant difference in infarct size between the 90-min and 120-min MCAO groups. % Edema also tended to increase depending on the duration of MCAO. The results suggest that the various focal ischemic rat models established in the present study can be used to evaluate in vivo neuroprotective activities of candidate compounds or to elucidate pathophysiological mechanisms of ischemic neuronal cell death.

• The Korean Journal of Nuclear Medicine
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• v.23 no.2
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• pp.149-154
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• 1989

Transient ischemic attacks (TIAs) is a syndrome resulting from brain ischemia lasting less than 24 hours. The mechanisms of TIAs may be similar to those of cerebral embolism and thrombosis, and thus TIAs may be followed by cerebral infarction. Despite the availability of CT scanning, the diagnosis and management of TIAs continue to be difficult. Recently SPECT has been advocated as a diagnostic imaging modality. We performed Tc-99m-HMPAO regional cerebral blood flow (rCBF) SPECT in 24 patients with the clinical diagnosis of TIAs to assess its ability to detect early changes of rCBF, and determine the diagnostic value. Ten men and fourteen women with an average of 51 years (range; 27-74 years) were included. All but 8 patients had normal brain CT prior to SPECT. The two patients had moderate degree of brain atrophy and the 6 patients nonspecific calcifications. Eighteen of the 24 patients had abnormal Tc-99m-HMPAO rCBF SPECT. Fifteen had unilateral involvement and the other three had bilateral involvements. Seventy-five percents of the defects were found in the left cerebral hemisphere. According to the distribution of the lesions (total number: 34 lesions), fourteen were in the parietal, eight in the temporal, and the remainders were elsewhere. Tc-99m-HMPAO rCBF SPECT is sensitive in detecting rCBF abnormalities in patients with TIAs, and represent the most accurate diagnostic tool available in the diagnosis of TIAs.

• Journal of Korean Medicine Rehabilitation
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• v.18 no.2
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• pp.33-43
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• 2008

Objectives : Sunghyangjungki-san(Xingxiangzhengqi-san) is a herb decoction prescribed frequently for stroke patients. The present study investigated neuroprotective effects of Sunghyangjungki-san(Xingxiangzhengqi-san) against the ischemic damage of the rat brain. Neuronal cell death under the cerebral ischemia is distinguished with the delayed cell death through apoptosis. Consequently, the effects of Sunghyangjungki-san(Xingxiangzhengqi-san) was evaluated with Bax and Bcl-2 expressions as apoptosis related factors in the brain tissues. Methods : The ischemic damage was induced by the middle cerebral artery occlusion(MCAO) method in Sprague-Dawley rats. Water extract of Sunghyangjungki-san(Xingxiangzhengqi-san) was treated for 5 days after the MCAO. Neurological scores and infarct size with TTC were measured. Bax and Bcl-2 expressions in the brain tissues were observed with immunohistochemistry. Results : Sunghyangjungki-san(Xingxiangzhengqi-san) treatment improved neurological score significantly at 5 days after the MCAO. Sunghyangjungki-san(Xingxiangzhengqi-san) treatment decreased infarct size by the MCAO, but it was not significant statistically. Sunghyangjungki-san(Xingxiangzhengqi-san) treatment attenuated Bax positive neurons significantly in the cerebral penumbra and the caudate putamen. Bcl-2 positive neurons were increased, but not significant. Sunghyangjungki-san(Xingxiangzhengqi-san) treatment increased Bcl-2/Bax expression ratios significantly in the cerebral penumbra and the caudate putamen. Conclusions : These results suggest that Sunghyangjungki-san(Xingxiangzhengqi-san) has a neuroprotective effect on the stroke with modulation of apoptosis related factors.

• Journal of Ginseng Research
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• v.46 no.2
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• pp.275-282
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• 2022

Background: Stroke is a neurological disorder characterized by brain tissue damage following a decrease in oxygen supply to brain due to blocked blood vessels. Reportedly, 80% of all stroke cases are classified as cerebral infarction, and the incidence rate of this condition increases with age. Herein, we compared the efficacies of Korean White ginseng (WG) and Korean Red Ginseng (RG) extracts (WGex and RGex, respectively) in an ischemic stroke mouse model and confirmed the underlying mechanisms of action. Methods: Mice were orally administered WGex or RGex 1 h before middle cerebral artery occlusion (MCAO), for 2 h; the size of the infarct area was measured 24 h after MCAO induction. Then, the neurological deficit score was evaluated and the efficacies of the two extracts were compared. Finally, their mechanisms of action were confirmed with tissue staining and protein quantification. Results: In the MCAO-induced ischemic stroke mouse model, WGex and RGex showed neuroprotective effects in the cortical region, with RGex demonstrating superior efficacy than WGex. Ginsenoside Rg1, a representative indicator substance, was not involved in mediating the effects of WGex and RGex. Conclusion: WGex and RGex could alleviate the brain injury caused by ischemia/reperfusion, with RGex showing a more potent effect. At 1,000 mg/kg body weight, only RGex reduced cerebral infarction and edema, and both anti-inflammatory and anti-apoptotic pathways were involved in mediating these effects.

• BMB Reports
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• v.35 no.1
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• pp.67-86
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• 2002

Three routes have been identified triggering neuronal death under physiological and pathological conditions. Excess activation of ionotropic glutamate receptors cause influx and accumulation of $Ca^{2+}$ and $Na^+$ that result in rapid swelling and subsequent neuronal death within a few hours. The second route is caused by oxidative stress due to accumulation of reactive oxygen and nitrogen species. Apoptosis or programmed cell death that often occurs during developmental process has been coined as additional route to pathological neuronal death in the mature nervous system. Evidence is being accumulated that excitotoxicity, oxidative stress, and apoptosis propagate through distinctive and mutually exclusive signal transduction pathway and contribute to neuronal loss following hypoxic-ischemic brain injury. Thus, the therapeutic intervention of hypoxic-ischemic neuronal injury should be aimed to prevent excitotoxicity, oxidative stress, and apoptosis in a concerted way.