Cerebral ischemia-reperfusion injury(CIRI) is an important factor hindering the recovery of ischemic stroke patients after blood flow recanalization. Mitochondria, serving as the "energy chamber" of cells, have multiple important physiological functions, such as supplying energy, metabolizing reactive oxygen species, storing calcium, and mediating programmed cell death. During CIRI, oxidative stress, calcium overload, inflammatory response, and other factors can easily lead to neuronal mitochondrial dyshomeostasis, which is the key pathological link leading to secondary injury. As reported, the mitochondrial quality control(MQC) system, mainly including mitochondrial biosynthesis, kinetics, autophagy, and derived vesicles, is an important endogenous mechanism to maintain mitochondrial homeostasis and plays an important protective role in the damage of mitochondrial structure and function caused by CIRI. This paper reviewed the mechanism of MQC and the research progress on MQC-targeting therapy of CIRI in recent 10 years to provide theoretical references for exploring new strategies for the prevention and treatment of ischemic stroke with traditional Chinese medicine.
Brain Ischemia/prevention & control* ; Calcium/metabolism* ; Humans ; Ischemic Stroke ; Mitochondria/pathology* ; Reactive Oxygen Species/metabolism* ; Reperfusion Injury/prevention & control*

Animals ; Berberine/therapeutic use* ; Brain Ischemia/prevention & control* ; Glutathione Peroxidase ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/prevention & control*

Salvianolic acid A (SAA) is a water-soluble component from the root of Salvia Miltiorrhiza Bge, a traditional Chinese medicine, which has been used for the treatment of cerebrovascular diseases for centuries. The present study aimed to determine the brain protective effects of SAA against cerebral ischemia reperfusion injury in rats, and to figure out whether SAA could protect the blood brain barrier (BBB) through matrix metallopeptidase 9 (MMP-9) inhibition. A focal cerebral ischemia reperfusion model was induced by middle cerebral artery occlusion (MCAO) for 1.5-h followed by 24-h reperfusion. SAA was administered intravenously at doses of 5, 10, and 20 mg·kg. SAA significantly reduced the infarct volumes and neurological deficit scores. Immunohistochemical analyses showed that SAA treatments could also improve the morphology of neurons in hippocampus CA1 and CA3 regions and increase the number of neurons. Western blotting analyses showed that SAA downregulated the levels of MMP-9 and upregulated the levels of tissue inhibitor of metalloproteinase 1 (TIMP-1) to attenuate BBB injury. SAA treatment significantly prevented MMP-9-induced degradation of ZO-1, claudin-5 and occludin proteins. SAA also prevented cerebral NF-κB p65 activation and reduced inflammation response. Our results suggested that SAA could be a promising agent to attenuate cerebral ischemia reperfusion injury through MMP-9 inhibition and anti-inflammation activities.
Animals ; Anti-Inflammatory Agents ; administration & dosage ; Blood-Brain Barrier ; drug effects ; enzymology ; immunology ; Brain ; Brain Ischemia ; drug therapy ; enzymology ; genetics ; Caffeic Acids ; administration & dosage ; Drugs, Chinese Herbal ; administration & dosage ; Humans ; Lactates ; administration & dosage ; Male ; Matrix Metalloproteinase 9 ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury ; enzymology ; genetics ; immunology ; prevention & control ; Salvia miltiorrhiza ; chemistry ; Tissue Inhibitor of Metalloproteinase-1 ; genetics ; metabolism ; Transcription Factor RelA ; genetics ; immunology

To investigate the protective effects of P2X7 receptor (P2X7R) inhibitor against cerebral ischemia/reperfusion (I/R) injury in rats and the possible mechanisms.
 Methods: The neurological deficit of rats was evaluated by Longa score. The infarct volume was examined by 2, 3, 5-triphenyltetrazolium chloride (TTC) staining. The expression levels of extracellular signal-regulated kinase (ERK), phosphorylation extracellular signal-regulated kinas p-ERK), connexin 43 (Cx43), Bax, Bcl-2 and cleaved caspase-3 were detected by Western blot.
 Results: Compared with sham group, the neurobehavioral score (P<0.05) and cerebral infarct volume (P<0.01) of rats in I/R group was increased. Compared with I/R group, brilliant blue G (BBG, the antagonist of P2X7R) or PD98059 (the inhibitor of EKR kinase) could reduce the neurobehavioral score (P<0.01) and cerebral infarct volume significantly (P<0.05). The neurobehavioral score and cerebral infarct volume was further decreased (P<0.05) when rats were treated with both BBG and PD98059. Compared with I/R group, the expression levels of p-ERK, Cx43, cleaved caspase-3 and the ratio of Bax/Bcl-2 were decreased by BBG or PD98059 pretreatment, and the protective effects were further enhanced when rats were treated with both BBG and PD98059 (P<0.05).
 Conclusion: Inhibition of P2X7R reduces the cerebral I/R injury of rats. ERK inhibition is probably involved in the protective effects of P2X7R inhibitor against cerebral I/R injury, which may be related to the reduction of Cx43 and cleaved caspase-3, and the ratio of Bax/Bcl-2.
Animals ; Brain Ischemia ; drug therapy ; prevention & control ; Gene Expression Regulation ; drug effects ; Phosphorylation ; drug effects ; Purinergic P2X Receptor Antagonists ; pharmacology ; therapeutic use ; Rats ; Receptors, Purinergic P2X7 ; Reperfusion Injury ; drug therapy ; prevention & control

OBJECTIVE: To investigate whether rapamycin treatment starting at 24 h after cerebral ischemia/reperfusion(I/R) has protective effect on brain injury in rats. METHODS: The rat I/R model was established by middle cerebral artery occlusion according to Longa's method. A total of 104 Sprague Dawley rats were randomly divided into sham group, model group, and rapamycin-treated groups (6 h or 24 h after modeling). Neurological function was assessed with neurological severity score (NSS). Triphenyl tetrazolium chloride (TTC) staining and Fluoro-Jade B (FJB) staining were used to examine the infarct volume and neuronal apoptosis, respectively. The expression of p-S6 protein in mTOR signaling pathway was detected by Western blot analysis. RESULTS: Compared with sham group, NSS of the model group was significantly increased and TTC staining indicated obvious infarct area (all <0.01). Furthermore, significantly increased number of FJB-positive cells and p-S6 expression in the penumbra area were shown in the model group (all <0.01). Compared with the model group, both rapamycin-treated groups demonstrated decreased NSS, infarction volume and FJB positive cells as well as p-S6 expression in the penumbra area (<0.05 or <0.01). There was no significant difference between the groups of rapamycin administrated 6 h and 24 h after modeling (all >0.05). CONCLUSIONS Rapamycin treatment starting at 24 h after I/R exhibits protective effect on brain injury in rats.
Animals ; Brain Ischemia ; drug therapy ; Immunosuppressive Agents ; therapeutic use ; Infarction, Middle Cerebral Artery ; drug therapy ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury ; prevention & control ; Sirolimus ; therapeutic use ; Treatment Outcome

OBJECTIVE: To observe the effects of "" acupuncture on cerebral blood flow in high-risk patients of cerebral ischemic stroke based on arterial spin labeling (ASL) and perfusion-weighted imaging (PWI), and to evaluate the clinical efficacy. METHODS: A total of 180 patients with transient ischemic attacks (TIA) / minor ischemic stroke (MIS) were randomly divided into an acupuncture A group, an acupuncture B group and a medication group, 60 cases in each group. The patients in the acupuncture A group were treated with "" acupuncture at Baihui (GV 20), Fengfu (GV 16), Yamen (GV 15), Dazhui (GV 14), Shenzhu (GV 12), Zhiyang (GV 9), Mingmen (GV 4), Yaoyangguan (GV 3) and Jingjiaji (EX-B 2), once a day; the patients in the acupuncture B group were treated with identical acupoints but was given once every other day; the patients in the medication group were treated with oral administration of nimodipine tablets, 30 mg, three times daily. All the three groups were treated for four weeks. ASL and PWI, including relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF), relative mean transit time (rMTT) and relative time to peak (rTTP), were conducted before and after treatment; the changes of the test indexes were compared before and after treatment. The clinical efficacy of the three groups was compared. RESULTS: Compared before treatment, the numbers of ASL normal perfusion in the 3 groups were significantly increased after treatment (all <0.01); the number of ASL normal perfusion in the acupuncture A group was higher than that in the acupuncture B group (<0.05), but was not significantly different from that in the medication group (>0.05). Compared before treatment, rCBV and rCBF in the 3 groups were significantly increased after treatment (all <0.01), and rMTT and rTTP were significantly reduced (all <0.01). After treatment, rCBV and rCBF in the acupuncture A group were higher than those in the acupuncture B group (all <0.05); the rMTT and rTTP in the acupuncture A group were lower than those in the acupuncture B group (all <0.05); the differences of PWI parameters after treatment were not statistically significant between the acupuncture A group and medication group (all >0.05). The total effective rate was 88.3% (53/60) in the acupuncture A group, 73.3% (44/60) in the acupuncture B group and 90.0% (54/60) in the medication group; the total effective rate in the acupuncture A group was superior to that in the acupuncture B group (<0.05), but was not significantly different from that in the medication group (>0.05). CONCLUSION "" acupuncture could effectively improve the hypoperfusion of cerebral blood flow in patients with high risk of cerebral ischemic stroke, reduce the incidence of severe CIS; acupuncture for once a day is better than once every other day.
Acupuncture Therapy ; Brain Ischemia ; prevention & control ; Cerebrovascular Circulation ; Humans ; Risk Factors ; Stroke

BackgroundRemote ischemic postconditioning (RIPostC) appears to protect distant organs from ischemia-reperfusion injury (IRI). However, cerebral protection results have remained inconclusive. In the present study, a meta-analysis was performed to compare stroke patients with and without RIPostC.

MethodsCNKI, WanFang, VIP, CBM, PubMed, and Cochrane Library databases were searched up to July 2016. Data were analyzed using both fixed-effects and random-effects models by Review Manager. For each outcome, risk ratio (RR) and mean difference (MD) with 95% confidence interval (CI) were calculated.

ResultsA total of 13 randomized controlled trials that enrolled a total of 794 study participants who suffered from or are at risk for brain IRI were selected. Compared with controls, RIPostC significantly reduced the recurrence of stroke or transient ischemic attacks (RR = 0.37; 95% CI: 0.26-0.55; P < 0.00001). Moreover, it can reduce the levels of the National Institutes of Health Stroke Scale score (MD: 1.96; 95% CI: 2.18-1.75; P < 0.00001), modified Rankin Scale score (MD: 0.73; 95% CI: 1.20-0.25; P = 0.00300), and high-sensitivity C-reactive protein (MD: 4.17; 95% CI: 4.71-3.62; P < 0.00001) between the two groups. There was no side effect of RIPostC using tourniquet cuff around the limb on ischemic stroke treating based on different intervention duration.

ConclusionThe present meta-analysis suggests that RIPostC might offer cerebral protection for stroke patients suffering from or are at risk of brain IRI.

Brain Ischemia ; prevention & control ; Humans ; Ischemic Attack, Transient ; prevention & control ; therapy ; Ischemic Postconditioning ; methods ; Randomized Controlled Trials as Topic ; Stroke ; prevention & control

OBJECTIVETo assess the association of CYP2C19 gene polymorphisms with the incidence of ischemic stroke among patients receiving clopidogrel therapy following coronary stenting for coronary artery disease.

METHODSClinical data of patients receiving clopidogrel therapy after coronary stenting were retrospectively studied. For a case-control study, 137 patients with acute cerebral infarction and 122 non-stroke patients were selected. Based on the variants of the CYP2C19 gene detected by a DNA microarray assay, the patients were further divided into the wild-type group(CYP2C19*1/*1) and mutant group(defined by the presence of at least one loss-of-function allele, including CYP2C19*1/*2, CYP2C19*1/*3, CYP2C19*2/*2, CYP2C19*2/*3 and CYP2C19*3/*3). The incidences of ischemic stroke in the two groups were compared through a chi-square analysis. The influence of CYP2C19 gene polymorphisms and clopidogrel therapy on the incidence of ischemic stroke was analyzed through multivariable logistic regression.

RESULTSA total of 259 patients were enrolled. The case and control groups showed no difference in terms of gender and age. There were 123 cases (47.5%) in the CYP2C19 wild-type group and 136 cases (52.5%) in the mutant group. The incidence of ischemic stroke of mutant group was significantly higher than that of wild-type group (59.9% vs. 44.3%, X2=6.398, P=0.042). Multivariate analysis revealed that loss-of-function polymorphisms of the CYP2C19 gene carried a 1.13 times greater risk for ischemic stroke compared to wild-type genotype (OR=2.13, 95%CI: 1.23-3.71).

CONCLUSIONThe efficacy of clopidogrel for the prevention of ischemic stroke in post-coronary stent patients may be reduced by the insufficiency of the CYP2C19 gene. The dosage of clopidogrel therapy should be adjusted based on its polymorphisms.

Brain Ischemia ; prevention & control ; Cytochrome P-450 CYP2C19 ; genetics ; Genotype ; Humans ; Percutaneous Coronary Intervention ; adverse effects ; Platelet Aggregation Inhibitors ; therapeutic use ; Polymorphism, Genetic ; Stents ; adverse effects ; Stroke ; prevention & control ; Ticlopidine ; analogs & derivatives ; therapeutic use

Hypoxic-ischemic encephalopathy (HIE) in neonates is the brain injury caused by perinatal asphyxia or hypoxia and is a major cause of death in neonates and nervous system dysfunction in infants and young children. Although to a certain degree, mild hypothermia therapy reduces the mortality of infants with moderate to severe HIE, it cannot achieve the expected improvements in nervous system dysfunction. Hence, it is of vital importance to search for effective therapeutic methods for HIE. The search for more therapies and better preventive measures based on the pathogenesis of HIE has resulted in much research. As an important link in the course of HIE, energy failure greatly affects the development and progression of HIE. This article reviews the research advances in the treatment and prevention of energy failure in the course of HIE.
Energy Metabolism ; Humans ; Hypothermia, Induced ; Hypoxia-Ischemia, Brain ; prevention & control ; therapy ; Infant, Newborn ; Infant, Newborn, Diseases ; prevention & control

OBJECTIVETo investigate the protective effect of propofol against focal cerebral ischemia/reperfusion (I/R) injury in rats and its relation with gap junction.

METHODSSeventy adult male SD rats were randomly divided into sham-operated group, I/R group, low-, moderate-, and high-dose propofol groups (25, 50, 100 mg/kg; P25, P50, P100 groups, respectively), I/R+CBX group and P100+CBX group. Thread occlusion was used to induce middle cerebral artery occlusion (MCAO) in the mice for 2 h followed by reperfusion for 24 h. Longa's scores were used to evaluate the neurological behavior of the rats. TTC staining was used to measure the cerebral infarction volume and Western blotting was performed to detect the expressions of Cx43, PKC, Bax, and Bcl-2 in the brain of the rats.

RESULTSCompared with the I/R group, the rats pretreated with moderate and high doses of propofol showed significantly reduced neurological behavior scores and cerebral infarction volume percentage, and the effect was more obvious in high-dose propofol pretreatment group. CBX obviously enhanced the protective effect of propofol against I/R injury. Compared with those in the sham-operated group, the protein expression of Cx43 and the Bax/Bcl-2 ratio were increased and the protein expression of PKC was reduced in I/R group, and these changes were significantly reversed by high-dose propofol pretreatment; the effects of propofol were further enhanced by CBX.

CONCLUSIONThe protective effect of propofol against cerebral I/R injury may involve the inhibition of the gap junction via PKC signaling and by reducing the Bax/Bcl-2 ratio.

Animals ; Brain ; metabolism ; Brain Ischemia ; prevention & control ; Connexin 43 ; metabolism ; Gap Junctions ; Infarction, Middle Cerebral Artery ; Male ; Propofol ; pharmacology ; Protein Kinase C ; metabolism ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury ; prevention & control ; Signal Transduction ; bcl-2-Associated X Protein ; metabolism