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1.
Braz. j. med. biol. res ; 55: e12145, 2022. graf
Article in English | LILACS-Express | LILACS | ID: biblio-1384152

ABSTRACT

Dexmedetomidine (DEX) is known to provide neuroprotection against cerebral ischemia and reperfusion injury (CIRI), but the exact mechanisms remain unclear. This study was conducted to investigate whether DEX pretreatment conferred neuroprotection against CIRI by inhibiting neuroinflammation through the JAK2/STAT3 signaling pathway. Middle cerebral artery occlusion (MCAO) was performed to establish a cerebral ischemia/reperfusion (I/R) model. Specific-pathogen-free male Sprague-Dawley rats were randomly divided into Sham, I/R, DEX, DEX+IL-6, and AG490 (a selective inhibitor of JAK2) groups. The Longa score, TTC staining, and HE staining were used to evaluate brain damage. ELISA was used to exam levels of TNF-α. Western blotting was used to assess the levels of JAK2, phosphorylated-JAK2 (p-JAK2), STAT3, and phosphorylated-STAT3 (p-STAT3). Our results suggested that both pretreatment with DEX and AG490 decreased the Longa score and cerebral infarct areas following cerebral I/R. After treatment with IL-6, the effects of DEX on abrogating these pathological changes were reduced. HE staining revealed that I/R-induced neuronal pathological changes were attenuated by DEX application, consistent with the AG490 group. However, these effects of DEX were abolished by IL-6. Furthermore, TNF-α levels were significantly increased in the I/R group, accompanied by an increase in the levels of the p-JAK2 and p-STAT3. DEX and AG490 pretreatment down-regulated the expressions of TNF-α, p-JAK2, and p-STAT3. In contrast, the down-regulation of TNF-α, p-JAK2, and p-STAT3 induced by DEX was reversed by IL-6. Collectively, our results indicated that DEX pretreatment conferred neuroprotection against CIRI by inhibiting neuroinflammation via negatively regulating the JAK2/STAT3 signaling pathway.

2.
Article in Chinese | WPRIM | ID: wpr-940750

ABSTRACT

Cerebral ischemia-reperfusion injury (CIRI) is a further injury of brain tissue after the recovery of blood supply in ischemic stroke, which seriously affects the quality of life of patients. The pathological mechanism of CIRI is complex, mainly involving excitatory amino acid toxicity, apoptosis, inflammation, and oxidative stress. Studies have proved that Chinese herbal medicines and their active components have unique advantages and good application prospects in the prevention and treatment of CIRI. Quercetin is a flavonoid ubiquitous in a variety of Chinese medicinal herbs. It can alleviate CIRI and reduce brain injury through inhibiting inflammation, oxidation, and apoptosis, protecting blood-brain barrier, and activating mitophagy. However, little is known about the specific mechanism and molecular targets. In view of the low bioavailability and poor solubility of quercetin, researchers have developed a variety of delivery systems to facilitate the dispersion of quercetin, improve chemical stability, and increase clinical application. Furthermore, researchers have tested the long-term safety of quercetin and confirmed that low-dose quercetin has good safety. By reviewing the relevant studies in recent years, we summarized the targets, mechanism, delivery, and safety of quercetin in the treatment of CIRI, aiming to provide a theoretical basis for the further development and application of quercetin.

3.
Article in Chinese | WPRIM | ID: wpr-940581

ABSTRACT

ObjectiveTo observe the protective effect of Sanhuatang and its modifications on the brain tissue of rats exposed to cerebral ischemia-reperfusion injury (CIRI) and explore its action mechanism and compatibility characteristics. MethodOne hundred and forty SD male rats of clean grade were randomly divided into the control group, sham-operation group, and operation group. The Longa suture method was employed to establish the CIRI model. The successfully modeled CIRI rats were further divided into five groups, namely the model group, nimodipine group, Sanhuatang without Notopterygii Rhizoma et Radix group, Notopterygii Rhizoma et Radix group, and Sanhuatang group, and treated with the corresponding medicines by gavage for five days. The cerebral infarct size in each group was examined by 2,3,5-triphenyltetrazolium chloride (TTC) staining, and the pathological changes in the brain tissue were observed by hematoxylin-eosin (HE) staining and electron microscopy. The mRNA and protein expression levels of Claudin-5, Occludin, and zonula occludens-1 (ZO-1) in brain tissues were detected by real-time fluorescence quantitative polymerase chain reaction (Real-time PCR) and Western blot, respectively. ResultCompared with the control group, the model group exhibited markedly increased infarct size, obvious changes in brain morphology and ultrastructure, and down-regulated mRNA and protein expression of Claudin-5, Occludin, and ZO-1 (P<0.01). Compared with the model group, both nimodipine and Sanhuatang significantly decreased the infarct size (P<0.01) and relived the pathological changes. The infarct sizes in the Sanhuatang without Notopterygii Rhizoma et Radix group and Notopterygii Rhizoma et Radix group were reduced without exhibiting a statistically significant difference. The mRNA and protein expression levels of Claudin-5, Occludin, and ZO-1 in the nimodipine group, Sanhuatang group, and Notopterygii Rhizoma et Radix group were up-regulated significantly in comparison with those in the model group (P<0.01, P<0.01). The mRNA and protein expression levels of Claudin-5 and ZO-1 were higher in the Notopterygii Rhizoma et Radix group than in the Sanhuatang without Notopterygii Rhizoma et Radix group (P<0.01, P<0.01). ConclusionSanhuatang exerts the protective effect against CIRI in rats possibly by regulating the expression of Claudin-5, Occludin, and ZO-1 and improving the blood-brain barrier function. Notopterygii Rhizoma et Radix in Sanhuatang may play an important role in the protection of rats from CIRI.

4.
Article in Chinese | WPRIM | ID: wpr-940296

ABSTRACT

ObjectiveTo study the effect of Huazhuo Jiedu Huoxue Tongluo (HJHT) prescription on the intestinal flora in rats with cerebral ischemia-reperfusion injury, and to explore the mechanism of Chinese medicinal prescription regulating intestinal flora to restore the balance of brain-gut axis. MethodFifty male SPF SD rats were randomly assigned into sham group, model group, high-dose HJHT group (25.0 g·kg-1), medium-dose HJHT group (12.5 g·kg-1), and low-dose HJHT group (6.25 g·kg-1), with 10 rats in each group. The rat model of permanent middle cerebral artery infarction was established according to Longa method and previous research experience, and reperfusion was performed 2 h after ischemia. The recovery of neurological function deficit and the percentage of cerebral infarction area were detected 72 h after administration. Real-time PCR was performed to detect the mRNA levels of Occludin and zonula occludens-1 (ZO-1) in rat colon. Hematoxylin-eosin (HE) staining was conducted to reveal the intestinal damage. The feces of 6 rats in each group were collected for 16S rRNA sequencing. The expression of Treg and Th17 in intestinal tissue, peripheral blood, and brain tissue were detected. ResultCompared with the sham group, the model group showed obvious neurological deficit (P<0.05) and large cerebral infarction area (P<0.05). High-dose and medium-doses HJHT alleviated the symptoms of neurological impairment (P<0.05) and reduce the cerebral infarction area (P<0.05) compared with the model group. Compared with the sham group, the model group showed destroyed structure of colonic mucosa and incomplete epithelial cells and goblet cells, while high-dose and medium-doses HJHT alleviated such changes. The mRNA levels of Occludin and ZO-1 in the model group were lower than those in the sham group (P<0.05),and the high-dose HJHT groups were higher than the model group (P<0.05). The intestinal flora structure was significantly different between the model group and the sham group while similar between the high-dose HJHT group and sham group. Compared with the sham group, the model group showed down-regulated expression of Treg and up-regulated expression of Th17 in the intestinal tissue, peripheral blood, and brain tissue, and high-dose and medium-dose HJHT alleviated the changes in the expression of Treg and Th17 in the model group (P<0.05). ConclusionHuazhuo Jiedu Huoxue Tongluo prescription may improve the permeability of intestinal wall by adjusting the abundance and diversity of intestinal microorganisms to reduce the migration of intestinal Th17 cells toward the ischemic lateral brain tissue, mitigate the inflammatory response, and thus alleviate the cerebral ischemia-reperfusion injury in rats.

5.
Chinese Critical Care Medicine ; (12): 325-328, 2022.
Article in Chinese | WPRIM | ID: wpr-931874

ABSTRACT

Cerebral ischemia/reperfusion (I/R) injury refers to an aggravated brain tissue damage caused by the restoration of blood supply after acute ischemia for a period of time. Its pathogenesis is complex, including oxidative stress, inflammatory response, and excitatory amino acid toxicity. The effective clinical treatments of cerebral I/R injury after ischemic stroke (IS) are limited. Nuclear factor E 2-related factor 2 (Nrf2), the most critical antioxidant transcription factor in cells, can coordinate multiple cytoprotective factors to inhibit oxidative stress. Since Nrf2 signaling pathway is considered to be one of the most important cellular defense mechanisms against oxidative stress, targeting Nrf2 intervention has become an attractive therapeutic strategy in the prevention and treatment of cerebral I/R injury. This review focuses on the structure, regulation and function of Nrf2 signaling pathway, as well as its activation and potential therapeutic targets in cerebral I/R injury. The important role and future potential of Nrf2 pathway in the pathogenesis of cerebral I/R injury were discussed.

6.
Acta Pharmaceutica Sinica B ; (6): 2330-2347, 2022.
Article in English | WPRIM | ID: wpr-929377

ABSTRACT

Ischemic brain stroke is pathologically characterized by tissue acidosis, sustained calcium entry and progressive cell death. Previous studies focusing on antagonizing N-methyl-d-aspartate (NMDA) receptors have failed to translate any clinical benefits, suggesting a non-NMDA mechanism involved in the sustained injury after stroke. Here, we report that inhibition of intracellular proton-sensitive Ca2+-permeable transient receptor potential vanilloid 3 (TRPV3) channel protects against cerebral ischemia/reperfusion (I/R) injury. TRPV3 expression is upregulated in mice subjected to cerebral I/R injury. Silencing of TRPV3 reduces intrinsic neuronal excitability, excitatory synaptic transmissions, and also attenuates cerebral I/R injury in mouse model of transient middle cerebral artery occlusion (tMCAO). Conversely, overexpressing or re-expressing TRPV3 increases neuronal excitability, excitatory synaptic transmissions and aggravates cerebral I/R injury. Furthermore, specific inhibition of TRPV3 by natural forsythoside B decreases neural excitability and attenuates cerebral I/R injury. Taken together, our findings for the first time reveal a causative role of neuronal TRPV3 channel in progressive cell death after stroke, and blocking overactive TRPV3 channel may provide therapeutic potential for ischemic brain injury.

7.
Article in Chinese | WPRIM | ID: wpr-927892

ABSTRACT

Objective: To investigate the effects of Zhongfeng capsule on the autophagy-related proteins expression in rats with cerebral ischemia/reperfusion injury (CI/ RI), and to explore its neural protection mechanisms of the decoction. Methods: Rat middle cerebral artery ischemia/reperfusion injury model (ischemia for 2 h, reperfusion for 24 h) was prepared by the improved line plug method. Sixty male SD rats were randomly divided into sham operation group, model group, butylphthalide group(0.054 g/kg), Zhongfeng capsule high-dose groups (1.08 g/kg), Zhongfeng capsule middle-dose groups (0.54 g/kg), Zhongfeng capsule low-dose groups (0.27 g/kg), with 10 rats in each group. Rats were treated with Zhongfeng capsule by gavage once a day for 10 days. The rats were sacrificed and the brain tissue was obtained after the experiment in each group. Score neurological deficit was evaluated after 24 h of the last intervention in rat of each group. The pathological changes of brain tissue were observed by HE staining. The serum levels of estradiol (E2) and follicle stimulating hormone (FSH) were determined by ELISA. The expressions of key genes and proteins of PI3K/Akt/Beclin1 signaling pathway in brain tissue were detected by qRT-PCR and Western blot respectively. Results: Compared with the sham operation group, the body weight and protein expressions of p-PI3k and p-Akt in brain tissue of rats were decreased significantly in the model group, while the brain index, neurological deficit score, gene and protein expressions of Beclin1 and LC3 were increased markedly in the model group(P<0.05 or P<0.01). In the model group, nerve cells of brain tissue were loosely packed, interstitial edema, triangular in shape, nuclear pyknosis and dark-blue staining were observed. Compared with the model group, the body weight of rats was increased obviously, the neurological deficit score was decreased significantly and the pathological injury of brain tissue was alleviated evidently in high-dose of Zhongfeng capsule group (P<0.05). The brain index, the gene and protein expressions of Beclin1 and LC3 were decreased apparently in Zhongfeng capsule treatment groups(P<0.05 or P<0.01), while the expressions of p-PI3k and p-Akt in brain tissue were increased evidently in Zhongfeng capsule treatment groups(P<0.05 or P<0.01). Conclusion: Zhongfeng capsule can inhibit autophagy and improve brain neurons lesion of CIRI rats, the mechanism may be related to regulate the expression of Beclin1 and LC3 in PI3K/Akt/Beclin1 signaling pathway.


Subject(s)
Animals , Autophagy-Related Proteins/pharmacology , Beclin-1/metabolism , Body Weight , Brain , Brain Ischemia/metabolism , Male , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Rats , Rats, Sprague-Dawley , Reperfusion Injury/drug therapy
8.
Article in Chinese | WPRIM | ID: wpr-905924

ABSTRACT

Objective:To observe and compare the protective effects of Tongqiao Huoxue decoction (TQHX) prepared by three methods against cerebral ischemia-reperfusion injury (CIRI), and to explore its mechanism through the glutamate (Glu) metabolic pathway in astrocytes. Method:The male SD rats of SPF grade were subjected to CIRI model induction by the modified middle cerebral artery occlusion method. The model rats were randomly divided into a model group, a sham operation group, and water-decocted, wine-decocted, and alcohol-extracted TQHX (6.3 g·kg<sup>-1</sup>·d<sup>-1</sup>) groups. The rats were treated correspondingly for 7 days. Those in the sham operation group and the model group were treated with an equal volume of normal saline by gavage. After the final treatment, the neurological function of rats was assessed by the modified neurological severity score (mNSS). Hematoxylin-eosin (HE) staining was used to observe the morphological changes of ischemic brain tissues in rats. High-performance liquid chromatography (HPLC) was used to detect glutamate (Glu) in ischemic brain tissues. The expression of glutamate transporter-1 (GLT-1) and glial fibrillary acidic protein (GFAP) and co-expression of glutamine synthetase (GS) and GFAP in ischemic brain tissues were detected by immunofluorescence assay. Western blot was used to detect the protein expression of GFAP, GLT-1, and GS. Result:Compared with the sham operation group, the model group showed increased mNSS (<italic>P</italic><0.01), large necrosis of cerebral cortex in ischemic brain tissues with disordered cell arrangement, obscure boundary, intracellular edema, and inflammatory infiltration, elevated Glu in ischemic brain tissues (<italic>P</italic><0.01), declining GLT-1-GFAP co-expression and GS-GFAP co-expression (<italic>P</italic><0.01), up-regulated expression of GFAP protein, and reduced protein expression of GLT-1 and GS(<italic>P<</italic>0.05,<italic>P<</italic>0.01). Compared with the model group, the TQHX groups showed decreased mNSS (<italic>P<</italic>0.01), relieved injury in the cerebral cortex and hippocampal nerve cells in ischemic brain tissues, reduced Glu expression(<italic>P<</italic>0.05,<italic>P<</italic>0.01), elevated co-expression of GLT-1 and GFAP (<italic>P<</italic>0.05,<italic>P<</italic>0.01), and up-regulated protein expression of GFAP and GLT-1(<italic>P<</italic>0.05,<italic>P<</italic>0.01). The co-expression of GS and GFAP (<italic>P<</italic>0.05,<italic>P<</italic>0.01)and the expression of GS (<italic>P<</italic>0.01)were increased in the wine-decocted and alcohol-extracted TQHX groups. Compared with the water-decocted TQHX group, the alcohol-extracted group showed increased GLT-1-GFAP and GS-GFAP co-expression(<italic>P<</italic>0.05); the wine-decocted and alcohol-extracted TQHX groups exhibited elevated GS protein expression (<italic>P<</italic>0.05); the alcohol-extracted TQHX group displayed declining Glu content (<italic>P</italic><0.01) and increased protein expression of GFAP and GLT-1 (<italic>P<</italic>0.05, <italic>P<</italic>0.01). Compared with the wine-decocted TQHX group, the alcohol-extracted TQHX group showed increased protein expression of GFAP and GLT-1(<italic>P<</italic>0.05,<italic>P<</italic>0.01). Conclusion:TQHX prepared by three methods can improve neurological deficits in CIRI rats. The effect is presumedly achieved by promoting the further activation of astrocytes, increasing the expression of GLT-1 and GS, promoting the clearance of Glu accumulated in the synaptic cleft by astrocytes through the Glu-glutamine (Gln) circulation, and reducing the excitotoxicity of Glu. The alcohol-extracted TQHX group was superior to the water-decocted and wine-decocted TQHX groups in reducing the content of Glu in ischemic brain tissues, promoting the activation of astrocytes, and enhancing the protein expression of GLT-1 and GS.

9.
Article in Chinese | WPRIM | ID: wpr-905918

ABSTRACT

Cerebral ischemia/reperfusion injury (CIRI) is a common feature and the main pathophysiological mechanism of ischemic stroke(IS), which is caused by a blood reperfusion injury in ischemic brain tissues. It can aggravate brain tissue injury and cause irreversible brain damage, seriously affecting the quality of life or even the life of patients. Hence, we must find out the exact mechanism as well as the effective therapeutic drugs and targets for CIRI. The Chinese medicine effective in Xingnao (restoring consciousness) and Kaiqiao (opening orifices) has been widely used in the treatment of CIRI and serves as a classic therapy for IS. In recent years, scholars have conducted extensive and in-depth studies on the mechanism and therapeutic targets of Chinese medicine in Xingnao and Kaiqiao. They found that those drugs could interfere with a series of changes after IS and achieve the remarkable curative effect. This study summarized the effect and mechanism of Chinese medicine in Xingnao and Kaiqiao in the treatment of CIRI, including reducing the inflammatory response and oxidative stress, alleviating brain edema and the toxicity of excitatory amino acids, reducing cell apoptosis, promoting angiogenesis and neurovascular remodeling, and improving blood-brain barrier injury. It is expected to provide references to clarify the mechanism and important targets of those drugs in resisting CIRI and ideas for the in-depth investigation and application of brain protection of Chinese medicine in Xingnao and Kaiqiao.

10.
China Pharmacy ; (12): 1811-1817, 2021.
Article in Chinese | WPRIM | ID: wpr-886272

ABSTRACT

OBJECTIVE:To obs erve the protective effect of protoca techuic aldehyde(PAL)on neurovascular unit (NVU) homeostasis damage in rats after cerebral ischemia-reperfusion injury (CIRI). METHODS :SD rats were randomly divided into sham operation group ,model group ,PAL high-dose and low-dose groups (10,20 mg/kg),with 11 rats in each group. Administration groups were given relevant medicine intragastrically. Sham operation group and model group were given the same volume of normal saline intragastrically ,10 mL/kg once a day ,for 5 days. After last administration ,CIRI model was induced by suture method ;the ultrastructural changes of NVU were observed by transmission electron microscope. Western blot assay was used to detect the expression of NUV related proteins (MAP-2,GFAP,AQP-4)in cerebral tissue. Immunofluorescence staining was used to observe the positive expression of above proteins in cerebral cortex. RESULTS :Compared with sham operation group , blood-brain barrier (BBB)structure of model group was destroyed severely ,the vascular lumen became narrower ,lateral edema of endothelial cells was severe ,and the thickness of basement membrane varied ;the nuclei of neurons were pyknosis and there was a large area of edema in the surrounding tissues ;the structure of glial cells was seriously damaged ,the cell body was shrunk and organelles were lost ;protein expression (or positive expression )of MAP- 2 in brain tissue (or cerebral cortex )were significantly decreased (P<0.05 or P<0.01),while protein expression (or positive expression ) of GFAP and AQP- 4 were increased significantly(P<0.01). After PAL intervention ,the rats had less BBB damage ,and the morphology of vascular lumen and basement membrane were not completely destroyed ;the damage of neurons was alleviated ,the pyknosis of neurons was decreased , the chromatin was homogeneous and the heterochromatin was decreased;the damage of glial cell structure was alleviated protein expression of GFAP and AQP- 4(except for low-dose group) in cerebral tissue and positive expression of MAP- 2 and GFAP protein in cerebral cortex were reversed @qq.com significantly (P<0.05 or P<0.01). CONCLUSIONS :PAL can protect the stability of NVU from damage in CIRI model rats; the mechanism may be related to up-regulating the expression of MAP- 2 protein in cerebral cortex and down-regulating the expression of GFAP and AQP- 4 protein in brain tissue.

11.
Article in English | WPRIM | ID: wpr-922098

ABSTRACT

OBJECTIVE@#To investigate the synergistic effect of Naoxintong Capsule (NXTC, ) and Guhong Injection (GHI, ) on cerebral ischemia-reperfusion (I/R) injury.@*METHODS@#Forty-eight Sprague-Dawley rats were divided into 6 groups: control group, oxygen and glucose deprivation (OGD) group, nimodipine group (9.375 mg/kg), NXTC group (0.5 g/kg), GHI group (5 mL/kg) and NXTC+GHI group (0.5 g/kg NXTC+5 mL/kg GHI), after the onset of reperfusion and once per day for the following 7 days. Blood was collected 1 h after final administration, and the sera were collected. Cultured primary rat brain microvascular endothelial cells (rBMECs) were subjected to OGD to establish a cell injury model. Untreated rBMECs were used as blank control. The cell counting kit-8 assay was used to assess cell viability using the sera. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels were assessed using an enzyme-linked immunosorbent assay. Apoptosis was evaluated after Hoechst33342 staining using fluorescence microscopy and flow cytometry. JC-1 staining was performed to assess changes in mitochondrial membrane potential.@*RESULTS@#Statistical analysis indicated that more than 95% of the cells were rBMECs. Compared with the OGD group, the cellular morphology of the all drug delivery groups improved. In particular, the combined drug group had the most significant effect. Compared with the OGD group, all drug intervention groups induced a decrease in the apoptotic rate of rBMECs, increased the SOD levels, and decreased the MDA levels (all P<0.01). Compared with the mono-therapy groups, the NXTC+GHI group exhibited a significant improvement in the number of apoptotic rBMECs (P<0.01). All drug intervention groups showed different degrees of increase in membrane potential, and the NXTC+GHI group was higher than the NXTC or GHI group (P<0.01).@*CONCLUSION@#The combinationa application of NXTC and GHI on cerebral I/R injury clearly resulted in protective benefits.


Subject(s)
Animals , Apoptosis , Brain , Brain Ischemia/drug therapy , Drugs, Chinese Herbal , Endothelial Cells , Glutamine/analogs & derivatives , Plant Extracts , Rats , Rats, Sprague-Dawley , Reperfusion Injury/drug therapy
12.
Article in Chinese | WPRIM | ID: wpr-909603

ABSTRACT

OBJECTIVE To explore the effect of total flavonoids of Rhododendra simsii (TFR) on improving cerebral ischemia/reperfusion injury (CIRI) and its relationship with STIM/Orai-regulated operational Ca2+influx (SOCE) pathway. METHODS Oxygen-glucose deprivation/reoxygenation (OGD/R) PC12 cells were used to simulate CIRI in vitro, and the intracellular Ca2+ concentration and apoptosis rate of PC12 cells were detected by laser confocal microscope and flow cytometry, respectively. The regulation of STIM/Orai on SOCE was analyzed by STIM/Orai gene silencing and STIM/Orai gene overexpression. The CIRI model was established by MCAO in SD rats. The activities of inflammatory cyto?kines IL-1, IL-6 and TNF-αin serum were detected by ELISA. The pathological changes of ischemic brain tissue and the infarction of rat brain tissue were detected by HE staining and TTC staining. The protein and mRNA expression levels of STIM1, STIM2, Orai1, caspase-3 and PKB in brain tissue were detected by Western blotting and RT-qPCR, respectively. RESULTS The results of in vitro experiment showed that the fluorescence intensity of Ca2+ and apoptosis rate in PC12 cells treated with TFR were significantly lower than those in OGD/R group, and this trend was enhanced by SOCE antagonist 2-APB. STIM1/STIM2/Orai1 gene silencing significantly reduced apoptosis and Ca2+overload in OGD/R model, while TFR combined with overexpression of STIM1/STIM2/Orai1 aggravated apoptosis and Ca2+overload. In the in vivo experiment, TFR significantly reduced the brain histopathological damage, infarction of brain tissue, the contents of IL-1, IL-6 and TNF-α in the serum in MCAO rats and down-regulated the expression of STIM1, STIM2, Orai1 and caspase-3 protein and mRNA in the brain tissue, and up-regulated the expression of PKB. The above effects were enhanced by the addition of 2-APB. CONCLUSION The above results indicate that TFR may reduce the contents of inflammatory factors and apoptosis, decrease Ca2+ overload and ameliorate brain injury by inhibiting SOCE pathway mediated by STIM and Orai, suggesting that it has a protective effect against subacute CIRI.

13.
Article in Chinese | WPRIM | ID: wpr-846017

ABSTRACT

Objective: To observe the neuroprotective effect of borneol combined with astragaloside IV (AST IV) and Panax notoginseng saponins (PNS) on cerebral ischemia reperfusion injury (CIRI) rat model through Notch signaling pathway. Methods: SD rats were randomly divided into sham group, model group, borneol (7.5 mg/kg) group, AST IV (25 mg/kg) group, PNS (10 mg/kg) group, AST IV (10 mg/kg) + PNS (25 mg/kg) group, borneol (7.5 mg/kg) + AST IV (25 mg/kg) + PNS (10 mg/kg) low dose group, borneol (15 mg/kg) + AST IV (20 mg/kg) + PNS (50 mg/kg) high dose group and edaravone (4 mg/kg) group. Rats in sham group and model group were ig 0.5% CMC-Na, edaravone group was ip drug, and the other groups were ig corresponding drugs, twice a day with an interval of 12 h. The right middle cerebral artery of rat was blocked by a suture method 2 h after last administration to establish a CIRI model. After 2 h of ischemia and 22 h of reperfusion, the eurological function scores were scored and pathological changes of ischemic cortex in brain tissues of rats were observed by HE staining. The expressions of neuron specific nuclear (NeuN) and endothelial barrier antigen (EBA) in ischemic cortex of brain tissue were detected by immunohistochemistry. The expressions of vascular endothelial growth factor (VEGF), Notch1, and intracellular domain of Notch (NICD) in ischemic cortex of brain tissue were detected by Western blotting. Results: The score of neural dysfunction and cell damage rate in model group were significantly increased (P < 0.01); The score of nerve function defect and rate of cell damage in each administration group were significantly reduced (P < 0.05, 0.01), the effect of borneol + AST IV + PNS group was better than that of single drug and AST IV + PNS group (P < 0.05, 0.01). NeuN and EBA protein expressions were significantly decreased in the ischemic cortex of model group (P < 0.01), while NeuN and EBA protein expressions were significantly enhanced in each administration group (P < 0.05, 0.01), and the effect of borneol + AST IV + PNS group was better than that of single drug and AST IV + PNS group (P < 0.05, 0.01). In model group, VEGF protein expression was increased significantly (P < 0.05), while NICD and Notch1 protein expression had no significant change. The expression of VEGF, NICD and Notch1 protein were significantly up-regulated in borneol + AST IV + PNS group (P < 0.01), and the effect of combination of three drugs was better than that of single drug and AST IV + PNS (P < 0.05, 0.01). Conclusion: Borneol, AST IV, and PNS have the effects of preventing neuronal and cerebral microvascular damage after CIRI, and the effect of combination of three drugs was better than that of single drug and AST IV + PNS, which may be related to the activation of the Notch signaling pathway and up-regulation of VEGF expression, thereby, exerting protective effects on ischemic brain tissue.

14.
Article in Chinese | WPRIM | ID: wpr-843894

ABSTRACT

Objective: To observe the effects of butylphthalide on cerebral ischemia-reperfusion injury in rats. Methods: We divided 90 SD rats into sham-operation group, model group, low-dose butylphthalide group, medium-dose butylphthalide group, high-dose butylphthalide group, and ATRA group. Neurological impairment score (NDS) was used to evaluate neurological function. TTC staining was used to calculate the volume of ischemic brain tissue. The xanthine oxidase method was used to detect SOD. The thiobarbituric acid colorimetry was used to detect MDA. ELISA was used to detect IL-6 and TNF-α expressions. The Real-time PCR was used to detect HO-1 gene expression. Western blot was used to detect Nrf2 and HO-1 protein expressions. Results: In low-, medium-, and high-butylphthalide groups, the NDS; volume of ischemic brain tissue; expressions of MDA, IL-6 and TNF-α; 2-△△Ct value of HO-1; protein expressions of Nrf2 and HO-1 were lower than those in model group (P<0.05), but SOD expression was higher than that in model group (P<0.05). The NDS; volume of ischemic brain tissue; expressions of MDA, IL-6 and TNF-α; 2-△△Ct value of HO-1; protein expressions of Nrf2 and HO-1 decreased in a dose-depended manner in low-, medium-, and high-butylphthalide groups, and SOD expression was increased in a dose-depended manner (P<0.05). Conclusion: Butylphthalide can play an antioxidant role by up-regulating Nrf2/HO-1 pathway, which benefits neuroprotective function in cerebral ischemia-reperfusion rats.

15.
Article in Chinese | WPRIM | ID: wpr-905436

ABSTRACT

Mitochondria, as the key passway of neuronal apoptosis after ischemia, is closely related to cerebral ischemia-reperfusion injury. Remote ischemic post-conditioning can alleviate cerebral ischemia-reperfusion injury, and its mechanism is related to alleviating mitochondrial injury and improving its dysfunction. In this paper, cytochrome C/caspase, mitophagy, mitochondrial ATP-sensitive K+ channel and mitochondrial permeability transitionpore were reviewed.

16.
China Pharmacy ; (12): 1287-1293, 2020.
Article in Chinese | WPRIM | ID: wpr-821791

ABSTRACT

OBJECTIVE:To st udy preventive effect and mec hanism of ginsenoside Rg 1 on focal cerebral ischemia-reperfusion injury(CIRI)model rats. METHODS :Totally 78 SD rats were randomly divided into sham operation group ,model group , butylphthalide control group (positive control ,10 mL/kg),ginsenoside Rg 1 low-dose,medium-dose and high-dose groups (10, 20,40 mg/kg),with 13 rats in each group. Administration groups were give relevant medicine intraperitoneally ,sham operation group and model group were given constant volume of normal saline intraperitoneally ,once a day ,for consecutive 7 d. After medication,except for the sham operation group ,focal CIRI model was induced by middle cerebral artery occlusion (MCAO) method in other groups. After modeling ,neurological deficit scoring was performed according to the modified neurological difict scoring standard ; TTC staining was used to detected the percentage of cerebral infarction of rats ;the cerebral water content was measured by dry/wet weight method ;serum contents of IL- 1β and IL-6 were detected by ELISA ;the protein expressions of p-p 38 MAPK and p-NF-κB p65 in cerebral tissue were determined by immunohistochemistry and Western blotting assay. RESULTS : Compared with sham operation ,neurological deficits score ,percentage of cerebral infarction and cerebral water content ,serum contents of IL- 1β and IL-6,positive expression numbers of cells and protein expressions of p-p 38 MAPK and p-NF-κB p65 in cerebral tissue were increased significantly in model group (P<0.05 or P<0.01). Compared with model group ,above index levels of administration groups were all decreased significantly (P<0.05 or P<0.01),and the effect of ginsenoside Rg 1 had a dose-dependent trend ;there was no significant difference of all above indexes between ginsenoside Rg 1 middle-dose,high-dose groups and butylphthalide control group (P>0.05). CONCLUSIONS :Ginsenoside Rg 1 has a certain preventive effect on focal CIRI model rats ,the mechanism of which may be associated with down-regulating the protein expression of p-p 38 MAPK and p-NF-κB p65,inhibiting the release of inflammatory factors such as IL- 1β and IL-6.

17.
Article in English | WPRIM | ID: wpr-812992

ABSTRACT

OBJECTIVES@#To examine the changes of coenzyme Q10 (CoQ10) and β-galactosyl transferase specific chaperone 1 (C1GALT1C1) in brain of rats with ischemic injury at different time points and to explore the protective mechanism of ultrashort wave (USW) on ischemic brain injury.@*METHODS@#Fifty SD rats were randomly divided into 5 groups (=10 per group): a sham group (control group) and 4 experimental group (ischemia for 2 h). The 4 experimental groups were set as a model 1 d group, a USW 1 d group, a model 3 d group and a USW 3 d group, respectively. Five rats were randomly selected for 2,3,5-triphenyltetrazoliumchloride (TTC) staining in each experimental group, and the remaining 5 rats were subjected to Western blotting and real-time PCR. The percentage of cerebral infarction volume and the relative expression level of CoQ10 and C1GALT1C1 in the brain were examined and compared.@*RESULTS@#The infarct volume percentage after TTC staining was zero in the sham group. With the progress of disease and USW therapy, the infarct volume percentage was decreased in the experimental groups (all <0.05); Western blotting and real-time PCR showed that the relative expression level of CoQ10 in the sham group was the highest, while in the experimental groups, the content of CoQ10 showed a upward trend with the extension of disease and USW therapy, with significant difference (all <0.05). The relative expression level of C1GALT1C1 in the sham group was the lowest, but in the experimental groups, they showed a downward trend with the extension of disease and USW therapy, with significant difference (all <0.05).@*CONCLUSIONS@#Non-caloric USW therapy may upregulate the expression of CoQ10 to suppress the expression of C1GALT1C1 in rats, leading to alleviating cerebral ischemic reperfusion injury.


Subject(s)
Animals , Brain , Brain Ischemia , Molecular Chaperones , Rats , Rats, Sprague-Dawley , Reperfusion Injury , Ubiquinone
18.
Article in Chinese | WPRIM | ID: wpr-872868

ABSTRACT

Objective:To investigate the effect of salvianolate lyophilized injection and Xueshuantong injection (lyophilized) on the permeability of blood-brain barrier (BBB) via inhibition of metallomatrix protease(MMPs) in cerebral ischemia/reperfusion injury rats. Method:The focal cerebral ischemia/reperfusion model in rats was built by middle cerebral artery occlusion/reperfusion (MCAO/R) technique. Male Wistar rats were randomly divided into sham operation group, ischemia/reperfusion (I/R) group, edaravone (Eda, 6 mg·kg-1) group, salvianolate lyophilized injection (SLI, 21 mg·kg-1) group, Xueshuantong (XST, 100 mg·kg-1) group and SLI combined with XST (SLI+XST, 21 mg·kg-1+100 mg·kg-1) group. Drugs were injected via tail vein for 2 d, while sham group and I/R group were injected with the same amount of normal saline. Neurological deficit score, hematoxylin-eosin (HE) staining and Nissl staining were assessed 2 d after MCAO/R. The permeability of BBB was observed by the leakage of IgG/CD31. The expressions of Claudin-5,Occludin,collagen-Ⅳ(Col- Ⅳ),Laminin,Fibronectin were observed by immunofluorescence staining,and MMP-2 and MMP-9 were observed by Western blot. Result:Compared with the I/R group, SLI group, XST group and SLI+XST group showed improvements in neurological deficit score, HE staining and Nissl staining. The leakage of IgG was alleviated; The positive expressions of Claudin-5,Occludin,Col-Ⅳ,Laminin,Fibronectin in ischemic penumbra were significantly up-regulated, while the expressions of MMP-2 and MMP-9 were down-regulated. The effect in improving SLI combined with XST was much better than a single factor. Conclusion:Salvianolate lyophilized injection and Xueshuantong injection (lyophilized) can alleviate cerebral ischemia/reperfusion injury and exert the synergistic effect when they are used in combination. The mechanisms might be associated with the improvement in the permeability of blood-brain barrier by inhibiting MMPs in cerebral ischemia/reperfusion injury rats.

19.
Chinese Pharmaceutical Journal ; (24): 1259-1265, 2020.
Article in Chinese | WPRIM | ID: wpr-857624

ABSTRACT

OBJECTIVE: To study the effects and mechanisms of danhong injection on cerebral ischemia reperfusion injury in rats with hyperlipidemia. METHODS: Hyperlipidemia model was established by feeding SD rats with high-fat diet for 6 weeks. Then hyperlipidemia rats were randomly divided into sham operation group, model group and danhong injection low (0.5 mL•kg-1), medium (1.0 mL•kg-1) and high (2.0 mL•kg-1) dose groups with six rats for each group. Danhong injection groups were injected for 7 consecutive days before the establishment of the model of middle cerebral artery occlusion (MCAO), and the corresponding dose was given once at 1 h before modeling and 6 h after reperfusion. After 24 h of reperfusion, rats were evaluated in terms of neurological function. The changes of histopathology were observed in the cerebral cortex of ischemic rats by HE staining; RT-PCR was used to detect the mRNA expressions of Nox2, Rac1, ASC, NLRP3, caspase-1, IL-1β and IL-18 in cerebral ischemia area. In addition, the content of triglyceride (TG) and total cholesterol (TC) in serum were detected by the kits. The expression of NLRP3 protein was evaluated by immunohistochemical. RESULTS: Compared with MCAO group, Danhong injection groups improved the reperfusion injury of cerebral ischemia in varying degrees, significantly reduced the mRNA expression of Nox2, Rac1, ASC, NLRP3, caspase-1, IL-1β and IL-18, increased the neurological score of MCAO rats, and reduced the contents of TC and TG besides the expression of NLRP3 protein. CONCLUSION: Danhong injection could effectively regulate blood lipid level and play a obvious protective effect on the reperfusion injury in MCAO rats with hyperlipidemia. The mechanism might be related to the inhibition of the formation of NLRP3 inflammatory body and the decrease of the inflammation-related factors expression of caspase-1, IL-1β and IL-18.

20.
Article in Chinese | WPRIM | ID: wpr-857044

ABSTRACT

Aim To observe the effects of astragaloside IV on autophagy and oxidative stress induced by oxy gen-glucose deprivation/reoxygenation in PCI2 cells. Methods PCI2 cells were divided into normal group, model group (ox-ygen-glucose deprivation/reoxygenation group) , astragaloside IV group, and autophagy inhibitor + astragaloside IV group. CCK-8 was used to detect cell viability, and ELISA to detect MDA, SOD and GSH-Px. Transmission electron microscope and MDC fluorescent staining were employed to observe the changes of au-tophagosome, and Western blot to detect the protein expression of Beclinl. Results Compared with normal group, the cell activity in model group decreased (P <0.05), MDA content increased, SOD and CSH-Px activity decreased (P < 0.05), and autophagosomes could be seen and the protein expression of Beclinl increased ( P < 0.05). Compared with model group, the cell activity in astragaloside IV group increased ( P < 0. 05), MDA content decreased, SOD and GSH-Px activity increased (P < 0.05), the number of autophagosomes and the protein expression of Beclinl increased (P<0.05). When autophagy inhibitor was given at the same time, the autophagy inhibitor could obviously antagonize the antioxidant effect of astragaloside IV while alleviating autophagy. Conclusions Astragaloside IV can protect PC 12 cells from oxidative stress injury induced by oxygen-glucose deprivation/reoxygenation by up-regulating autophagy.

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