• Journal of Korean Neurosurgical Society
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• v.39 no.2
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• pp.130-135
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• 2006

Objective : After ischemic stroke, partial recovery of function frequently occurs and may depend on the plasticity of axonal connections. Here, we examine whether blockade of the Nogo/NogoReceptor[NgR] pathway might enhance axonal sprouting and thereby recovery after focal brain infarction. Methods : Adult male Sprague Dawley rats weighing $250{\sim}350g$ were used. Left middle cerebral artery occlusion[MCAO] was induced with a intraluminal filament. An osmotic mini pump [Alzet 2ML4, Alza Scientific Products, Palo Alto, CA] for the infusion of NgR-Ecto[310]-Fc to block Nogo/NgR pathway was implanted 1 week after cerebral ischemia. Prior to induction of ischemia, all animals received training in the staircase and rotarod test. Two weeks after biotin dextran amine injection, animals were perfused transcardially with PBS, followed by 4% paraformadehyde/PBS solution. Brain and cervical spinal cord were dissected. Eight coronal sections spaced at 1mm intervals throughout the forebrain of each animal with cresyl violet acetate for determination of infarction size. Images of each section were digitized and the infarct area per section was measured with image analysis software. Results : Histological examination at 11 weeks post-MCAO demonstrates reproducible stroke lesions and no significant difference in the size of the stroke between the NgR[310]Ecto-Fc protein treated group and the control group. Behavioral recovery is significantly better and more rapid in the NgR-Ecto[310]-Fe treated group. Blockade of NgR enhances axonal sprouting from the uninjured cerebral cortex and improves the return of motor task performance. Conclusion : Pharmacological interruption of NgR allows a greater degree of axonal plasticity in response this is associated with improved functional recovery of complicated motor tasks.

• Biomolecules & Therapeutics
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• v.23 no.6
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• pp.531-538
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• 2015

Preceding infection or inflammation such as bacterial meningitis has been associated with poor outcomes after stroke. Previously, we reported that intracorpus callosum microinjection of lipopolysaccharides (LPS) strongly accelerated the ischemia/reperfusionevoked brain tissue damage via recruiting inflammatory cells into the ischemic lesion. Simvastatin, 3-hydroxy-3-methylgultaryl (HMG)-CoA reductase inhibitor, has been shown to reduce inflammatory responses in vascular diseases. Thus, we investigated whether simvastatin could reduce the LPS-accelerated ischemic injury. Simvastatin (20 mg/kg) was orally administered to rats prior to cerebral ischemic insults (4 times at 72, 48, 25, and 1-h pre-ischemia). LPS was microinjected into rat corpus callosum 1 day before the ischemic injury. Treatment of simvastatin reduced the LPS-accelerated infarct size by 73%, and decreased the ischemia/reperfusion-induced expressions of pro-inflammatory mediators such as iNOS, COX-2 and IL-$1{\beta}$ in LPS-injected rat brains. However, simvastatin did not reduce the infiltration of microglial/macrophageal cells into the LPS-pretreated brain lesion. In vitro migration assay also showed that simvastatin did not inhibit the monocyte chemoattractant protein-1-evoked migration of microglial/macrophageal cells. Instead, simvastatin inhibited the nuclear translocation of NF-${\kappa}B$, a key signaling event in expressions of various proinflammatory mediators, by decreasing the degradation of $I{\kappa}B$. The present results indicate that simvastatin may be beneficial particularly to the accelerated cerebral ischemic injury under inflammatory or infectious conditions.

• The Korean Journal of Physiology and Pharmacology
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• v.13 no.3
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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.

• Preventive Nutrition and Food Science
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• v.16 no.3
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• pp.217-223
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• 2011

Ischemic stroke constitutes about 80% of all stroke incidences. It is characterized by brain cell death in a region where cerebral arteries supplying blood are occluded. Under these ischemic conditions, apoptosis is responsible for the cell death, at least in part. Goat's-beard (Aruncus dioicus var. kamtschaticus) is a perennial plant that grows naturally in the alpine regions of Korea. In the present study, we first determined whether water extract of goat's-beard (HY1646) and some of its fractions prepared by partitioning with organic solvents could improve the viability of human hepatocellular carcinoma cells (HepG2) cultured under hypoxic condition by blocking apoptotic pathways. Based on the in vitro findings, we subsequently investigated whether HY1646 and the ethyl acetate fraction (EA) selected from cell culture-based screening could attenuate brain injury in a rat middle cerebral artery occlusion (MCAO) model of ischemia (2 hr), followed by 22 hours of reperfusion. The cell number was sustained close to that initially plated in the presence of HY1646 even after 24 hr of cell culture under hypoxic condition (3% $O_2$), at which time the cell number reached almost zero in the absence of HY1646. This improvement in cell viability was attributed to the delay in apoptosis, identified by the formation of DNA ladder in gel electrophoresis. Of fractions soluble in hexane, ethyl acetate (EA) and butanol, EA was chosen for the animal experiments because EA demonstrated the best cell viability at the lowest concentration (10 ${\mu}g$/mL). HY1646 (200 mg/kg) and EA (10 and 20 mg/kg) significantly reduced infarct size, an index of brain injury, by 16.6, 40.0 and 61.0%, respectively, as assessed by 2,3,5-triphenyl tetrazolium chloride staining. The findings suggest that prophylactic intake of goat's beard might be beneficial for preventing ischemic stroke.

• Preventive Nutrition and Food Science
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• v.15 no.4
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• pp.255-261
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• 2010

Ischemic stroke, a major cause of death and disability worldwide, is caused by occlusion of cerebral arteries that, coupled with or without reperfusion, results in prolonged ischemia (hypoxia and hypoglycemia) and, ultimately, brain damage. In this study, we examined whether methanol extract of the whole plant of Cassia mimosoides var. nomame Makino that grows naturally in Korea, as well as Japan and China, and some of its fractions obtained by partitioning with organic solvents could protect human hepatocellular carcinoma cells (HepG2) under hypoxic condition by inhibiting apoptosis. We also investigated if these extracts could attenuate brain damage in a rat model of 2 hr of ischemia, generated by middle cerebral artery occlusion, and 22 hr of reperfusion. The whole extract ($100{\mu}g$/mL) maintained the cell number at more than half of that initially plated, even after 24 hr of cell culture under hypoxic condition (3% $O_2$). In the absence of the whole extract, almost all of the cells were dead by this time point. This improvement of cell viability came from a delay of apoptosis, which was confirmed by observing the timing of the formation of a DNA ladder when assessed by gel electrophoresis. Of fractions soluble in hexane, ethyl acetate (EA), butanol and water, EA extracts were selected for the animal experiments, as they improved cell viability at the lowest concentration ($10{\mu}g$/mL). The whole extract (200 mg/kg) and EA extract (10 and 20 mg/kg) significantly reduced infarct size, a measure of brain damage, by 34.7, 33.8 and 45.2.0%, respectively, when assessed by 2,3,5-triphenyl tetrazolium chloride staining. The results suggest that intake of Cassia mimosoides var. nomame Makino might be beneficial for preventing ischemic stroke through inhibition of brain cell apoptosis.

• 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.

• The Journal of Korean Medicine
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• v.26 no.2 s.62
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• pp.217-230
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• 2005

Objectives: Chungpaesagan-tang (CPSGT), which is frequently used for treating patients of cerebrovascular disease, has not been reported by clinical doctors concerning the effect of neuronal aptosis caused by brain ischemia. To study the effect of CPSGT on focal cerebral ischemia in normal and diabetic rats and SHR, focal cerebral ischemia was induced by transient MCAO, and after onset CPSGT was administrated. Methods: Rats (Sprague-Dawley) were divided into four groups: sham-operated group, MCA-occluded group, CPSGT­administrated group after MCA occlusion, and normal group. The MCA was occluded by intraluminal method. CPSGT was administrated orally twice (l and 4 hours) after middle cerebral artery occlusion. All groups were sacrificed at 24 hours after the surgery. The brain tissue Was stained with $2\%$ triphenyl tetrazolium chloride (TTC) or $1\%$ cresyl violet solution, to examine effect of CPSGT on ischemic brain tissue. The blood samples were obtained from the heart.~. Tumor necrosis $factor-\alpha$ level and interleukin-6 level of serum was measured from sera using enzyme-linked immunoabsorbent assay (ELISA). Then changes of immunohistochemical expression of $TNF-\alpha$ in ischemic damaged areas were observed. Results: In NC+MCAO+CP and DM+MCAO+CP, CPSGT significantly (p<0.01) decreased the number of neuron cells compared to the control group. CPSGT markedly reduced (p<0.01) the infarct size of the forebrain in distance from the interaural line on cerebral ischemia in diabetic rats. CPSGT significantly reduced the $TNF-\alpha$ expression in penumbra region of damaged hemisphere in diabetic rats. Conclusions: CPSGT had a protective effect on cerebral ischemia in SD rats, especially in diabetic rats compared with normal SD rats.

• 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 Ginseng Research
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• v.40 no.2
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• pp.196-202
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• 2016

Background: Ginsenoside Rd (GSRd), a main component of the root of Panax ginseng, exhibits anti-inflammation functions and decreases infarct size in many injuries and ischemia diseases such as focal cerebral ischemia. M1 Macrophages are regarded as one of the key inflammatory cells having functions for disease progression. Methods: To investigate the effect of GSRd on renal ischemia/reperfusion injury (IRI) and macrophage functional status, and their regulatory role on mouse polarized macrophages in vitro, GSRd (10-100 mg/kg) and vehicle were applied to mice 30 min before renal IRI modeling. Renal functions were reflected by blood serum creatinine and blood urea nitrogen level and histopathological examination. M1 polarized macrophages infiltration was identified by flow cytometry analysis and immunofluorescence staining with $CD11b^+$, $iNOS^+$/interleukin-12/tumor necrosis factor-${\alpha}$ labeling. For the in vitro study, GSRd ($10-100{\mu}g/mL$) and vehicle were added in the culture medium of M1 macrophages to assess their regulatory function on polarization phenotype. Results: In vivo data showed a protective role of GSRd at 50 mg/kg on Day 3. Serum level of serum creatinine and blood urea nitrogen significantly dropped compared with other groups. Reduced renal tissue damage and M1 macrophage infiltration showed on hematoxylin-eosin staining and flow cytometry and immunofluorescence staining confirmed this improvement. With GSRd administration, in vitro cultured M1 macrophages secreted less inflammatory cytokines such as interleukin-12 and tumor necrosis factor-${\alpha}$. Furthermore, macrophage polarization-related pancake-like morphology gradually changed along with increasing concentration of GSRd in the medium. Conclusion: These findings demonstrate that GSRd possess a protective function against renal ischemia/reperfusion injury via downregulating M1 macrophage polarization.