The miR-9-5p/CXCL11 pathway is a key target of hydrogen sulfide-mediated inhibition of neuroinflammation in hypoxic ischemic brain injury

We previously showed that hydrogen sulfide(H2S)has a neuroprotective effect in the context of hypoxic ischemic brain injury in neonatal mice.However,the precise mechanism underlying the role of H2S in this situation remains unclear.In this study,we used a neonatal mouse model of hypoxic ischemic brain injury and a lipopolysaccharide-stimulated BV2 cell model and found that treatment with L-cysteine,a H2S precursor,attenuated the cerebral infarction and cerebral atrophy induced by hypoxia and ischemia and increased the expression of miR-9-5p and cystathionineβsynthase(a major H2S synthetase in the brain)in the prefrontal cortex.We also found that an miR-9-5p inhibitor blocked the expression of cystathionineβsynthase in the prefrontal cortex in mice with brain injury caused by hypoxia and ischemia.Furthermore,miR-9-5p overexpression increased cystathionine-β-synthase and H2S expression in the injured prefrontal cortex of mice with hypoxic ischemic brain injury.L-cysteine decreased the expression of CXCL11,an miR-9-5p target gene,in the prefrontal cortex of the mouse model and in lipopolysaccharide-stimulated BV-2 cells and increased the levels of proinflammatory cytokines BNIP3,FSTL1,SOCS2 and SOCS5,while treatment with an miR-9-5p inhibitor reversed these changes.These findings suggest that H2S can reduce neuroinflammation in a neonatal mouse model of hypoxic ischemic brain injury through regulating the miR-9-5p/CXCL11 axis and restoringβ-synthase expression,thereby playing a role in reducing neuroinflammation in hypoxic ischemic brain injury.

Dabrafenib,an inhibitor of RIP3 kinase-dependent necroptosis,reduces ischemic brain injury

Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases （RIPK） associated with the tumor necrosis factor-alpha （TNF-a）/death receptor. Recent evidence shows RIPK inhibitors are neuroprotective and al- leviate ischemic brain injury in a number of animal models, however, most have not yet undergone clinical trials and safety in humans remains in question. Dabrafenib, originally identified as a B-raf inhibitor that is currently used to treat melanoma, was later revealed to be a potent RIPK3 inhibitor at micromolar con- centrations. Here, we investigated whether Dabrafenib would show a similar neuroprotective effect in mice subjected to ischemic brain injury by photothrombosis. Dabrafenib administered intraperitoneally at 10 mg/ kg one hour after photothrombosis-induced focal ischemic injury significantly reduced infarct lesion size in C57BL6 mice the following day, accompanied by a markedly attenuated upregulation of TNF-u. However, subsequent lower doses （5 mg/kg/day） failed to sustain this neuroprotective effect after 4 days. Dabrafenib bl ocked lipopolysaccharides-induced activation of TNF-ct in bone marrow-derived macrophages, suggesting that Dabrafenib may attenuate TNF-ct-induced necroptotic pathway after ischemic brain injury. Since Dab- rafenib is already in clinical use for the treatment of melanoma, it might be repurposed for stroke therapy.

Urokinase-type plasminogen activator promotes synaptic repair in the ischemic brain

The central nervous system has a very high energy requirement. Accord- ingly, despite representing only 2% of the body＇s mass, the brain uses 20% of the total oxygen consumption. Importantly, because most of this energy is used to maintain synaptic activity, even a mild decrease in its supply to the brain has deleterious implications for synaptic function.

Empowering sonic hedgehog to rescue brain cells after ischemic stroke

Ischemic stroke occurs when blood supply to the brain is interrupted. This can cause irreversible injury to the cen- tral nervous system （CNS） tissue. Each year in the United States almost 800,000 people experience a new or recur- rent stroke. 15% of stroke patients die shortly after insult and only 10% recover completely, leaving the majority of surviving stroke patients with disabilities. Tissue-type plasminogen activator （tPA） is the only available therapy for stroke but its clinical use is limited because of associ- ated danger of intracranial hemorrhage. Therefore, there is an emergent need for stroke therapeutics that are safe and effective when administered at a later time point after insult.

Expression of hypoxia inducible factor-1 alpha and ischemic erythropoietin tolerance in the brain of cerebral ischemic tolerance model rats

BACKGROUND： Hypoxia inducible factor-1 alpha （HIF-1 （x） and erythropoietin（EPO）, possessing neuroprotective effect in the cerebral ischemia, might play an important role in the formation of cerebral ischemic tolerance （IT）. OBJECTIVE：To observe the neuroprotective effect of cerebral ischemic preconditioning（IPC） of rats, and the expression and mechanism of HIF-1α and target gene erythropoietin in the brain tissue following the formation of cerebral IT. DESIGN ： A randomized and controlled observation SETTING： Department of Neurology, the Affiliated Hospital of Medical College, Qingdao University MATERIALS： Totally 84 enrolled adult healthy male Wistar rats of clean grade, weighing 250 to 300 g, were provided by the Animal Experimental Department, Tongji Medical College of Huazhong University of Science and Technology. Ready-to-use SABC reagent kit and rabbit anti-rat HIF-1α monoclonal antibody were purchased from Boshide Bioengineering Co.Ltd （Wuhan）; Rabbit anti-rat EPO monoclonal antibody was purchased from Santa Cruz Company （USA）. METHODS： This experiment was carried out in the Department of Anatomy, Medical College, Qingdao University during March 2005 to March 2006. ① The 84 rats were divided into 3 groups by a lot： IPC group （n=40）, sham-operation group （n=40） and control group （n=4）. In the IPC group, middle cerebral artery was occluded for 2 hours respectively on the 1^st, 3^rd, 7^th, 14^th and 21^st days of the reperfusion following 10-minute preischemia was made using a modified middle cerebral artery second suture method from Zea-Longa. The rats were sacrificed 22 hours after reperfusion in the end of middle cerebral artery occlusion （MCAO）. That was to say, after 10-minute preischemia, suture was exited to the extemal carotid artery and embedded subcutaneously. Middle cerebral artery was occluded again to form the second reperfusion at the set time point after reperfusion. Twenty-two hours later, rats were sacrificed; In the sham-operation group,the preischemia was substituted by sham-operation（only common carotid artery and crotch were exposed, and MCAO by suture was omitted）, and the other procedures were the same as those in the IPC group. In the control group, rats were given sham-operation twice at an interval of one day, and they were sacrificed 24 hours after the second sham-operation. ② Brain tissue was taken from the rats in each group. Cerebral infarction area of each layer was measured with TTC staining, and total cerebral infarction volume （The total cerebral infarction area of each layerxinterspace ） was calculated. After brain tissue was stained by haematoxylin-esoin （HE）, the form of nerve cells was observed under an optical microscope, and the expressions of HIF-1α（and EPO protein in the brain tissue were detected with immunohistochemical method. MAIN OUTCOME MEASURES： ①Cerebral infarction volume;②form of nerve cell; ③ the expression of HIF-1α and EPO protein in the brain tissue. RESULTS：Totally 84 rats were enrolled in the experiment. The dead rats were randomly supplied during the experiment, and finally 84 rats entered the stage of result analysis. ① Detection of cerebral infarction volume of rats in each group： Cerebral infarction volume in the IPC group was significantly smaller than that in the sham-operation group on the 1^st, 3^rd and 7^th days after reperfusion respectively [（161.2±6.9） mm^3 vs （219.9±11.2） mm^3, （134.9±9.0） mm^3 vs （218.6±13.0） mm^3, （142.9±13.7） mm^3 vs （221.3±14.2） mm^3, t=-8.924, 10.587,7.947, P〈 0.01]. ② Observation of nerve cell form of brain tissue： HE staining showed that the ischemic degree, range and cerebral edema degree of IPC group were significantly milder than those of sham-operation group. ③ The expressions of HIF-1α and EPO protein in cerebral cortex and hippocampus ： The expression of HIF-1αof IPC group was significantly higher than that of sham-operation group on the 1^st, 3^rd and 7^th days after reperfusion respectively （125.93±3.79 vs 117.65±5.60, 140.63±4.64 vs 119.33±4.26, 131.15±2.74 vs 107.60±3.89, t=2.449, 6.763,9.899,P 〈 0.05-0.01）. The expression of EPO of IPC group was significantly higher than that of sham-operation group on the 3^rd and 7^th days after perfusion respectively （141.68±3.29 vs 126.33±4.51, 138.88±2.59 vs 125.58±6.18,t=5.499,3.970, P〈 0.05）. CONCLUSION ： ①IPC can protect the never cells in rat brain and the best time to onset of cerebral IT induced by IPC is 1 to 7 days after reperfusion. ② Neuroprotective effect of cerebral IT might be related to the expression of HIF-1α and its target gene EPO.

Ischemic postconditioning protects against ischemic brain injury by up-regulation of acid-sensing ion channel 2a

Ischemic postconditioning renders brain tissue tolerant to brain ischemia,thereby alleviating ischemic brain injury.However,the exact mechanism of action is still unclear.In this study,a rat model of global brain ischemia was subjected to ischemic postconditioning treatment using the vessel occlusion method.After 2 hours of ischemia,the bilateral common carotid arteries were blocked immediately for 10 seconds and then perfused for 10 seconds.This procedure was repeated six times.Ischemic postconditioning was found to mitigate hippocampal CA1 neuronal damage in rats with brain ischemia,and up-regulate acid-sensing ion channel 2a expression at the m RNA and protein level.These findings suggest that ischemic postconditioning up-regulates acid-sensing ion channel 2a expression in the rat hippocampus after global brain ischemia,which promotes neuronal tolerance to ischemic brain injury.

Vascular endothelial growth factor: an attractive target in the treatment of hypoxic/ischemic brain injury

Cerebral hypoxia or ischemia results in cell death and cerebral edema, as well as other cellular reactions such as angiogenesis and the reestablishment of functional microvasculature to promote recovery from brain injury. Vascular endothelial growth factor is expressed in the central nervous system after hypoxic/ischemic brain injury, and is involved in the process of brain repair via the regulation of angiogenesis, neurogenesis, neurite outgrowth, and cerebral edema, which all require vascular endothelial growth factor signaling. In this review, we focus on the role of the vascular endothelial growth factor signaling pathway in the response to hypoxic/ischemic brain injury, and discuss potential therapeutic interventions.

Mechanisms and status of research on the protective effects of traditional Chinese medicine against ischemic brain injury

Ischemic brain injury occurs when the metabolic needs of brain tissue cannot be met due to insufficient blood supply to the brain.It is one of the main causes of death and adult disability worldwide.The recurrence rate of ischemic brain injury is high.It places a heavy economic burden on families and society,and seriously affects human health and quality of life.In traditional Chinese medicine,ischemic stroke belongs to the category of“stroke”.The use of traditional Chinese medicine to treat stroke has a long history.After years of experimental research,a large amount of theoretical knowledge and practical experience have been accumulated.Promoting blood circulation and removing blood stasis is the basis of traditional Chinese medicine theory on the treatment of ischemic stroke.Commonly used single Chinese medicines include Chuangxiong(Ligusticum chuanxiong hort),Danggui(Angelica sinensis),Danshen(Salvia miltiorrhiza Bunge),Honghua(Carthamus tinctorius L.),Mudanpi(Moutan Cortex),and Huangqi(Astragali Radix).Buyang Huanwu decoction,Xinglou Chengqi decoction,Taohong Siwu decoction,and other traditional Chinese medicine prescriptions are believed to have a protective effect against brain damage caused by ischemic stroke.With the development of modern medical technology,the mechanism of traditional Chinese medicine treatments for ischemic brain injury has gradually been explored.This article reviews the mechanisms of traditional Chinese medicine’s protection against ischemic brain injury and its current clinical application.

Repair and regeneration properties of Ginkgo biloba after ischemic brain injury

The irretrievable fate of neurons rhetoric for the first half of this dominated the neuroscience century, a position that was fiercely contested and recently debunked by extensive studies carried out in the field of neuroregeneration research. The turning point came in the year 1928, when Ramon Y. Cajal＇s （Lobato, 2008） work suggested that the regenerative capacity of neurons, though limited, could exist beyond their physical be- ing and depended on the environment surrounding them. That the manipulation of the restrictive environment surrounding the neuron could aid the regenerative process was conclusively established by Aguayo and colleagues （Richardson et al., 1980）. Since then, various strategies have been employed to target the different phases of regeneration which include： cell-replacement and augmenting endogenous neurogenesis, the use of trophic factors, reversal of the inhibitory cues, and induction of signal- ing pathways that stimulate axon growth and guidance （Horner and Gage. 2000）.

Evidence for a therapeutic effect of Braintone on ischemic brain damage

This study used a novel combination of in vivo and in vitro experiments to show that Braintone had neuroprotective effects and clarified the molecular mechanisms underlying its efficacy. The Chinese herbal extract Braintone is composed of Radix Rhodiolase Essence, Radix Notoginseng Essence, Fofium Ginkgo Essence and Rhizoma Chuanxiong. In vivo experiments showed that cerebral infarction volume was reduced, hemispheric water content decreased, and neurological deficits were alleviated in a rat model of permanent middle cerebral artery occlusion after administration of 87.5, 175 or 350 mg/kg Braintone for 7 consecutive days. Western blot analysis showed that Braintone enhanced the expression of hypoxia-inducible factor la, heme oxygenase-1 and vascular endothe- lial growth factor in the ischemic cortex of these rats. The 350 mg/kg dose of Braintone produced the most dramatic effects. For the in vitro experiments, prior to oxygen-glucose deprivation, rats were intragastrically injected with 440, 880 or 1 760 mg/kg Braintone to prepare a Braintone-co ntaining serum, which was used to pre-treat human umbilical vein endothelial cells for 24 hours. Human umbilical vein endothelial cell injury was alleviated with this pre-treatment. Western blot and real-time PCR analysis showed that the Braintone-containing serum increased the levels of hy- poxia-inducible factor la mRNA and protein, heine oxygenase-1 protein and vascular endothelial growth factor mRNA in oxygen-glucose deprived human umbilical vein endothelial cells. The 1 760 mg/kg dose produced the greatest increases in expression. Collectively, these experimental findings suggest that Braintone has neuroprotective effects on ischemia-induced brain damage via the up-regulation of hypoxia-inducible factor la, heme oxygenase-1 and vascular endothelial growth factor expression in vascular endothelial cells.

Exploring the mechanism of neuronal apoptosis and brain developmental damage in the hippocampus of hypoxicischemic neonatal rats based on BDNF/TrkB/CREB pathway

Objective:Based on the BDNF/TrkB/CREB pathway,to explore the mechanism of neuronal apoptosis and brain developmental injury in the hippocampus of hypoxic-ischemic neonatal rats.Methods:Wistar young rats were ligated on one side of the common carotid artery and placed in an 8%oxygen and 92%nitrogen hypoxia box for 2 h to prepare hypoxic-ischemic brain injury models.Healthy rats were used as the control group.Control group and model group were selected,with 10 rats in each group,and the learning and memory ability was tested by Y-maze;2,3,5-triphenyltetrazolium chloride(TTC)staining was used to detect brain tissue damage;Western blot was performed to determine the expression of brain-derived neurotrophic factor(BDNF),tyrosine protein kinase B(TrKB)and cAMP-response element binding protein(CREB)in hippocampal tissue.Another 15 mice in the control group and 60 mice in the model group were divided into negative control group(NC),BDNF overexpression group(LV-BDNF),TrkB overexpression group(LV-TrkB),and CREB overexpression group(LV-CREB),blank vector,BDNF,TrkB,CREB adenovirus overexpression vector was injected into the tail vein.Y-maze test for learning and memory ability;TTC staining method to detect brain tissue damage;neuronal apoptosis in the hippocampus were detected by terminal-deoxynucleoitidyl transferase mediated nick end labeling;Western blot to detect the level of neuronal apoptosis in the hippocampus.Apoptosis-related protein B-cell lymphoma-2(Bcl-2),BCL2associated X protein(Bcl-2 Assaciated X,Bax)and nuclear factor kappaB(NFκB)expression.Results:The learning and memory ability of the young mice in the model group was significantly reduced,the brain infarct volume was significantly increased,the expressions of BDNF and TrkB proteins in the hippocampus were significantly increased,and the expression of CREB proteins was significantly decreased;After overexpression of BDNF and TrkB CREB,in the LVBDNF,LVTrkB,and LVCREB group,the learning and memory ability of young mice were significantly improved,the brain infarct volume were significantly reduced,the hippocampal neuronal apoptosis were significantly reduced,The protein expression of Bax and NFκB were significantly decreased and the protein expression of Bcl2 were significantly enhanced.Conclusion:The expression of BDNF/TrkB/CREB is abnormal in HIBI model young mice.Overexpression of BDNF/TrkB/CREB can improve the learning and memory ability of young mice,repair brain tissue damage,and inhibit neuronal apoptosis.Therefore,the mechanism of HIBI may be related to BDNF/TrkB/CREB pathways.

Possible divergence of serum-and glucocorticoid-inducible kinase function in ischemic brain injury

As recent medical progress decreases the incidence of certain diseases, ischemic brain injury remains one of the major dis- eases that threaten human lives, especially in western countries. Ischemic brain injury occurs as a result of lack of oxygen and nutrients due to obstruction of blood flow in the brain, and often leads to neurological disorders such as cerebral palsy, depression, and ultimately, death. Around 800,000 Americans suffer a new or recurrent stroke, and more than 130,000 people die annually in the United States （Goldstein et al., 2011）. Despite much effort in searching for an effective treatment, at most a few reagents are approved for therapeutic medication in many countries.

EFFECT OF MILD HYPOTHERMIA ON ACTIVITY NITRIC OXIDE SYNTHASE IN CORTICAL NEURONS AND GLYCEMIA LEVELS OF NEONATAL RATS WITH HYPOXIC ISCHEMIC BRAIN DAMAGE

Through investigating the effect of mild hypothermia on activity of nitric oxide snythase (NOS) in cortical neurons and glycemia levels of neonatal rats with hypoxic ischemic brain damage (HIBD). We studied the mechanism of protecting hypoxic ischemic neurons of mild hypothermia. We established neonatal rat HIBD models, used NOS immunohistochemistry and glycemia determination by micromethod. The number of cortical NOS positive neurons after hypoxic ischemia was significantly decreased as compared with controls. The glycemia levels was significantly increased than that controls. No significant difference was found in number of cortical NOS positive neurons and glycemia levels between 31℃ and 34℃ mild hypothemia. The results imply that hypothermia can decrease overproduction of NO through inhibiting the increase of the activity of NOS, and increase the glycemia levels, thus protect the hypoxic ischemic neurons.

Effect of nitric oxide synthase inhibitor N^G-nitro-L-arginine on the content of amino acid in ischemic brain tissues of rats

BACKGROUND： Nitric oxide synthase （NOS） inhibrtors have been widely used to investigate the role of NO on cerebral ischemic injury, but the results are controversial. Moreover, it has been considered to aggravate the ischemic neuronal damage with the release of excessively excitatory amino acids （EAA） during cerebral ischemia. On the other hand, some inhibitory amino acid is suggested to be important for the neuronal protection against ischemic brain damage. Our study has recently showed that treatment with the NOS inhibitor NG-nitro-L-arginine （L-NA） reduced focal cerebral ischemic damage. The effect of L-NA on the contents of excitatory and inhibitory amino acid in the rat brain following cerebral ischemia is still unclear. OBJECTIVE： By evaluating the effect of NOS inhibitor, L-NA on the contents of aspartate, glutamate, glycine and γ-aminobutyric acid （GABA） in striatum, hippocampus and cortex in the rat brain following cerebral ischemia respectively, to investigate the beneficial effect of L-NA on cerebral ischemic injury and the possible mechanism. DESIGN： A randomized and controlled experiment SETTING ： Department of Pharmacology, Hebei Academy of Medical Sciences MATERIALS： A total of 42 male healthy SD rats （grade Ⅱ, weighting 250-300 g） were provided by the Experimental Animal Center of Hebei Province （Certification： 04036）. Aspartate, glutamate, glycine, GABA, L-NA and 2,3,5-triphenyltetrazolium chloride （TTC） were obtained from Sigma Chemicals Co, St Louis, MO, USA. HPLC-ultraviolet detector system consisted of Agilent 1100 HPLC. METHODS： The experiment was carried out in Department of Pharmrcology, Hebei Academy of Medical Sciences from June 2005 to June 2006. Rats were randomly divided into three groups： sham-operated group （n = 6）, ischemic group （n = 18）, L-NA group （n = 18）. The model of focal cerebral ischemia in rat was prepared with intraluminal line occlusion methods. In sham-operated rats, the external carotid artery was surgically prepared, but the filament was not inserted. Each group was further divided into 3 subgroups （n = 6 for each）： drugs were administrated at 2, 6 and 12 hours after the middle cerebral artery occlusion （MCAO） respectively. L-NA （20 mg/kg, ip） was administrated, twice a day, for 3 consecutive days. Same volume of normal saline was administrated in ischemic and sham operation groups. The changes of infarcted volume and the contents of amino acids were respectively assayed. Image analysis software was used for the measurement of the infarcted area. The results were expressed as a percentage of the infarcted volume of cerebral/volume of whole brain （IV%） in order to control for edema formation. The contents of aspartate, glutamate, glycine and GABA in striatum, hippocampus and cortex in the rat brain following cerebral ischemia were respectively measured by HPLC method. All data were analyzed with one-way ANOVA and Dunnett＇s test. MAIN OUTCOME MEASURES： （1） The volume of cerebral infarction; （2） The contents of aspartate, glutamate glycine and GABA in brain tissue after cerebral ischemia. RESULTS ： All 42 rats were involved in the final analysis. （1） Infarcted volume： Volume was 0 in sham-operated group. When L-NA was administrated at 2 and 6 hours after MCAO, the infarcted volume was （20.13±3.59）% and （23.12±5.84）% in L-NA group, which was not similar to that in ischemic group [（22.10±3.98）%, （25.38± 5.37）%, P〉 0.05]. However, the infarcted volume was markedly decreased compared with that of ischemic group when L-NA was administrated at 12 hours after MCAO [（26.11±3.55）% and （37.15±3.58）%, P 〈 0.01]. Changes of amino acid content： At 2 and 6 hours after ischemia, the contents of aspartate, glutamate, glycine and GABA in striatum, hippocampus and cortex in ischemic group were significantly increased compared with those in sham-operated group （ P〈 0.05-0.01）. However, contents in L-NA group were similar to those in ischemic group （P 〉 0.05）. At 12 hours after ischemia, the contents of aspartate [（0.21 ±0.06）, （0.36±0.05）, （0.29±0.12） mg/g] and glutamate [（0.55±0.06）, （0.78±0.10）, （0.52±0.10） mg/g] in striatum, hippocampus and cortex in L-NA group were significantly decreased compared with those in ischemic group [（0.49±0.17）, （0.63± 0.03）, （0.51±0.15） mg/g; （0.98±0.30）, （1.15±0.15）, （0.93±0.15） mg/g, P〈 0.05-0.01]. Glycine in hippocampus was （0.40±0.07） mg/g, which was higher than that in ischemic group [（0.21±0.07） mg/g, P 〈 0.05]. GABA in striatum, hippocampus and cortex was （0.93±0.10）, （0.62±0.12） and （0.81 ±0.10） mg/g, respectively, which was higher than that in ischemic group [（0.60±0.08）, （0.37±0.17）, （0.59±0.10） mg/g, P 〈 0.05-0.01]. CONCLUSION ： It may be concluded that L-NA have beneficial effect on ischemic cerebral injury in ischemic later stage in rats. The possible mechanism is that L-NA can decrease the contents of aspartate and glutamate, increase the contents of glycine and GABA.

The superiority and feasibility of 2,3,5-triphenyltetrazolium chloride-stained brain tissues for molecular biology experiments based on microglial properties

Background:TTC(2,3,5-triphenyltetrazolium chloride)staining is the most commonly used method in identifying and assessing cerebral infarct volumes in the transient middle cerebral artery occlusion model.Given that microglia exhibit different morphologies in different regions after ischemic stroke,we demonstrate the superiority and necessity of using TTC-stained brain tissue to analyze the expression of various proteins or genes in different regions based on microglia character.Methods:We compared brain tissue(left for 10 min on ice)from the improved TTC staining method with penumbra from the traditional sampling method.We identified the feasibility and necessity of the improved staining method using real time(RT)-PCR,Western blot,and immunofluorescence analysis.Results:There was no protein and RNA degradation in the TTC-stained brain tissue group.However,the TREM2 specifically expressed on the microglia showed a significant difference between two groups in the penumbra region.Conclusions:TTC-stained brain tissue can be used for molecular biology experiments without any restrictions.In addition,TTC-stained brain tissue shows greater superiority due to its precise positioning.

S100B protein in serum is elevated after global cerebral ischemic injury

BACKGROUND:S100B protein in patients with cardiac arrest,hemorrhagic shock and other causes of global cerebral ischemic injury will be dramatically increased.Ischemic brain injury may elevate the level of serum S100 B protein and the severity of brain damage.METHODS:This article is a critical and descriptive review on S100 B protein in serum after ischemic brain injury.We searched Pubmed database with key words or terms such as "S100B protein", "cardiac arrest", "hemorrhagic shock" and "ischemia reperfusion injury" appeared in the last five years.RESULTS:S100B protein in patients with cardiac arrest,hemorrhagic shock and other causes of ischemic brain injury will be dramatically increased.Ischemic brain injury elevated the level of serum S100 B protein,and the severity of brain damage.CONCLUSION:The level of S100 B protein in serum is elevated after ischemic brain injury,but its mechanism is unclear.

The role of glycogen synthase kinase 3 beta in brain injury induced by myocardial ischemia/reperfusion injury in a rat model of diabetes mellitus

Myocardial ischemia/reperfusion injury can lead to severe brain injury.Glycogen synthase kinase 3 beta is known to be involved in myocardial ischemia/reperfusion injury and diabetes mellitus.However,the precise role of glycogen synthase kinase 3 beta in myocardial ischemia/reperfusion injury-induced brain injury is unclear.In this study,we observed the effects of glycogen synthase kinase 3 beta on brain injury induced by myocardial ischemia/reperfusion injury in diabetic rats.Rat models of diabetes mellitus were generated via intraperitoneal injection of streptozotocin.Models of myocardial ischemia/reperfusion injury were generated by occluding the anterior descending branch of the left coronary artery.Post-conditioning comprised three cycles of ischemia/reperfusion.Immunohistochemical staining and western blot assays demonstrated that after 48 hours of reperfusion,the structure of the brain was seriously damaged in the experimental rats compared with normal controls.Expression of Bax,interleukin-6,interleukin-8,terminal deoxynucleotidyl transferase d UTP nick end labeling,and cleaved caspase-3 in the brain was significantly increased,while expression of Bcl-2,interleukin-10,and phospho-glycogen synthase kinase 3 beta was decreased.Diabetes mellitus can aggravate inflammatory reactions and apoptosis.Ischemic post-conditioning with glycogen synthase kinase 3 beta inhibitor lithium chloride can effectively reverse these changes.Our results showed that myocardial ischemic post-conditioning attenuated myocardial ischemia/reperfusion injury-induced brain injury by activating glycogen synthase kinase 3 beta.According to these results,glycogen synthase kinase 3 beta appears to be an important factor in brain injury induced by myocardial ischemia/reperfusion injury.

Effects of Remifentanil Pretreatment on Inflammatory Response in Rats with Acute Cerebral Ischemia Injury

[Objectives]This study was conducted to investigate the effects of remifentanil pretreatment on inflammatory factors in rats with acute cerebral ischemia.[Methods]Sixty SD rats were randomly divided into the normal control group,sham operation group,ischemic brain injury group,and remifentanil pretreatment group.Except the normal control group,each group was divided into three subgroups(six in each group)according to the sampling time points of 6,12 and 24 h after execution.After modeling,the rats were scored for neurological deficit,and observed for pathological changes of neurons in the brain tissue by HE staining and the brain infarct volume by TTC staining,and the expression levels of TNF-α,IL-6 and IL-8 were detected by RT-PCR.[Results]HE staining:No significant changes were observed in the pathological morphology of the brain tissue in the blank group and sham operation group;and the neuronal structure of rats in the acute cerebral ischemia group was obviously damaged,and the neuronal damage in the remifentanil pretreatment group was less than that in the acute cerebral ischemia group at each time point.TTC staining:The gray brain infarct area in the remifentanil pretreatment group was significantly smaller than that in the cerebral ischemia group(P<0.05).RT-PCR detection results:The expression levels of TNF-α,IL-6 and IL-8 in the blank group and sham surgery group did not show significant changes at different times(P>0.05);and compared with the cerebral ischemia group,the expression levels of TNF-α,IL-6,and IL-8 in the remifentanil pretreatment group were significantly reduced at all time points(P<0.05).[Conclusions]Remifentanil pretreatment could protect the brain by reducing the expression of inflammatory factors after cerebral ischemia injury.

神经生长因子治疗新生儿缺氧缺血性脑病的临床疗效观察

目的观察神经生长因子治疗新生儿缺氧缺血性脑病(HIE)的临床疗效。方法将52例确诊为HIE的新生儿随机分为治疗组(n=26)和对照组(n=26),治疗组在对照组常规治疗的基础上应用神经生长因子(NGF)静脉滴注,10d为1个疗程。结果在临床疗效方面,治疗组明显优于对照组。结论神经生长因子治疗HIE疗效明显。

Regulation of mitophagy in ischemic brain injury

The selective degradation of damaged or excessive mitochondria by autophagy is termed mitophagy. Mitophagy is crucial for mitochondrial quality control and has been implicated in several neurodegenerative disorders as well as in ischemic brain injury. Emerging evidence suggested that the role of mitophagy in cerebral ischemia may depend on different pathological processes. In particular, a neuroprotective role of mitophagy has been proposed, and the regulation of mitophagy seems to be important in cell survival. For these reasons, extensive investigations aimed to profile the mitophagy process and its underlying molecular mechanisms have been executed in recent years. In this review, we summarize the current knowledge regarding the mitophagy process and its role in cerebral ischemia, and focus on the pathological events and molecules that regulate mitophagy in ischemic brain injury.