• The Korean Journal of Physiology and Pharmacology
• /
• v.12 no.5
• /
• pp.275-280
• /
• 2008

A brief ischemic insult induces significant protection against subsequent massive ischemic events. The molecular mechanisms known as preconditioning (PC)-induced ischemic tolerance are not completely understood. We investigated whether kinetic changes of cyclooxygenase (COX)-2 during reperfusion time-periods after PC were related to ischemic tolerance. Rats were given PC by occlusion of middle cerebral artery (MCAO) for 10 min and sacrificed after the indicated time-periods of reperfusion (1, 2, 4, 8, 12, 18 or 24 h). In PC-treated rats, focal ischemia was induced by occlusion of MCA for 24 h and brain infarct volume was then studied to determine whether different reperfusion time influenced the damage. We report that the most significant protection against focal ischemia was obtained in rats with 8 h reperfusion after PC. Administration of indomethacin (10 mg/kg, oral) or rofecoxib (5 mg/kg, oral) 48 h prior to PC counteracted the effect of PC. Immunohistochemical analysis showed that COX-2 and HO-l protein were induced in PC-treated rat brain, which was significantly inhibited by rofecoxib. Taken together, we concluded that the kinetic changes of COX-2 expression during the reperfusion period after PC might be partly responsible for ischemic tolerance.

• Laboraroty Animal Research
• /
• v.34 no.4
• /
• pp.195-202
• /
• 2018

Hyperglycemia is one of the major risk factors for stroke. Hyperglycemia can lead to a more extensive infarct volume, aggravate neuronal damage after cerebral ischemia. ${\alpha}$-Synuclein is especially abundant in neuronal tissue, where it underlies the etiopathology of several neurodegenerative diseases. This study investigated whether hyperglycemic conditions regulate the expression of ${\alpha}$-synuclein in middle cerebral artery occlusion (MCAO)-induced cerebral ischemic injury. Male Sprague-Dawley rats were treated with streptozotocin (40 mg/kg) via intraperitoneal injection to induce hyperglycemic conditions. MCAO were performed four weeks after streptozotocin injection to induce focal cerebral ischemia, and cerebral cortex tissues were obtained 24 hours after MCAO. We confirmed that MCAO induced neurological functional deficits and cerebral infarction, and these changes were more extensive in diabetic animals compared to non-diabetic animals. Moreover, we identified a decrease in ${\alpha}$-synuclein after MCAO injury. Diabetic animals showed a more serious decrease in ${\alpha}$-synuclein than non-diabetic animals. Western blot and reverse-transcription PCR analyses confirmed more extensive decreases in ${\alpha}$-synuclein expression in MCAO-injured animals with diabetic condition than these of non-diabetic animals. It is accepted that ${\alpha}$-synuclein modulates neuronal cell death and exerts a neuroprotective effect. Thus, the results of this study suggest that hyperglycemic conditions cause more serious brain damage in ischemic brain injuries by decreasing ${\alpha}$-synuclein expression.

• The Korean Journal of Physiology and Pharmacology
• /
• v.25 no.2
• /
• pp.97-109
• /
• 2021

Neonatal hypoxia/ischemia (H/I), injures white matter, results in neuronal loss, disturbs myelin formation, and neural network development. Neuroinflammation and oxidative stress have been reported in neonatal hypoxic brain injuries. We investigated whether Paeoniflorin treatment reduced H/I-induced inflammation and oxidative stress and improved white matter integrity in a neonatal rodent model. Seven-day old Sprague-Dawley pups were exposed to H/I. Paeoniflorin (6.25, 12.5, or 25 mg/kg body weight) was administered every day via oral gavage from postpartum day 3 (P3) to P14, and an hour before induction of H/I. Pups were sacrificed 24 h (P8) and 72 h (P10) following H/I. Paeoniflorin reduced the apoptosis of neurons and attenuated cerebral infarct volume. Elevated expression of cleaved caspase-3 and Bad were regulated. Paeoniflorin decreased oxidative stress by lowering levels of malondialdehyde and reactive oxygen species generation and while, and it enhanced glutathione content. Microglial activation and the TLR4/NF-κB signaling were significantly down-regulated. The degree of inflammatory mediators (interleukin 1β and tumor necrosis factor-α) were reduced. Paeoniflorin markedly prevented white matter injury via improving expression of myelin binding protein and increasing O1-positive olidgodendrocyte and O4-positive oligodendrocyte counts. The present investigation demonstrates the potent protective efficiency of paeoniflorin supplementation against H/I-induced brain injury by effectually preventing neuronal loss, microglial activation, and white matter injury via reducing oxidative stress and inflammatory pathways.

• Molecules and Cells
• /
• v.45 no.4
• /
• pp.216-230
• /
• 2022

SERTA domain-containing protein 1 (Sertad1) is upregulated in the models of DNA damage and Alzheimer's disease, contributing to neuronal death. However, the role and mechanism of Sertad1 in ischemic/hypoxic neurological injury remain unclear. In the present study, our results showed that the expression of Sertad1 was upregulated in a mouse middle cerebral artery occlusion and reperfusion model and in HT22 cells after oxygen-glucose deprivation/reoxygenation (OGD/R). Sertad1 knockdown significantly ameliorated ischemia-induced brain infarct volume, neurological deficits and neuronal apoptosis. In addition, it significantly ameliorated the OGD/R-induced inhibition of cell viability and apoptotic cell death in HT22 cells. Sertad1 knockdown significantly inhibited the ischemic/hypoxic-induced expression of p-Rb, B-Myb, and Bim in vivo and in vitro. However, Sertad1 overexpression significantly exacerbated the OGD/R-induced inhibition of cell viability and apoptotic cell death and p-Rb, B-Myb, and Bim expression in HT22 cells. In further studies, we demonstrated that Sertad1 directly binds to CDK4 and the CDK4 inhibitor ON123300 restores the effects of Sertad1 overexpression on OGD/R-induced apoptotic cell death and p-Rb, B-Myb, and Bim expression in HT22 cells. These results suggested that Sertad1 contributed to ischemic/hypoxic neurological injury by activating the CDK4/p-Rb pathway.

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

• The Korean Journal of Nuclear Medicine
• /
• v.28 no.1
• /
• pp.37-43
• /
• 1994

The coronary collateral vessels have revealed their significance in terms of reduction of infarct size, preservation left ventricular function, and prevention of left ventricular aneurysm in patients with myocardial infarction. The purpose of this study were to evaluated the relation between collateral circulation and $^{99m}Tc$-MIBI Heart SPECT in patient with acute myocardial infarction and their clinical significance. The fifty six MI patients with antegrade TIMI perfusion grade 0 and 1 were studied. The patients were classified into two groups; Group I inclueded 30 patients with grade 2, 3 Collateral flow. Group II inclueded 26 patients with grade 0, 1 Collateral flow. Collateral filling were graded from 0 to 3: 0- none, 1- Filling of side branch only, 2- Partial filling of the epicardial segment, 3- Complete filling of epicardial segment. Clinical variables, left ventricular function, $^{99m}Tc$-MIBI Heart SPECT were analyzed with angiographic finding. Results were following: 1) Collateral visualization was found to be greater in patient with involvement of right coronary artery (RCA). The collateral development site of infarct related artery was RCA 15 cases, left anterior descending artery (LAD) 10 cases, left circumflex artery (LCX) 5 cases, and the collateral circulation from LAD to RCA was 13 cases (40.6%). 2) There was a tendency to be decreased in peak CK activity with group I. 3) The presence of good collateral channels was more frequently $^{99m}Tc$-MIBI reversible perfusion defect (83.4% vs 15.3%, p<0.05). 4) No differences of left ventricular end diastolic volume (LVEDV), left ventricular end systolic volume (LVESV), ejection fraction (EF) were noted between group I and group II. The presence of good collateral channels did affect the frequency of occurrence of $^{99m}Tc$-MIBI reversible perfusion defect.

• The Korean Journal of Physiology and Pharmacology
• /
• v.21 no.5
• /
• pp.475-485
• /
• 2017

The present study aimed to explore the neuroprotective effect and possible mechanisms of rhGLP-1 (7-36) against transient ischemia/reperfusion injuries induced by middle cerebral artery occlusion (MCAO) in type 2 diabetic rats. First, diabetic rats were established by a combination of a high-fat diet and low-dose streptozotocin (STZ) (30 mg/kg, intraperitoneally). Second, they were subjected to MCAO for 2 h, then treated with rhGLP-1 (7-36) (10, 20, $40{\mu}g/kg$ i.p.) at the same time of reperfusion. In the following 3 days, they were injected with rhGLP-1 (7-36) at the same dose and route for three times each day. After 72 h, hypoglycemic effects were assessed by blood glucose changes, and neuroprotective effects were evaluated by neurological deficits, infarct volume and histomorphology. Mechanisms were investigated by detecting the distribution and expression of the nuclear factor erythroid-derived factor 2 related factor 2 (Nrf2) in ischemic brain tissue, the levels of phospho-PI3 kinase (PI3K)/PI3K ratio and heme-oxygenase-1 (HO-l), as well as the activities of superoxide dismutase (SOD) and the contents of malondialdehyde (MDA). Our results showed that rhGLP-1 (7-36) significantly reduced blood glucose and infarction volume, alleviated neurological deficits, enhanced the density of surviving neurons and vascular proliferation. The nuclear positive cells ratio and expression of Nrf2, the levels of P-PI3K/PI3K ratio and HO-l increased, the activities of SOD increased and the contents of MDA decreased. The current results indicated the protective effect of rhGLP-1 (7-36) in diabetic rats following MCAO/R that may be concerned with reducing blood glucose, up-regulating expression of Nrf2/HO-1 and increasing the activities of SOD.

• The Korea Journal of Herbology
• /
• v.23 no.2
• /
• pp.225-233
• /
• 2008

Objectives : The purpose of the present study was to development of neuroprotective antioxidant agents. For the purpose, we investigated the neuroprotective effect of anti oxidant herb, the root of Polygonum cuspidatum on transient focal cerebral ischemia in rats. Methods : The roots of Polygonum cuspidatum were extracted by 85% MeOH (PCE). Radical scavenging effects were investigated using DPPH assay and TBARs (Thiobarbituric acid reaction substance) assay in brian homogenates. Neuroprotective effect was investigated using transient focal cerebral ischemia rat model (2 h of ischemia, 22 h of reperfusion) by behavioral test and measurement of brain damage using 2, 3, 5-triphenyltetrazolium chloride staining. Results : PCE showed potent and dose dependent radical scavenging effects in DPPH and TBARs assay. Oral administration of PCE reduced brain infarct volume by 29.7% and improved the sensory motor functional deficit by 29% compared with vehicle treated group. Conclusions : PCE showed radical scavenging effects and neuroprotective effect on stroke rat model. Therefore, Polygonum cuspidatum could be a candidate for the development of neuroprotective-antioxidant agents.

• Journal of Korean Neurosurgical Society
• /
• v.61 no.2
• /
• pp.267-276
• /
• 2018

Objective : The beneficial effect of hypothermia after hemicraniectomy in malignant middle cerebral artery (MCA) infarction has been controversial. We aim to investigate the safety and clinical efficacy of hypothermia after hemicraniectomy in malignant MCA infarction. Methods : From October 2012 to February 2016, 20 patients underwent hypothermia (Blanketrol III, Cincinnati Sub-Zero, Cincinnati, OH, USA) at $34^{\circ}C$ after hemicraniectomy in malignant MCA infarction (hypothermia group). The indication of hypothermia included acute cerebral infarction >2/3 of MCA territory and a Glasgow coma scale (GCS) score <11 with a midline shift >10 mm or transtentorial herniation sign (a fixed and dilated pupil). We retrospectively collected 27 patients, as the control group, who had undergone hemicraniectomy alone and simultaneously met the inclusion criteria of hypothermia between January 2010 and September 2012, before hypothermia was implemented as a treatment strategy in Dong-A University Hospital. We compared the mortality rate between the two groups and investigated hypothermia-related complications, such as postoperative bleeding, pneumonia, sepsis and arrhythmia. Results : The age, preoperative infarct volume, GCS score, National institutes of Health Stroke Scale score, and degree of midline shift were not significantly different between the two groups. Of the 20 patients in the hypothermia group, 11 patients were induced with hypothermia immediately after hemicraniectomy and hypothermia was initiated in 9 patients after the decision of hypothermia during postoperative care. The duration of hypothermia was $4{\pm}2days$ (range, 1 to 7 days). The side effects of hypothermia included two patients with arrhythmia, one with sepsis, one with pneumonia, and one with hypotension. Three cases of hypothermia were discontinued due to these side effects (one sepsis, one hypotension, and one bradycardia). The mortality rate of the hypothermia group was 15.0% and that of the control group was 40.7% (p=0.056). On the basis of the logistic regression analysis, hypothermia was considered to contribute to the decrease in mortality rate (odds ratio, 6.21; 95% confidence interval, 1.04 to 37.05; p=0.045). Conclusion : This study suggests that hypothermia after hemicraniectomy is a viable option when the progression of patients with malignant MCA infarction indicate poor prognosis.

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