• Proceedings of the PSK Conference
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• 2002.10a
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• pp.421.2-421.2
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• 2002

Recent studies show that KR-31378 ［(2S.3SAR)-N"-cyano-N-(6-amino-3A-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N${\cdots}$-benzylguanidine］ has the neuroprotective effect as evidenced by the limitation of the size of infarct of the ischemia-reperfusion injury after an administration of KR-31378. In the literature. however. kinetics of KR-31378 distribution into the brain has not been systematically studied. (omitted)

• The Korean Journal of Physiology and Pharmacology
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• v.1 no.6
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• pp.665-672
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• 1997

This study aimed to investigate the mechanism of cerebroprotection of platelet-activating factor(PAF) antagonists in transient cerebral ischemia of rat. Right middle cerebral artery(MCA) of Sprague-Dawley rat was occluded for 2 hours using an intraluminal filament technique. After 22 hours of reperfusion, morphometrically detectable infarct was developed in the cortex and striatum identical to the territory of MCA. The infarct size was significantly reduced by PAF antagonists, BN 52021 and CV-6209, as well as an inducible nitric oxide synthase(iNOS) inhibitor aminoguanidine(1 mg/kg, i.p., respectively) administered 5 min after MCA occlusion. PAF antagonists significantly inhibited the enzymatic activities of both myeloperoxidase and iNOS in the cerebral hemisphere ipsilateral to ischemia, whereas aminoguanidine did not inhibit myeloperoxidase activity but significantly inhibited the iNOS activity. These results suggest that PAF antagonists exert a cerebroprotective effect against ischemic brain damage through inhibition of leukocyte infiltration and iNOS activity in the postischemic brain.

• Investigative Magnetic Resonance Imaging
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• v.3 no.2
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• pp.146-153
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• 1999

Purpose : To evaluate the proton MR spectroscopy (MRS) findings of early and late ischemic infarcts and to compare these MRS findings with clinical symptoms. Materials and Methods : We obtained MRs spectra of 28 consecutive patients with early ischemic infarct (15 me, 13 women) between 2-10 (mean 6.2) days after stroke onset. Follow-up MRS was carried out between 20-32 (mean 25) days in 12 patients. The MRs spectra were acquired at 1.5T MR unit using single voxel technique with PRESS sequence, TR of 2000ms, TE of 288 (144)ms, and voxel size of 2cm x 2cm x 2cm in the three areas; an infarct lesion, the brain parenchyma adjacent to the lesion, and contralateral normal brain parenchyma. The NAA/creatine, choline/creatine, and lactate/creatine ratios were calculated in each spectrum. The spectra of MRS were compared with clinical symptoms. Results : In early infarct, decreased NAA/creatine ratio (n=22) and increased lactate/creatine ratio (n=25) were found in the infarct lesion. Choline/creastine ratio was within normal range (n=25). On follow-up MRS in late stage, NAA/creatine ratio in the infarct lesion decreased further (n=5), did not change (n=6), or increased (n=1). Lactate/creatine ratio became less elevated (n=10), or did not changed (n=2). Choline/creatine ratio had a trend for increase. The decreased NAA/creatine and increased lactate/creatine ratios were correlated well with the severity of symptoms, respectively. Conclusion : Decreased NAA/creatine and increased lactate/creatine ratios were common MRS findings characteristic in early ischemic infarct and correlated well with clinical severity. On follow-up MRS in late stage, NAA/creatine ratio decreased further or did not change, and lactate/creatine ratio became less elevated.

• Journal of Korean Neurosurgical Society
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• v.40 no.3
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• pp.180-185
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• 2006

Objective : Middle cerebral artery occlusion[MCAO] has widely been used to produce ischemic brain lesions. The lesions induced by MCAO tend to be variable in size because of the variance in the collateral blood supply found in the mouse brain. To establish a less invasive and reproducible focal ischemia model in mice, we modified the technique used for rat photo thrombosis model. Methods : Male C57BL/6 mice were subjected to focal cerebral ischemia by photothrombosis of cortical microvessels. Cerebral infarction was produced by intraperitoneal injection of Rose Bengal, a photosensitive dye and by focal illumination through the skull. Motor impairment was assessed by the accelerating rotarod and staircase tests. The brain was perfusion-fixed for histological determination of infarct volume four weeks after stroke. Results : The lesion was located in the frontal and parietal cortex and the underlying white matter was partly affected. A relatively constant infarct volume was achieved one month after photothrombosis. The presence of the photothrombotic lesion was associated with severe impairment of the motor performance measured by the rotarod and staircase tests. Conclusion : Photothrombotic infarction in mice is highly reproducible in size and location. This procedure can provide a simple method to produce cerebral infarction in a unilateral motor cortex lesion. In addition, it can provide a suitable model for study of potential neuroprotective and therapeutic agents in human stroke.

• The Korean Journal of Physiology and Pharmacology
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• v.18 no.6
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• pp.481-487
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• 2014

Ischemic postconditioning (IPost) could decrease ischemia-reperfusion (IR) injury. It has not yet reported whether IPost is useful when ischemic heart disease is accompanied with co-morbidities like hyperthyroidism. The aim of this study was to examine the effect of IPost on myocardial IR injury in hyperthyroid male rats. Hyperthyroidism was induced with administration of thyroxine in drinking water (12 mg/L) over a period of 21 days. After thoracotomy, the hearts of control and hyperthyroid rats were perfused in the Langendorff apparatus and subjected to 30 minutes global ischemia, followed by 120 minutes reperfusion; IPost, intermittent early reperfusion, was induced instantly following ischemia. In control rats, IPost significantly improved the left ventricular developed pressure (LVDP) and ${\pm}dp/dt$ during reperfusion (p<0.05); however it had no effect in hyperthyroid rats. In addition, hyperthyroidism significantly increased basal $NO_x$ (nitrate+nitrite) content in serum ($125.5{\pm}5.4{\mu}mol/L$ vs. $102.8{\pm}3.7{\mu}mol/L$; p<0.05) and heart ($34.9{\pm}4.1{\mu}mol/L$ vs. $19.9{\pm}1.94{\mu}mol/L$; p<0.05). In hyperthyroid groups, heart $NO_x$ concentration significantly increased after IR and IPost, whereas in the control groups, heart $NO_x$ were significantly higher after IR and lower after IPost (p<0.05). IPost reduced infarct size (p<0.05) only in control groups. In hyperthyroid group subjected to IPost, aminoguanidine, an inducible nitric oxide (NO) inhibitor, significantly reduced both the infarct size and heart $NO_x$ concentrations. In conclusion, unlike normal rats, IPost cycles following reperfusion does not provide cardioprotection against IR injury in hyperthyroid rats; an effect that may be due to NO overproduction because it is restored by iNOS inhibition.

• The Journal of Korean Medicine
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• v.21 no.2
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• pp.68-78
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• 2000

Objective : This research was performed to investigate protective effects of Sophora subprostrata, against ischemic brain damage after a middle cerebral artery(MCA) occlusion. The effect was estimated using histological test, neurobehavioural test, and biochemical test. Methods : Rats(Sprague-Dawley) were divided into four groups: Sham operated group, MCA occluded group, Sophora subprostrata administrated group after MCA occlusion, and Normal group. The MCA was occluded by intraluminal method. Sophora subprostrata was administrated orally twice(l and 4 hours) after middle cerebral artery occlusion. The neurobeavioural test was performed at 3 hours, 6 hours, 9 hours and 24 hours after the surgery by posture reflex test and swimming behavioural test. All groups were sacrificed at 24 hours after the surgery. The brain tissue was stained with 2% triphenyl tetrazolium chioride(TTC) or 1 % cresyl violet solution, to examine effect of Sophora subprostrata on ischemic brain tissue. The blood samples were obtained from the heart of rats. Tumor necrosis factor-a level was measured from sera using Enzyme-Linked Immunoabsorbent Assay(ELISA). Results : The results showed that (1) Sophora subprostrata reduced infarct size and total infarct volume by 54.8% compared to the control group, (2) that neuronal death, which was shown by decrease in cell number and size, was attenuated significantly in the boundary area of the infarction, (3) that serum $TNF-{\alpha}$ㆍlevel was reduced significantly, and finally, there was significant recovery of motor deficit at 3 hours after MCA occluded by Swimming behavioural test. Conclusions :In conclusion, Sophora subprostrata has protective effects against ischemic brain damage at the early stage of ischemia.

• 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.

• Biomolecules & Therapeutics
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• v.25 no.2
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• pp.149-157
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• 2017

The interleukin-1 receptor antagonist (IL-1RA) is a potential stroke treatment candidate. Intranasal delivery is a novel method thereby a therapeutic protein can be penetrated into the brain parenchyma by bypassing the blood-brain barrier. Thus, this study tested whether intranasal IL-1RA can provide neuroprotection and brain penetration in transient cerebral ischemia. In male Sprague-Dawley rats, focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 1 h. The rats simultaneously received 50 mg/kg human IL-1RA through the intranasal (IN group) or intraperitoneal route (IP group). The other rats were given 0.5 mL/kg normal saline (EC group). Neurobehavioral function, infarct size, and the concentration of the administered human IL-1RA in the brain tissue were assessed. In addition, the cellular distribution of intranasal IL-1RA in the brain and its effect on proinflammatory cytokines expression were evaluated. Intranasal IL-1RA improved neurological deficit and reduced infarct size until 7 days after MCAO (p<0.05). The concentrations of the human IL-1RA in the brain tissue 24 h after MCAO were significantly greater in the IN group than in the IP group (p<0.05). The human IL-1RA was confirmed to be co-localized with neuron and microglia. Furthermore, the IN group had lower expression of $interleukin-1{\beta}$ and tumor necrosis $factor-{\alpha}$ at 6 h after MCAO than the EC group (p<0.05). These results suggest that intranasal IL-1RA can reach the brain parenchyma more efficiently and provide superior neuroprotection in the transient focal cerebral ischemia.

• Journal of Chest Surgery
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• v.32 no.9
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• pp.773-780
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• 1999

Background: It has been demonstrated that brief periods of calcium depletion and repletion (calcium-free preconditioning, CP) have cardioprotective effects as seen in ischemic preconditioning(IP) which enhances the recovery of post-ischemic contractile dysfunction and reduces the incidence of reperfusion-induced arrhythmia or infarct size after a prolonged ischemia. In the present study, we tested this paradoxical phenomenon in isolated rabbit hearts. Material and Method: Hearts isolated from New Zealand white rabbits(1.5∼2.0 Kg body weight) were perfused with Tyrode solution using the Langendorff technique. After stabilizing the baseline hemodynamics, the hearts were subjected to 45 minutes of global ischemia followed by 120 minutes of reperfusion with IP(IP group, n=7) or without IP (ischemic control group, n=7). IP was induced by a single episode of 5 minutes global ischemia and 10 minutes reperfusion. In the CP group(n=7), the hearts were subjected to perfusion with Tyrode solution with calcium depletion for 5 minutes and repletion for 10 minutes, and 45 minutes of ischemia and 120 minutes of reperfusion. Left ventricular function including developed pressure, dP/dt, heart rate, left ventricular end-diastolic pressure and coronary flow was measured. Infarct size was determined by staining with 1% triphenyltetrazolium chloride and planimetry. Data were analyzed by a one-way analysis of variance and Tukey's post-hoc test. Result: In comparison with the ischemic control group, IP significantly enhanced the recovery of the left ventricular function including the left ventricular developed pressure, contractility, and coronary flow; in contrast, these functional parameters of the CP group tended to be lower than those of the ischemic control group. However, the infarct size was significantly reduced by IP or CP(p<0.05). Conclusion: These results suggest that in isolated Langendorff-perfused rabbit heart model, CP(induced by single episode of 5 minutes calcium depletion and 10 minutes repletion) could not improve the post-ischemic contractile dysfunction(after a 45-minute global ischemia) but it has an infarct size-limiting effect.

• Journal of Korean Neurosurgical Society
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• v.29 no.9
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• pp.1171-1178
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• 2000

Objective : The purpose of the present study was to determine the appropriate time of clinical intervention by observing and analyzing the changes in the size of infarct, penumbra and cerebral edema and the extend of neurological deficit due to reperfusion damage according to time in a reversible cerebral ischemic model of reperfusing blood flow after inducing ischemia by maintaining middle cerebral artery occlusion for 2 hours(h) in rats. Methods : The rats were divided according to reperfusion time into control group(0 h reperfusion time) and experimental groups(0.5, 1, 2, 3, 4, 5, 6, 12, and 24 h of reperfusion time). Results : Changes in the size of infarction due to reperfusion damage were 0.93, 1.48 and 1.16% at 0.5, 1 and 2 h after reperfusion, respectively, and although a statistical significance was not present compared to 1.35% of the control group, damages increased drastically up to 6 h(6.64%), and the size increased were 6.65 and 6.78% at 12 and 24 h, respectively. Also there was no significant difference after 6 h up to 24 h in the size of infarction. In the areas where infarction occurred, reperfusion damage increased significantly with time in cortex than in subcortex. Accordingly, the size of penumbra area also showed a statistically significant decrease from 2 h up to 6 h after reperfusion, and 6 h after reperfusion, the area almost disappeared, becoming permanent infarction. Thus, reperfusion damage showed a significant increase from 2 h up to 6 h after reperfusion, and became steady thereafter. As for the mean ratio of the extend of cerebral edema, the control group and reperfusion 0.5 h group were 1.073 and 1.081, respectively ; up to 2 h thereafter, the ratio decreased to 1.01 but increased again with time ; and in reperfusion 12 h and reperfusion 24 h, the ratios were 1.070 and 1.075, respectively, showing similar size with that of control group. As for neurological deficit scores, the score of the control group was 2.67, that of reperfusion 2 h was 2, those of reperfusion 3 h and 6 h groups were 3.2 and 3.8, respectively, and those of reperfusion 12 h and 24 h groups were 4.2 and 4.6, respectively. Thus, as for the test results, the neurological deficit increased with time 2 h after reperfusion, and in reperfusion 12 and 24 h groups, almost all the symptoms appeared. Conclusion : As shown in these results, although the changes in the size of infarction due to reperfusion damage did not increase up to 2 h after reperfusion in the experimental groups compared to the control group, damage increased significantly thereafter up to 6 h, and the size remained about the same from 6 h to 24 h after reperfusion, becoming permanent infarction ; thus, the appropriate time of intervention according to the present study is at least 6 h before after maintaining reperfusion, including the time of cerebral artery occlusion.