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Objective: To investigate the protective effects of icaritin (ICT), one of the active ingredients in Epimedii Folium, on mouse model of cerebral ischemia-reperfusion (I/R) in vivo. Methods: ICR mice were subjected to an 1 h transient middle cerebral artery occlusion (MCAO) and followed by 24 h of reperfusion. Neurological deficits, infarct volume, brain edema and survive rate were measured, respectively. The levels of brain IL-1β TNF-α ROS and DNA-binding activity of NF-κB p65 were measured by ELISA kits. The levels of malondialdehyde (MDA) and activities of superoxide dismutase (SOD) were detected by spectrophotometry, and the release of nitric oxide (NO) were detected by Griess kit. Results: ICT markedly reduced the neurological deficit scores, brain edema, infarct volume and increased the survival rate of the cerebral I/R mice. The expression of IL-1β TNF-α NO, MDA and DNA-binding activity of NF-κB p65 were significantly inhibited by ICT, while the activity of SOD were up-regulated at the same time. Conclusion: ICT possessed significant neuroprotective effects in cerebral I/R mice, which might be related to prevent neuroinflammatory and oxidative damage.
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Cardiac arrest (CA) is a fatal condition with low resuscitation rate and high mortality rate. Most of the survivors have neurological sequelae affecting their quality of life. Targeted temperature management (TTM) has been suggested by a number of studies to increase the survival rate and improve neurological outcome of CA. It is highly recommended by the International Liaison Committee on Resuscitation (ILCOR) for unconscious patients after resuscitation. In this review, we discuss the pathological mechanism of brain injury in CA and applications of TTM in adults with CA, with the aim of providing valuable information for clinical application.
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To observe the effect of active components group of Xiaoxuming decoction (XXMD) on brain mitochondria in cerebral ischemia/reperfusion rats during early recovery period, and study its protective mechanism for nerves in cerebral ischemia/reperfusion rats during early recovery period. Cerebral ischemia model of middle cerebral artery occlusion in rats was established by suture method, and reperfusion was conducted 2 h later. The degree of cerebral ischemia in rats was evaluated by using Zea-Longa's standard grading method, and the model rats were randomly divided into model group, Xiaoxuming decoction active components low, medium and high dose groups and positive drug Ginaton group, with sham operated rats as control group. Gradient centrifugation was used to extract the mitochondria from rat brain after 5 days of drug administration. Then the mitochondrial respiratory function was measured by Clark oxygen electrode method; mitochondrial membrane potential and the mitochondrial reactive oxygen species(ROS) level were detected by fluorescence probe methods; and the activity of mitochondrial succinodehydrogenase (SDH) and the content of ATP in the ischemic region of MCAO rats were measured by spectrophotometric method. The results showed that as compared with the model group, XXMD could significantly improve mitochondrial respiratory activity, increase the activity of SDH, reduce the level of ROS, increase mitochondrial membrane potential and obviously promote the synthesis of ATP in brain tissues. The results indicated that XXMD active components group could alleviate the energy metabolism disorders, protect brain mitochondrial damage and improve mitochondrial function in MCAO rats, which may be the mechanism of its neuroprotection activity.
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Objective To research the protective effect of Ento-I against cerebral ischemia-reperfusion injury in rats, and to evaluate its analgesic and anticoagulating effects in mice. Methods The ischemic model was established with line embolism to block the middle cerebral artery of male rats. The 56 rats were randomly assigned into 7 groups of sham-operation, blank-matrix, normal saline, Ento-I plastic of 3 doses (6.67, 3.33, 1.67 mg/kg), and ozagrel sodium (8.3 mg/kg, ip). The effect of Ento-I plastic on anti-cerebral ischemia was measured by nervous function scores and the areas of cerebral infarction were determined by TTC staining for the calculation of cerebral infarction rates. The analgesic effect of Ento-I plastic was determined with acetic acid-induced twisting experiment. Sixty KM mice were randomly allocated into blank-matrix, aspirin, aspirin-plastic, and Ento-I plastic of 3 doses (5, 10 and 20 mg/kg), the number of mouse twisting were recorded right after intraperitoneal injection of 0.7% acetic acid solution at the time of 1 h after the last administration. Moreover, the anticoagulant activity of Ento-I plastic was tested by glass capillary method. Results The results of acetic acid-induced twisting experiment displayed that Ento-I plastic of all 3 dose groups (5, 10 and 20 mg/kg) could significantly reduce the number of body torsion and increase the inhibitory rates of twisting, compared with that of blank matrix group (the inhibitory rates of twisting for 3 dose groups were 21.79%, 48.89%, and 56.15%, respectively), with dose-response manner. According to the results of glass capillary test, the clotting time of mouse blood could be significantly prolonged by mid- (10 mg/ kg) and low-dose (5 mg/kg) of Ento-I plastic with corresponding clotting time of (155.20±54.19) s and (155.80±73.84) s, compared with normal saline group at (92.10±24.61) and blank-matrix group at (80.40±48.09, P<0.05). The experiment results of the isch emia-reperfusion injury by line embolism method in rats exhibited that Ento-I plastic in mid-dose (3.33 mg/kg) could significantly re duce the neurological scores after 24 h of reperfusion injury, from (2.33±0.52) of normal saline group to (1.00±0.00) of mid-dose group (P<0.01). The results from TTC staining revealed that the cerebral infarction rates of normal saline group and blank- matrix group were (24.89±7.24) % and (27.72±7.89)%, respectively, whereas those of 6.67 mg/kg and 3.33 mg/kg group of Ento-I plastic were (14.01±2.65) % and (14.73±4.94)%, respectively. Compared to the 2 negative-control groups, both the high- and mid-dose of Ento-I plastic could significantly reduce the cerebral infarction rates after ischemic reperfusion injury in rats (P<0.01). Conclusion Ento-I plastic demonstrates strong analgesic and anticoagulant effects, and could substantially reduce the neurological scores and reduce cerebral infarction rates for ischemia-reperfusion injured rats. These are likely to be the mechanism of action for Ento-I plastic realizing its anti-cerebral ischemia effect.
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Objective To research the protective effect of Ento-Ⅰagainst cerebral ischemia-reperfusion injury in rats,and to evaluate its analgesic and anticoagulating effects in mice. Methods The ischemic model was established with line embolism to block the middle cerebral artery of male rats. The 56 rats were randomly assigned into 7 groups of sham-operation,blank-matrix,nor? mal saline,Ento-Ⅰplastic of 3 doses(6.67,3.33,1.67 mg/kg),and ozagrel sodium(8.3 mg/kg,ip). The effect of Ento-Ⅰplastic on anti-cerebral ischemia was measured by nervous function scores and the areas of cerebral infarction were determined by TTC staining for the calculation of cerebral infarction rates. The analgesic effect of Ento-Ⅰplastic was determined with acetic acid-induced twisting experiment. Sixty KM mice were randomly allocated into blank-matrix,aspirin,aspirin-plastic,and Ento-Ⅰplastic of 3 doses(5,10 and 20 mg/kg),the number of mouse twisting were recorded right after intraperitoneal injection of 0.7%acetic acid solution at the time of 1 h after the last administration. Moreover,the anticoagulant activity of Ento-Ⅰplastic was tested by glass capillary method. Re?sults The results of acetic acid-induced twisting experiment displayed that Ento-Ⅰplastic of all 3 dose groups(5,10 and 20 mg/kg) could significantly reduce the number of body torsion and increase the inhibitory rates of twisting,compared with that of blank matrix group(the inhibitory rates of twisting for 3 dose groups were 21.79%,48.89%,and 56.15%,respectively),with dose-response man?ner. According to the results of glass capillary test,the clotting time of mouse blood could be significantly prolonged by mid-(10 mg/kg)and low-dose(5 mg/kg)of Ento-Ⅰplastic with corresponding clotting time of(155.20±54.19)s and(155.80±73.84)s,compared with normal saline group at(92.10 ± 24.61)and blank-matrix group at(80.40 ± 48.09,P<0.05). The experiment results of the isch?emia-reperfusion injury by line embolism method in rats exhibited that Ento-Ⅰplastic in mid-dose(3.33 mg/kg)could significantly re?duce the neurological scores after 24 h of reperfusion injury,from(2.33 ± 0.52)of normal saline group to(1.00 ± 0.00)of mid-dose group(P<0.01). The results from TTC staining revealed that the cerebral infarction rates of normal saline group and blank-matrix group were(24.89±7.24)%and(27.72±7.89)%,respectively,whereas those of 6.67 mg/kg and 3.33 mg/kg group of Ento-Ⅰplastic were(14.01±2.65)%and(14.73±4.94)%,respectively. Compared to the 2 negative-control groups,both the high-and mid-dose of Ento-Ⅰplastic could significantly reduce the cerebral infarction rates after ischemic reperfusion injury in rats (P<0.01). Conclu?sion Ento-Ⅰplastic demonstrates strong analgesic and anticoagulant effects,and could substantially reduce the neurological scores and reduce cerebral infarction rates for ischemia-reperfusion injured rats. These are likely to be the mechanism of action for Ento-Ⅰplastic realizing its anti-cerebral ischemia effect.
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Objective To investigate the protection of agmatine on blood brain barrier (BBB) permeability and the effect on the expression of aquaporin 4 (AQP4) and matrix metalloproteinase 9 (MMP9) in ischemic reperfusion injury rats.Methods Sixty healthy male Sprague-Dawley rats were randomly divided into normal control group (NC),model group and agmatine group,and there were 20 rats in each group.Normal control group was treated with intraperitoneal injection of saline in 2 hours after incision and suture of skin.Model group was treated with intraperitoneal injection of saline in 2 hours after the establishment of middle cerebral artery occulation (MCAO) model.Agmatine group was treated with intraperitoneal injection of agmatine (AGM) in 2 hours after the establishment of MCAO model.The damage of blood brain barrier was detected by measuring the permeability of blood brain barrier.The infarct size of brain was observed with TTC staining.The morphological changes of neurons were observed with electron microscope.The expressions of AQP4 and MMP9 were detected using immunohistochemical method.Results The permeability of BBB of agmatine treatment group (0.31±0.10) decreased significantly compared with the model group (0.46±0.09) (P＜0.05),but was still significantly higher than the normal control group (0.24±0.12) (P＜0.05).There was no infarction area in normal control group and the infarction areas of agmatine group decreased obviously compared with the model group.Compared with model group,the number of neurons with morphological changes reduced significantly and the degree of pathological changes of neurons was obviously improved in agmatine group.Compared with normal control group,the expression of AQP4 and MMP9 in ischemic penumbra of left cerebral hemisphere parietal cortex in the rats of model group and agmatine group increased significantly(P＜0.05).And the expression of AQP4 and MMP9 in model group was significantly higher than that of agmatine group(P＜0.05).Conclusion Agmatine has a protective effect on BBB with ischemia-reperfusion injury due to its down-regulation the expression of AQP-4 and MMP-9.
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Sublethal ischemic preconditioning (IPC) is a powerful inducer of ischemic brain tolerance. However, its underlying mechanisms are still not well understood. In this study, we chose four different IPC paradigms, namely 5 min (5 min duration), 5×5 min (5 min duration, 2 episodes, 15-min interval), 5×5×5 min (5 min duration, 3 episodes, 15-min intervals), and 15 min (15 min duration), and demonstrated that three episodes of 5 min IPC activated autophagy to the greatest extent 24 h after IPC, as evidenced by Beclin expression and LC3-I/II conversion. Autophagic activation was mediated by the tuberous sclerosis type 1 (TSC1)-mTor signal pathway as IPC increased TSC1 but decreased mTor phosphorylation. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and hematoxylin and eosin staining confirmed that IPC protected against cerebral ischemic/reperfusion (I/R) injury. Critically, 3-methyladenine, an inhibitor of autophagy, abolished the neuroprotection of IPC and, by contrast, rapamycin, an autophagy inducer, potentiated it. Cleaved caspase-3 expression, neurological scores, and infarct volume in different groups further confirmed the protection of IPC against I/R injury. Taken together, our data indicate that autophagy activation might underlie the protection of IPC against ischemic injury by inhibiting apoptosis.
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Animals , Male , Rats , Apoptosis/physiology , Autophagy/physiology , Brain Ischemia/physiopathology , Ischemic Preconditioning/methods , Nerve Degeneration/prevention & control , Reperfusion Injury/metabolism , Adenine/analogs & derivatives , Adenine/pharmacology , Brain Ischemia/prevention & control , /metabolism , Cerebrum/injuries , In Situ Nick-End Labeling , Immunosuppressive Agents/pharmacology , Rats, Sprague-Dawley , Sirolimus/pharmacology , Time Factors , TOR Serine-Threonine Kinases/metabolism , Tumor Suppressor Proteins/metabolismABSTRACT
Objective To observe the influence of electroacupuncure(EA) at different therapeutic time windows on the effects of inosine on neuronal apoptosis and expression of heat-shock-proteins-70 (HSP70)after focal cerebral ischemic reperfusion injury (CIRI) in rats.Methods The model was established by ligation of the artery for 2 hour.EA was delivered to “baihui” and “dazhui” through acupuncture needles 0.5 hr,2 hr,6 hr and 12 hr respectively following MCAO.The expression level of HSP70 and the number of apoptotic cells were examined by immunohistochemical technique and TUNEL,comparing the average optical density of HSP70 and the number of apoptotic positive cells of cortex penumbra and hippocampus CA1 area in rat brain.Results Compared with the model group,the average optical density of HSP70 in every EA group was increased in apoptotic positive cells of cortex penumbra and hippocampus CA1 area 0.5 h (89.98± 6.55),(128.73 ± 8.03),2 h (90.96±6.38),(132.25±8.78),6 h (93.71±6.12),(132.58±7.04),12 (96.19±7.30),(133.57±6.19)and the number of apoptotic positive cells of cortex penumbra in every EA group was decreased 0.5 h (1.80±0.84),2 h (3.40± 1.14),6 h (5.00± 1.00),12 h (5.00±2.45).The number of apoptotic cells of hippocampus CA1 area was decreased just in the EA group of 0.5 h (1.60± 1.89).Conclusion EA could increase the expression level of HSP70 and at the same time decrease the number of apoptotic cells,EA plays an important part in protecting the neuronal cells of brain after focal cerebral ischemic reperfusion injury.The acupuncture treatment should be taken as far as early.
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0.05).The cerebral infarcted area in SHR were significantly greater than that in SD rats [(42.6?5.6)% vs(29.5?6.7)%,P
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OBJECTIVE: To investigate the protective effects of tea polyphenol (TP) on lung injury caused by global cerebral ischemic-reperfusion and its mechanism. METHODS: Improved Pulsinelli-brierley method was applied to induce damage model by global cerebral ischemia model for 15 min and global cerebral ischemia-perfusion for 3 h. Some indexes were observed, including morphology change of cerebral and lung tissue, activity of superoxide dismutase (SOD), concentration of malondialdehyde (MDA) and expression of lipopolysaccharide receptor CD14. Healthy rats were divided into sham group, model group and nimodipine group. RESULTS: As compared with sham group, there were pathologic damage of lung and brain and the positive expression of CD14 cell of lung in model group. As compared with model group, the activity of SOD were increased significantly (P
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Objective To investigate the effects of pre-ischemic administration of L-NAME on brain protective effects of simvastatin against focal cerebral ischemic/reperfusion injury in rats. Methods ① Animals were subjected to transient 2-hour middle cerebral artery occlusion(MCAO)with the use of the intraluminal filament method previously described by Zea Longa. ② 54 male rats were treated with simvastatin or vehicle by gavage two weeks before MCAO, and L-NAME was injected into laterar ventricle of rats 45 minutes before MCAO. After neurological deficit was assessed at 22 hours of reperfusion, rats were killed, and the brains were rapidly removed. The coronal sections of the brains were prepared and stained with 2% TTC, and the infarct volumes were determined. Another 54 male rats were performed as description above except that the brain tissues were made into homogenate at 22 hours of reperfusion, and the contents of lactic acid(LA) and MDA, and the activities of superoxide dismutase(SOD) in the brain tissues were also measured. Results Administration of simvastatin significantly reduced the size of brain infarct, improved neurological deficits, decreased the contents of LA and MDA and increased the activities of SOD, but L-NAME could abrogate these effects. Conclutions L-NAME could abrogate the protection of simvastatin against ischemic/reperfusion injury,which may be by inhibiting the expression and activity of endothelial NO synthase(eNOS) up-regulated by simvastatin.
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Objective To explore the expression of singal transducers and activators of transcription(STAT 3) during focal cerebral ischemic reperfusive injury in rats and the relationship between ischemic neuronal damage and it.Methods Using immunohistochemical method of avidinbiotin peroxidase complex (ABC) we observed the distribution of positive cells in STAT 3 protein immunoreaction after focal cerebral ischemic reperfusive injury in rats.Results STAT 3 immunoreactive positive cells were not found in the cortex and striatum of normal and sham operative rat brains and nonischemic hemisphere brain after cerebral ischemia,small amount of STAT 3 immunity positive cells were induced in the embolism la teral infarction area 12 h after reperfusive injury,and peaked after 24 h,especially in ischemic lateral striatum and around cortex,small number of nerve cells in around infarction still showed positive expression after one week.The difference had remarkable significance( P
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0.05).The expression began to increase around the infarction at 12h reperfusion,it reached the peak at the 3th day in the boundary zone and then it gradually decreased.Conclusion The overexpression of IL 6 played an important role in the course of cerebral ischemic reperfusion, and could damage the brain tissue.
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Objective To study the effect of Nimotop on the permeability of blood-brain barrier (BBB) and cerebral infarction size after cerebral ischemic reperfusion (CIR) in rats.Methods CIR models were established by occluding unilateral middle cerebral arteries(MCA) of rats for 2 hours and then reperfused. The models were divided into 2 groups:Nimotop group and the saline control group,each group had CIR 6、12、24、48 and 72 h sub-groups. As soon as reperfusion,Nimotop or saline was abdominal abministrated(2 mg/kg weight) respectively per 12 h. Fluorophotometry and transmission electron microscopy were used to detect the permeability of BBB,the rate of infarction size was calculated by 2,3,5-triphenyl tetrazolium chloride(TTC) dyeing.Results Following reperfusion,the permeability of BBB and the rate of cerebral infarction size were increased. The permeability of BBB had two peaks. The first peak took place at 12h after CIR. The second peak was at 48 h after CIR. These changes were more severe in Nimotop group than in saline group( P
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Objective To explore the therapeutical effect and its mechanism of tissue kallikrein (TK) on cerebral ischemic-reperfusion rat.Methods 36 rats were randomly divided into three groups: sham operation group, NS group [administrated with normal sodium 2 ml/(kg?d)], TK group [administrated with TK 17.5?10-3U/(kg?d)]. The NS and TK groups rats were injected intraperitoneally with NS or TK for three consecutive days. After that, neurological function and the infarct volume was appraised in each of group. Meanwhile, the ischemic tissue were detected by Nissl's staining. TUNEL staining and immunohistochemistry were used to examine the caspase-3,TNF-?,IL-1,NSE,GFAP,vWF expression in ischemic tissue.Results Compared with NS group, TK group significantly reduced the loss of neurological function and the infarct volume and improved the change of pathology in ischemic tissue(all P
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Aim To explore the mechanism of neuro-protecting effects of TGRP on ischemic cerebral injury.Methods The middle cerebral artery was occluded for 2 h to produce focal ischemic followed by 24 h reperfusion.HE staining,TUNEL labeling and immunohistochemical methods were used to investigate changes of neuronal apoptosis and expression of the apoptosis-related proteins after administration of TGRP.Result TGRP decreased the pathologic changes significantly.The apoptosis of neural cells and the expression of Bax positive cells in the TGRP groups significantly decreased compared with the control group(P