• The Journal of Korean Medicine
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• v.20 no.4
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• pp.82-92
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• 2000

The purpose of the present study was to explore the proper method for animal stroke model of Oriental medicine To this end, brain ischemia was induced by distal middle cerebral artery occlusion(dMCAO) and proximal middle cerebral artery occlusion(pMCAO) and evaluated with the method of Triphenyl Tetrazolium Chloride (TTC) staining and Swimming Behavior Test. Results demonstrated that first, infarct size and volume of pMCAO group were significantly bigger that those of dMCAO group. Second, analysis of swimming behavior test revealed that the percentage of left turning angles of pMCAO was significantly bigger than that of dMCAO. Third, during swimming behavior test, there were peculiar traces of small successive circles that represent motor dysfunction and conscious disturbance among dMCAO group. The results of the study thus indicate that non-invasive intraluminal method of pMCAO was the appropriate animal stroke model for Oriental medicine in the light of brain ischemia as hemiplesia and conscious disturbance.

• Journal of Acupuncture Research
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• v.36 no.4
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• pp.220-229
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• 2019

Background: The therapeutic potential of Bee Venom Pharmacopuncture (BVP) on acute ischemic cerebral infraction was determined in mice in vivo and in vitro. Methods: Analysis of acute ischemic cerebral infraction was performed using 7 week old male ICR mice (n = 20) and microglial BV-2 cells. Bee venom ($5{\mu}g/kg$) was injected into the caudal vein of middle cerebral artery occlusion (MCAo) mice (1 hour after reperfusion, 3 hours after MCAo probe insertion), and also used to treat LPS-stimulated microglial BV-2 cells (1, 2, $5{\mu}g/mL$). Markers of inflammation were monitored. Results: NO declined statistically significantly in BVP treated MCAo mice compared to the untreated MCAo group (p < 0.05). Compared to the MCAo group, the BVP-treated MCAo group showed a decreased production volume of malondialdehyde, but an increased glutathione/oxidized glutathione ratio. Compared to the untreated MCAo group, the BVP treated MCAo group showed a statistically significant decline in TNF and $IL-1{\beta}$ levels (p < 0.05). BVP inhibited the levels of p65, p50, $p-I{\kappa}B-{\alpha}$, and levels of p-ERK1/2, p-JNK2, p-P38 declined. Conclusion: BVP is effective at dampening the inflammatory response in vivo and in vitro and may supplement rt-PA treatment.

• Journal of Oriental Neuropsychiatry
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• v.26 no.3
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• pp.319-336
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• 2015

Objectives: The object of this study was to evaluate the cognition and motor function recovery effects of Sungshim-san (SSS), a traditional Korean cardio-protective polyherbal formula in the severe rat stroke, permanent middle cerebral artery occlusion (pMCAO) model. Methods: The experimental animals were divided into 6 groups. SSS aqueous extracts (yield=16.82%; 400, 200 and 100 mg/kg) were administered orally by using Sonde, once daily, for 28 continuous days from 24 hrs post-pMCAO. Donepezil 10 mg/kg, a representative drug for dementia, was used as a reference drug. The body weight changes, infarct/defect sizes, sensorimotor function and cognitive motor behavior were serially monitored. Limb placing and body-swing test for sensorimotor functions were conducted at 1 day before operation (base line), and 1, 3, 7, 14, 21 and 28 days post-pMCAO; and water maze test for the cognitive motor behavior was conducted at 14 and 28 days post-pMCAO, respectively. Results: Focal cerebral cortex infarct and defects due to pMCAO resulted in marked decreases of body weight, disorders of sensorimotor functions and cognitive motor behaviors. However, the pMCAO-related ischemic damages were markedly and dose-dependently inhibited by treatment with SSS 400 and 200 mg/kg, respectively. Donepezil markedly decreased the body weight and gains, as compared with pMCAO control rats; however, SSS 400 and 200 mg/kg favorably ameliorated the pMCAO-induced decreases in body weight and gains. SSS 100 mg/kg treated rats did not show any favorable effects on the pMCAO-related ischemic damages, as compared with pMCAO control rats. Conclusions: The results of the study indicated that oral administration of SSS 400 and 200 mg/kg accelerated cognition and motor function recovery in the rat pMCAO model. The treatment effect was potentially mediated by neuroprotection via the known augmentation of cerebral antioxidant defense system of SSS itself or its individual herbal components. Especially, the overall effects of SSS 200 mg/kg were similar to those of donepezil 10 mg/kg, but less toxic.

• The Korean Journal of Physiology and Pharmacology
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• v.14 no.6
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• pp.435-440
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• 2010

Valproic acid (VPA) is a well-known anti-epileptic and mood stabilizing drug. A growing number of reports demonstrate that VPA is neuroprotective against various insults. Despite intensive efforts to develop new therapeutics for stroke over the past two decades, all treatments have thus far failed to show clinical effect because of treatment-limiting side effects of the drugs. Therefore, a safety-validated drug like VPA would be an attractive candidate if it has neuroprotective effects against ischemic insults. The present study was undertaken to examine whether pre- and post-insult treatments with VPA protect against brain infarct and neurological deficits in mouse transient (tMCAO) and permanent middle cerebral artery occlusion (pMCAO) models. In the tMCAO (2 hr MCAO and 22 hr reperfusion) model, intraperitoneal injection of VPA (300 mg/kg, Lp.) 30 min prior to MCAO significantly reduced the infarct size and the neurological deficit. VPA treatment immediately after reperfusion significantly reduced the infarct size. The administration of VPA at 4 hr after reperfusion failed to reduce the infarct size and the neurological deficit. In the pM CAO model, treatment with VPA (300 mg/kg, i.p.) 30 min prior to MCAO significantly attenuated the infarct size, but did not affect the neurological deficit. Western blot analysis of acetylated H3 and H4 protein levels in extracts from the ischemic cortical area showed that treatment with VPA increased the expression of acetylated H3 and H4 at 2 hrs after MCAO. These results demonstrated that treatment with VPA prior to ischemia attenuated ischemic brain damage in both mice tMCAO and pMCAO models and treatment with VPA immediately after reperfusion reduced the infarct area in the tMCAO model. VPA could therefore be evaluated for clinical use in stroke patients.

• The Korean Journal of Physiology and Pharmacology
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• v.14 no.3
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• pp.151-156
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• 2010

This study was performed to investigate the role of glutamate neurotransmitter system on gastrointestinal motility in a middle cerebral artery occlusion (MCAO) model of rats. The right middle cerebral artery was occluded by surgical operation, and intestinal transit and geometric center as a parameter of gastrointestinal motility and expression of c-Fos protein in the insular cortex and cingulate cortex were measured at 2 and 12 h after MCAO. Intestinal transit was $66.3{\pm}7.5%$ and $62.3{\pm}5.7%$ 2 and 12 h after sham operation, respectively, and MCAO significantly decreased intestinal transit to $39.0{\pm}3.5%$ and $47.0{\pm}5.1%$ at 2 and 12 h after the occlusion, respectively (p<0.01). The geometric center was $5.6{\pm}0.4$ and $5.2{\pm}0.9$ at 2 and 12 h after sham operation, respectively, and MCAO significantly decreased geometric center to $2.9{\pm}0.8$ and $3.0{\pm}0.3$ at 2 and 12 h after the occlusion, respectively (p<0.01). In control animals, injection of atropine decreased intestinal transit to $35.9{\pm}5.2%$, and injection of glutamate NMDA receptor antagonist, MK-801, decreased intestinal transit to $28.8{\pm}9.5%$. Pretreatment with MK-801, a glutamate NMDA receptor antagonist, in the MCAO group decreased intestinal transit to $11.8{\pm}3.2%$, which was significantly decreased compared to MCAO group (p<0.01). MCAO markedly increased the expression of c-Fos protein in the insular cortex and cingulate cortex ipsilateral to the occlusion 2 h after MCAO, and pretreatment with MK-801 produced marked reduction of c-Fos protein expression compared to MCAO group (p<0.01). These results suggest that modulation of gastrointestinal motility after MCAO might be partially mediated through a glutamate NMDA receptor system.

• Journal of agriculture & life science
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• v.50 no.3
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• pp.129-139
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• 2016

Curcumin plays a protective role in brain injury through its anti-oxidant and anti-inflammatory activities. Moreover, peroxiredoxin-5 exerts a protective effect against oxidative stress. The aim of this study was to investigate whether curcumin modulated the peroxiredoxin-5 expression in focal cerebral ischemic animal model. Middle cerebral artery occlusion(MCAO) was performed to induce cerebral ischemic injury in rats. Adult male rats were injected intraperitoneally with vehicle or curcumin(50mg/kg B.W.) 1 h after MCAO and cerebral cortex tissues were collected 24 h after MCAO. Photographs of hematoxylin and eosin staining showed that MCAO induced necrotic changes with scalloped shrunken form and apoptotic changes with nuclear chromatin condensations. However, curcumin treatment attenuated MCAO-induced histopathological changes. Moreover, this study clearly showed that peroxiredoxin-5 expression was decreased in MCAO operated animal with vehicle using a proteomics approach. However, this decrease in peroxiredoxin-5 expression was attenuated by curcumin treatment. Reverse-transcription PCR and Western blot analyses confirmed that curcumin treatment alleviated the MCAO injury-induced decrease in peroxiredoxin-5 expression(p<0.05). These results demonstrated that curcumin regulates peroxiredoxin-5 expression in MCAO animal model. In conclusion, our findings suggest that curcumin exerts a neuroprotective effect in cerebral ischemia by attenuating the MCAO-induced decrease in peroxiredoxin-5 expression.

• Korean Journal of Oriental Medicine
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• v.13 no.1 s.19
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• pp.153-160
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• 2007

In the post-genome era, analysis of the cellular transcriptome using microarray or the cellular proteome using a 2-D gel electrophoresis and MALDI-TOF mass spectrometry are most widely used. Stroke is one of the most important causes of death along with cancer and cardiac disease. When pathological change of cells in developed from cerebral ischemia accompanied by stroke administration of neuroprotective drugs before stroke can decreases the degeneration of neuronal cells. The purpose of the present study was to assess the neuroprotective effect and protein expression after administration of P004, middle cerebral artery model of cerebral ischemia in rats. SD rats were subjected to middle cerebral artery occlusion. P004 (1,000 mg/kg) was administered 2 times at 0, 90 minutes after middle cerebral artery occlusion (MCAo). Rats were killed at 48 hours, and infarct area and volume were determined by histology and computerized image analysis. We investigated the protein expression profile on the global ischemia induced by MCAo. This proteomic analysis enable us to identify several proteins differently expressed in infarct brain tissue. The aims of this study were to do investigation comparing the neuroprotection activities of P004 and to understand the mechanism of acted as neuroprotective drug.

• Journal of Korean Academy of Nursing
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• v.41 no.2
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• pp.197-203
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• 2011

Purpose: This study was done to identify whether pre-conditioning exercise has neuroprotective effects against cerebral ischemia, through enhance brain microvascular integrity. Methods: Adult male Sprague-Dawley rats were randomly divided into four groups: 1) Normal (n=10); 2) Exercise (n=10); 3) Middle cerebral artery occlusion (MCAo), n=10); 4) Exercise+MCAo (n= 10). Both exercise groups ran on a treadmill at a speed of 15 m/min, 30 min/day for 4 weeks, then, MCAo was performed for 90 min. Brain infarction was measured by Nissl staining. Examination of the remaining neuronal cell after MCAo, and microvascular protein expression on the motor cortex, showed the expression of Neuronal Nuclei (NeuN), Vascular endothelial growth factor (VEGF) & laminin. Results: After 48 hr of MCAo, the infarct volume was significantly reduced in the Ex+MCAo group ($15.6{\pm}2.7%$) compared to the MCAo group ($44.9{\pm}3.8%$) (p<.05), and many neuronal cells were detected in the Ex+ MCAo group ($70.8{\pm}3.9%$) compared to the MCAo group ($43.4{\pm}5.1%$) (p<.05). The immunoreactivity of laminin, as a marker of microvessels and Vascular endothelial growth factor (VEGF) were intensively increased in the Ex+MCAo group compared to the MCAo group. Conclusion: These findings suggest that the neuroprotective effects of exercise pre-conditioning reduce ischemic brain injury through strengthening the microvascular integrity after cerebral ischemia.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1998.11a
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• pp.143-143
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• 1998

Antagonists acting at the glycine site of the NMDA receptor have been gaining safer alternatives for stroke therapy because they have few adverse effect competitive and noncompetitive NMDA antagonists. Therefore, the neuroprotect novel glycine site antagonist KC0244 were evaluated in a rat model of transient comparison with GV150526A in a developmental phase. Middle cerebral artery oc was produced by insertion of a silicone-coated 4-0 nylon monofilament to the o in male Sprague-Dawley rats under isoflurane anesthesia. After 90 or 120 min retracted and the ischemic tissue reperfused. In 90-min MCAO model, GV150526A was administered 30 min before MCAO or immediately after MCAO. In 120-min MC KC0244 or GV150526A (10 mg/kg, i.p.) was administered 1 hr before MCAO or imme MCAO. Infarct volume was measured 24 hr after MCAO using the 2,3,5-triphe chloride staining method. In 90-min MCAO model, treatments with GV1505 significantly reduce infarct volume although they tended to slightly reduce cor approximately 19% compared with the nontreated group. In 120-min MCAO model with GV150526A did not either significantly reduce infarct volume although the reduce total infarct volume by approximately 16% compared with the vehicle-tre However, 1-hr preischemic and immediate treatments with KC0244 reduced total i 39 and 30% (corrected total infarct volume by 44 and 32%), respectively, co vehicle-treated control group. The results suggest that KC0244 can provid against transient focal ischemic damage with greater in vivo potency than GV150

• Biomolecules & Therapeutics
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• v.28 no.2
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• pp.152-162
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• 2020

Cerebral ischemia exhibits a multiplicity of pathophysiological mechanisms. During ischemic stroke, the reactive oxygen species (ROS) concentration rises to a peak during reperfusion, possibly underlying neuronal death. Recombinant human erythropoietin (EPO) supplementation is one method of treating neurodegenerative disease by reducing the generation of ROS. We investigated the therapeutic effect of PEGylated EPO (P-EPO) on ischemic stroke. Mice were administered P-EPO (5,000 U/kg) via intravenous injection, and middle cerebral artery occlusion (MCAO) followed by reperfusion was performed to induce in vivo ischemic stroke. P-EPO ameliorated MCAO-induced neurological deficit and reduced behavioral disorder and the infarct area. Moreover, lipid peroxidation, expression of inflammatory proteins (cyclooxygenase-2 and inducible nitric oxide synthase), and cytokine levels in blood were reduced by the P-EPO treatment. In addition, higher activation of nuclear factor kappa B (NF-κB) was found in the brain after MCAO, but NF-κB activation was reduced in the P-EPO-injected group. Treatment with the NF-κB inhibitor PS-1145 (5 mg/kg) abolished the P-EPO-induced reduction of infarct volume, neuronal death, neuroinflammation, and oxidative stress. Moreover, P-EPO was more effective than EPO (5,000 U/kg) and similar to a tissue plasminogen activator (10 mg/kg). An in vitro study revealed that P-EPO (25, 50, and 100 U/mL) treatment protected against rotenone (100 nM)-induced neuronal loss, neuroinflammation, oxidative stress, and NF-κB activity. These results indicate that the administration of P-EPO exerted neuroprotective effects on cerebral ischemia damage through anti-oxidant and anti-inflammatory properties by inhibiting NF-κB activation.