• Biomolecules & Therapeutics
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• v.25 no.4
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• pp.383-389
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• 2017

Dexmedetomidine is an ${\alpha}2$-adrenergic receptor agonist that exhibits a protective effect on ischemia-reperfusion injury of the heart, kidney, and other organs. In the present study, we examined the neuroprotective action and potential mechanisms of dexmedetomidine against ischemia-reperfusion induced cerebral injury. Transient focal cerebral ischemia-reperfusion injury was induced in Sprague-Dawley rats by middle cerebral artery occlusion. After the ischemic insult, animals then received intravenous dexmedetomidine of $1{\mu}g/kg$ load dose, followed by $0.05{\mu}g/kg/min$ infusion for 2 h. After 24 h of reperfusion, neurological function, brain edema, and the morphology of the hippocampal CA1 region were evaluated. The levels and mRNA expressions of interleukin-$1{\beta}$, interleukin-6 and tumor nevrosis factor-${\alpha}$ as well as the protein expression of inducible nitric oxide synthase, cyclooxygenase-2, nuclear factor-${\kappa}Bp65$, inhibitor of ${\kappa}B{\alpha}$ and phosphorylated of ${\kappa}B{\alpha}$ in hippocampus were assessed. We found that dexmedetomidine reduced focal cerebral ischemia-reperfusion injury in rats by inhibiting the expression and release of inflammatory cytokines and mediators. Inhibition of the nuclear factor-${\kappa}B$ pathway may be a mechanism underlying the neuroprotective action of dexmedetomidine against focal cerebral I/R injury.

• The Korean Journal of Physiology and Pharmacology
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• v.28 no.3
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• pp.239-252
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• 2024

Dexmedetomidine displays multiple mechanisms of neuroprotection in ameliorating ischemic brain injury. In this study, we explored the beneficial effects of dexmedetomidine on blood-brain barrier (BBB) integrity and neuroinflammation in cerebral ischemia/reperfusion injury. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 1.5 h and reperfusion for 24 h to establish a rat model of cerebral ischemia/reperfusion injury. Dexmedetomidine (9 ㎍/kg) was administered to rats 30 min after MCAO through intravenous injection, and SB203580 (a p38 MAPK inhibitor, 200 ㎍/kg) was injected intraperitoneally 30 min before MCAO. Brain damages were evaluated by 2,3,5-triphenyltetrazolium chloride staining, hematoxylin-eosin staining, Nissl staining, and brain water content assessment. BBB permeability was examined by Evans blue staining. Expression levels of claudin-5, zonula occludens-1, occludin, and matrix metalloproteinase-9 (MMP-9) as well as M1/M2 phenotypes-associated markers were assessed using immunofluorescence, RT-qPCR, Western blotting, and gelatin zymography. Enzyme-linked immunosorbent assay was used to examine inflammatory cytokine levels. We found that dexmedetomidine or SB203580 attenuated infarct volume, brain edema, BBB permeability, and neuroinflammation, and promoted M2 microglial polarization after cerebral ischemia/reperfusion injury. Increased MMP-9 activity by ischemia/reperfusion injury was inhibited by dexmedetomidine or SB203580. Dexmedetomidine inhibited the activation of the ERK, JNK, and p38 MAPK pathways. Moreover, activation of JNK or p38 MAPK reversed the protective effects of dexmedetomidine against ischemic brain injury. Overall, dexmedetomidine ameliorated brain injury by alleviating BBB permeability and promoting M2 polarization in experimental cerebral ischemia/reperfusion injury model by inhibiting the activation of JNK and p38 MAPK pathways.

• Journal of Korean Neurosurgical Society
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• v.30 no.1
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• pp.12-19
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• 2001

Objective : Albumin is a very useful drug for the improving of cerebral blood volume and the oncotic effect in cerebral ischemia or cerebral vasospasm. The purpose of this study was to examine the morphological and neurological effect of albumin therapy on reperfusion injury following transient focal cerebral ischemia. Materials and Methods : 18 Male Sprague-Dawley rats weighing 270-320g were used. The ischemia model was produced by 2-hour period of transient middle cerebral artery occlusion with a poly-L-lysin coated intraluminal suture. The agent(20% human serum albumin[HSA]) or control solution(NaCl 0.9%) was administered intravenously at a dosage of 1% of body weight immediate after reperfusion following a 2-hour period occlusion. Neurological function was evaluated by the postural reflex and the forlimb placing test during occlusion(at 60 min) and daily for 3 days thereafter. The brain was perfusion-fixed, and infarct volumes and brain edema were measured. Results : The HSA significantly improved the neurological score in treated group. The rats of albumin treatment group showed significantly reduced total infarct volume(by 34%) and brain edema(by 81%) compared with salinetreated rats. Conclusion : HSA showed a substantial effect on the transient focal cerebral ischemia and reperfusion injury model. These results may indicate its usefulness in treating reperfusion injury patients after thrombolysis treatment for the thrombo-embolic major cerebral artery occlusions.

• The Korean Journal of Physiology and Pharmacology
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• v.5 no.3
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• pp.205-212
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• 2001

It has been proposed that nitirc oxide is involved in the pathogenesis of cerebral ischemia-reperfusion. Because superoxide production is also enhanced during reperfusion, the cytotoxic oxidant peroxynitrite could be formed, but it is not known if this occurs following global forebrain ischemia-reperfusion. We examined whether peroxynitrite generation is increased in the vulnerable regions after forebrain ischemia-reperfusion. Transient forebrain ischemia was produced in the conscious rat by four-vessel occlusion. Rats were subjected to 10 or 15 min of forebrain ischemia. Immunohistochemical method was used to detect 3-nitrotyrosine, a marker of peroxynitrite production. 3-Nitrotyrosine immunoreactivity was enhanced in the hippocampal CA1 area 3 days after reperfusion. Furthermore, in rats subjected to ischemia for 15 min, this change was also observed in the lateral striatal region and the lateral septal nucleus $2{\sim}3$ days after reperfusion. The cresyl violet staining of adjacent sections showed that neuronal cell death was induced in parallel with the nitrotyrosine immunoreactivity in the hippocampal CA1 area and the lateral striatal region. Our findings suggest that oxygen free radical accumulation and consequent peroxynitrite production play a role in neuronal death caused by cerebral ischemia-reperfusion.

• Journal of Korean Neurosurgical Society
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• v.38 no.3
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• pp.221-226
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• 2005

Objective : Reactive oxygen metabolites and polymorphonuclear leukocytes have been implicated in the pathophysiology of reperfusion injury. The mechanisms involved in superoxide-mediated leukocyte adherence remain unclear, however, nitric oxide[NO] may contribute to this response. The present study is undertaken to elucidate mechamisms controlling NO based mechanisms that regulated leukocyte-endothelial interactions in the cerebral vasculature after global cerebral ischemia and reperfusion. Methods : Pial venular leukocyte adherence of anesthetized newborn piglets was quantified by in situ fluorescence videomicroscopy through closed cranial windows during basal conditions and during 2hours of reperfusion after global ischemia induced by 9minutes of asphyxia. Nitric oxide synthase[NOS] was inhibited by local window superfusion of L-nitroarginine[NA]; superfusion of sodium nitroprusside[SNP] was used to donate NO. Results : The mean number of adherent leukocytes to cerebral venules in the 9minutes asphyxia and 2hours reperfusion group were $161{\pm}19$ compared with $13{\pm}4$ in the nonasphyxial group. Superfusion of L-NA through the cranial window for 2hours resulted in leukocyte adherence similar to that observed during the initial 2hours of reperfusion after asphyxia. Leukocyte adherence was not additionally increased in asphyxic animal treated with L-NA. SNP inhibited asphyxia induced leukocyte adherence back to control levels. Conclusions : Nitric oxide inhibits leukocyte adherence to cerebral venules during the initial hours of reperfusion after asphyxia, and that NO supplementation inhibit asphyxia induced leukocyte adherence back to control levels. These results indicate that NO is an important factor in ischemia-reperfusion induced leukocyte adherence.

• Journal of Korean Neurosurgical Society
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• v.29 no.10
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• pp.1289-1295
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• 2000

Purpose : Recent evidence suggests a possible role for leukocytes in brain injury following ischemia and reperfusion. This study examined the temporal profile of ischemic tissue damage and leukocyte response after transient middle cerebral artery occlusion(MCAO) with reperfusion in the mouse. Methods : Focal cerebral ischemia was made by temporary occluding of the stem of the proximal MCA. Two groups of the mouse were investigated : (1) sham operation(n＝10), and (2)those having the arterial occlusion released after 90 minute(n＝20). By 4 hours(n＝10) and 24 hours(n＝10) after the onset of ischemia-reperfusion, fluorescein videoimages were under-taken in the pial venules of the mouse using a closed cranial window technique. Rhodamine 6G was administered as a $80-100{\mu}l/min$ i.v. loading dose and a $30-40{\mu}l/min$ i.v. maintenance dose in saline to selectively label circulating leukocytes. Neuropathologic evaluation for brain injury was accomplished using the histochemical stain 2,3,5-triphen-yltetrazolium chloride(TTC) and hematoxylin and eosin(H & E) stain. Results : The mean number of adherent leukocytes to cerebral venules in the 90 minutes MCAO and 24 hours reperfusion group were $306{\pm}24$ compared with $72{\pm}8$ in the sham operation group. In the TTC staining method, the cortical infarct affecting 34.8% of hemispheric volume were created in all of animals (n＝10) undergoing 90 minute MCAO with 24 hours reperfusion, but the infarcted area were not found in the other(sham operation and 90 minute MCAO with 4 hours reperfusion)groups. In the H & E stain, the brain tissue following 90 minute MCAO with 4 hours reperfusion revealed only a pyknosis of the nuclei with shrunken cytoplasm, but infiltrated leukocytes were not observed. After 24 hours of reperfusion, a many leukocytes were infiltrated within parenchyma and blood vessles. Conclusions : These findings demonstrate the feasiblity of continous in vivo monitoring of leukocyte adherence in cerebral venules and suggest that reperfusion induced leukocyte adherence to venular endothelium may contribute to tissue injury following focal cerebral ischemia.

• The Korean Journal of Physiology and Pharmacology
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• v.24 no.1
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• pp.11-18
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• 2020

The present study was aimed to explore the neuroprotective role of imatinib in global ischemia-reperfusion-induced cerebral injury along with possible mechanisms. Global ischemia was induced in mice by bilateral carotid artery occlusion for 20 min, which was followed by reperfusion for 24 h by restoring the blood flow to the brain. The extent of cerebral injury was assessed after 24 h of global ischemia by measuring the locomotor activity (actophotometer test), motor coordination (inclined beam walking test), neurological severity score, learning and memory (object recognition test) and cerebral infarction (triphenyl tetrazolium chloride stain). Ischemia-reperfusion injury produced significant cerebral infarction, impaired the behavioral parameters and decreased the expression of connexin 43 and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in the brain. A single dose administration of imatinib (20 and 40 mg/kg) attenuated ischemia-reperfusion-induced behavioral deficits and the extent of cerebral infarction along with the restoration of connexin 43 and p-STAT3 levels. However, administration of AG490, a selective Janus-activated kinase 2 (JAK2)/STAT3 inhibitor, abolished the neuroprotective actions of imatinib and decreased the expression of connexin 43 and p-STAT3. It is concluded that imatinib has the potential of attenuating global ischemia-reperfusion-induced cerebral injury, which may be possibly attributed to activation of JAK2/STAT3 signaling pathway along with the increase in the expression of connexin 43.

• The Korean Journal of Pharmacology
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• v.29 no.1
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• pp.1-8
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• 1993

To elucidate involvement of platelet-activating factor (PAF) in cerebral ischemia-reperfusion injury, male Sprague-Dawley rats and albino mice of either sex were subjected to a 10-min bilateral carotid artery occlusion and 6-hr recirculation. The McGraw stroke index in mice was markedly inhibited by PAF antagonists, BN 52021 and CV 6209 (1 mg/kg, i.p., each) When they were administered 10 min before bilateral carotid artery occlusion or 1 hr after reperfusion. The increases in brain water content were significantly attenuated by treatment with BN 52021 or CV 6209 in both animals. BN 52021 exhibited a significant improvement in the postischemic blood pressure change in association with a beneficial effect on the delayed dilatation of pial arterioles after 10 min of ischemia. Thus it is suggested that PAF plays an important role as an endogenous mediator in development of cerebral ischemia-reperfusion injury, and further, specific antagonists to PAF will be able to prevent or reverse the pathological sequelae of cerebral ischemia.

• The Korea Journal of Herbology
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• v.28 no.2
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• pp.1-7
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• 2013

Objectives : Sesamin, a major lignan in sesame seeds, has been reported to have neuroprotective effects against in vitro ischemia and in vivo MCAo-reperfusion cerebral ischemia model, however, there is no reports in an in vivo global cerebral ischemia model. The purpose of the study was to investigate the neuroprotective effect of sesamin in global cerebral ischemia induced by four-vessel occlusion (4-VO) in rats through inhibition of microglial activation in this model. Methods : The neuroprotective effects were investigated using a 10 min of 4-VO ischemia rat model by measuring intact pyramidal neurons in the CA1 region of the hippocampus using Nissle staining. The antiinflammatory or reducing neurotoxicity effect was investigated using immunohistochemisty, RT-PCR and western blot analysis of inflammatory or neurotoxic mediators. Results : Intraperitoneal injection of sesamin at doses of 0.3, 1.0, 3.0, and 10.0 mg/kg at 0 min and 90 min after ischemia conferred 26.6%, 30.1%, 42.5%, and 30.5% neuroprotection, respectively, compared to the vehicle-treated control group. A 3.0 mg/kg dose of sesamin inhibited microglia activation and consequently, cyclooxygenase-2, inducible nitric oxide, and interleukine-$1{\beta}$ expressions at 48 h after reperfusion. Conclusions : Sesamin protects neuronal cell death through inhibition of microglial activation or the production of neurotoxic metabolites and proinflammatory mediators by microglia such as COX-2, iNOS and IL-$1{\beta}$ in global cerebral ischemia.

• The Journal of the Society of Stroke on Korean Medicine
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• v.10 no.1
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• pp.8-19
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• 2009

Scutellaria Radix, originated from Scutellaria baicalensis Georgi, is one of the most important medicine in traditional Oriental medicine, and possesses anti-bacterial activity and sedative effects, can be applied in the treatment of a range of conditions including diarrhea and hepatitis. It is reported that chronic global ischemia induces neuronal damage in selective, vulnerable regions of the brain, especially the hippocampus and cerebral cortex. In the present study, to investigate the effect of Scutellaria Radix extract on cerebral disease, the changes of regional cerebral blood flow and pial arterial diameter on ischemia/reperfusion state was determinated by Laser-Doppler Flowmetry and some parameters concerned with oxidative stress also measured. When SRe were administered for five days with the concentration of 100 mg/kg, GSH activity significantly increased. But SRe administeration showed no significant change in lipid peroxidation. When the activities of CAT, Cu, Zn-SOD and GSH were measured, CAT and GSH were activated by SRe administration. When 1 and 3 ㎍/㎖ SRe was applied to the neuronal cell cultures, the quantities of LDH was significantly reduced when compared with cultures treated only with NMDA. Through this study, it can be concluded that the ischemia/reperfusion induced brain stress may have contributed to cerebral damage in rats, and the present study provides clear evidence for the beneficial effect of SRe on ischemia induced brain injury.