Electroacupuncture reduces injury to the blood-brain barrier following cerebral ischemia/reperfusion injury

This study used electroacupuncture at Renzhong （DU26） and Baihui （DU20） in a rat model of cerebral ischemia/reperfusion injury. Neurological deficit scores, western blotting, and reverse transcription-PCR results demonstrated that electroacupuncture markedly reduced neurological deficits, decreased corpus striatum aquaporin-4 protein and mRNA expression, and relieved damage to the blood-brain barrier in a rat model of cerebral ischemia/reperfusion injury. These results suggest that electroacupuncture most likely protects the blood-brain barrier by regulating aquaporin-4 expression following cerebral ischemia/reperfusion injury.

Puerarin protects brain tissue against cerebral ischemia/reperfusion injury by inhibiting the inflammatory response

Puerarin, a traditional Chinese medicine, exerts a powerful neuroprotective effect in cerebral ischemia/reperfusion injury, but its mechanism is unknown. Here, we established rat models of middle cerebral artery ischemia/reperfusion injury using the suture method. Puerarin （100 mg/kg） was administered intraperitoneally 30 minutes before middle cerebral artery occlusion and 8 hours after reperfusion. Twenty-four hours after reperfusion, we found that puerarin significantly improved neurological deficit, reduced infarct size and brain water content, and notably diminished the expression of Toll-like receptor-4, myeloid differentiation factor 88, nuclear factor kappa B and tumor necrosis factor-α in the ischemic region. These data indicate that puerarin exerts an anti-inflammatory protective effect on brain tissue with ischemia/reperfusion damage by downregulating the expression of multiple inflammatory factors.

Matrix metalloproteinase-9 expression and blood brain barrier permeability in the rat brain after cerebral ischemia/reperfusion injury

BACKGROUND： The integrity of the blood brain barrier （BBB） plays an important role in the patho-physiological process of cerebral ischemia/reperfusion injury. It has been recently observed that metalloproteinase-9 （MMP-9） is closely related to cerebral ischemia/reperfusion injury OBJECTIVE： This study was designed to observe MMP-9 expression in the rat brain after cerebral ischemia/reperfusion injury and to investigate its correlation to BBB permeability. DESIGN, TIME AND SETTING： This study, a randomized controlled animal experiment, was performed at the Institute of Neurobiology, Central South University between September 2005 and March 2006. MATERIALS： Ninety healthy male SD rats, aged 3-4 months, weighing 200-280 g, were used in the present study. Rabbit anti-rat MMP-9 polyclonal antibody （Boster, Wuhan, China） and Evans blue （Sigma, USA） were also used. METHODS： All rats were randomly divided into 9 groups with 10 rats in each group： normal control group, sham-operated group, and ischemia for 2 hours followed by reperfusion for 3, 6, 12 hours, 1, 2, 4 and 7 days groups. In the ischemia/reperfusion groups, rats were subjected to ischemia/reperfusion injury by suture occlusion of the right middle cerebral artery. In the sham-operated group, rats were merely subjected to vessel dissociation. In the normal control group, rats were not modeled. MAIN OUTCOME MEASURES： BBB permeability was assessed by determining the level of effusion of Evans blue. MMP-9 expression was detected by an immunohistochemical method. RESULTS： All 90 rats were included in the final analysis. BBB permeability alteration was closely correlated to ischemia/reperfusion time. BBB permeability began to increase at ischemia/reperfusion for 3 hours, then it gradually reached a peak level at ischemia/reperfusion for 1 day, and thereafter it gradually decreased. MMP-9 expression began to increase at ischemia/reperfusion for 3 hours, then gradually reached its peak level 2 days after perfusion, and thereafter it gradually decreased. CONCLUSION： MMP-9 expression increases in rat brain tissue after focal cerebral ischemia/reperfusion injury, which correlates with increased permeability of the BBB.

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 Chuanxiongqin hydrochloride on increasing the fluidity of brain cell membrane and scavenging free radicals in model rats with ischemia/reperfusion injury

BACKGROUND: The fluidity of cell membrane can be affected by various factors. Many experiments have confirmed that the ischemia/reperfusion of organic tissue can increase the contents of free radicals, which lead to high rigidity and low fluidity of cell membrane, and the conditions can be changed by Chuanxiongqin. OBJECTIVE: To observe the effect and mechanism of Chuanxiongqin hydrochloride on the fluidity of brain cell membrane in rat models of ischemia/reperfusion. DESIGN: A completely randomized controlled animal trial. SETTINGS: Institute of Brain Sciences; Department of Physiology, Medical College, Datong University. MATERIALS: Twenty male grade Ⅰ Wistar rats of 170-220 g were randomly divided into model group (n =10) and control group (n =10). Chuanxiongqin hydrochloride (molecular mass was 172.2) was purchased from the National Institute for the Control of Pharmaceutical and Biological Products (batch number: 0817-9803); Spin labelers: 5-doxyl-stearlic acid methylester (5DS), 16-doxyl-stearlic acid methylester (16DS), xanthine, xanthine oxidase (XOD) and 5,5-dimeth-1-pyrroline- N-oxide (DMPO) from Sigma Company; Bruker ESP 300 electron paramagnetic resonance (EPR) spectrometer by Bruker Company (Germany). METHODS: The experiments were carried out in the State Key Laboratory of Natural and Biomimetic Drugs, Peking University from June 2001 to July 2002. In the model group, rats were made into models of cerebral ischemia by 30-minute ligation and 2-hour reperfusion of common carotid arteries; The rats in the control group were not made into models. The order parameter (S) and rotational correlation time (τc) were detected with the ESR spectrometer by means of spin labeling. The greater the S and τc, the smaller the fluidity. Meanwhile, the clearance rate of free radicals was detected with ESR spin trapping. The measurement data were compared using the t test. MAIN OUTCOME MEASURES: The S, τc and clearance rates of O2 · and OH· free radicals were compared between the model group and control group. RESULTS: The S and τc in the model group [0.738 4±0.003 5; (8.472±0.027)×10-10 s/circle] were obviously different from those in the control group [0.683 9±0.008 3; (7.945±0.082)×10-10 s/circle, t =5.731, 5.918, P < 0.05], which suggested that ischemia/reperfusion injury decreased the fluidity of brain cell membrane. After adding Chuanxiongqin hydrochloride, there were no obvious differences between the model group [0.688 5±0.030 5; (7.886±0.341)×10-10 s/circle] and control group (P > 0.05), indicating that Chuanxiongqin hydrochloride could recover the fluidity of brain cell membrane after ischemia/reperfusion injury close to the level in the normal control group. Chuanxiongqin hydrochloride could directly scavenge the O2 · and OH· free radicals, and the maximal clearance rates were 83.92% and 44.99% respectively. CONCLUSION: Chuanxiongqin hydrochloride increases the fluidity of membrane of ischemia-injured brain cell by scavenging both O2 ·and OH· free radicals.

Advantages of nanocarriers for basic research in the field of traumatic brain injury

A major challenge for the efficient treatment of traumatic brain injury is the need for therapeutic molecules to cross the blood-brain barrier to enter and accumulate in brain tissue.To overcome this problem,researchers have begun to focus on nanocarriers and other brain-targeting drug delivery systems.In this review,we summarize the epidemiology,basic pathophysiology,current clinical treatment,the establishment of models,and the evaluation indicators that are commonly used for traumatic brain injury.We also report the current status of traumatic brain injury when treated with nanocarriers such as liposomes and vesicles.Nanocarriers can overcome a variety of key biological barriers,improve drug bioavailability,increase intracellular penetration and retention time,achieve drug enrichment,control drug release,and achieve brain-targeting drug delivery.However,the application of nanocarriers remains in the basic research stage and has yet to be fully translated to the clinic.

Preventive administration of cromakalim reduces aquaporin-4 expression and blood-brain barrier permeability in a rat model of cerebral ischemia/reperfusion injury

Cromakalim,an adenosine triphosphate-sensitive potassium channel opener,exhibits protective effects on cerebral ischemia/reperfusion injury.However,there is controversy as to whether this effect is associated with aquaporin-4 and blood-brain barrier permeability.Immunohistochemistry results show that preventive administration of cromakalim decreased aquaporin-4 and IgG protein expression in rats with ischemia/reperfusion injury;it also reduced blood-brain barrier permeability,and alleviated brain edema,ultimately providing neuroprotection.

Regulatory mechanisms of AQP-4 on blood-brain barrier damage after cerebral ischemia reperfusion injury

Aquaporin-4 （AQP-4）, a water-channel protein,is highly expressed in the brain, which is important ele- ments in the formation of brain edema and plays an important role in the rapid transmembrane transport. AQP-4 ex- pression up-regulates after ischemia-reperfusion injury in rats, making the astrocytic endfeet swelling, with the con- sequence of the injury of blood-brain barrier（BBB） , increasing the permeability of BBB, render too much water in the blood flow to the brain parenchyma, which results in cytotoxic edema, disordering the stability of the central nervous system. In addintion, the increased permeability of BBB is one of the important reasons for the cerebral stroke, therefore, it is essential that research the relationship between AQP-4 with BBB further and restore the blood-brain barrier injury be a new strategy for the prevention and treatment of stroke, worthy of further research.

Phycocyanin for protecting brain ischemia-reperfusion injury and its effect on the expression of Caspase-3 mRNA

BACKGROUND ; Phycecyanin can anti-oxidize and clear free radial. Whether its protective effect on brain is related to Caspase-3, the promoter and operator of apoptosis, is highly concerned. OBJECTIVE： To observe phycocyanin for protecting nerve function and reducing the size of cerebral infarction of rats with brain ischemia-reperfusion and its effect on the expression of Cespese-3 mRNA. DESIGN ： A randomized controlled experiment. SETTING ： Institute of Cerebrovascular Disease, Affiliated Hospital of Medical College of Qingdao University MATERIALS： Totally 84 adult healthy female Wistar rats, weighing 210 to 250 g, of clean grade, were provided by the Animal Experimental Center of Shandong University. Phycocyanin （Institute of Oceanography of Chinese Academy of Sciences） was used. METHODS： This experiment was carried out in the Key Laboratory for Prevention and Treatment of Brain Diseases during May to December 2005. ① The rats were randomized into sham-operation group （n=4）, control group （n=-40） and phycocyanin-treated group （n=-40）. Middle cerebral artery occlusion/reperfusion （MACO/R） models were created on the rats of control and phycocyanin-treated groups with suture-occluded method by inserting a thread into left side extemal-internal carotid artery. In the sham-operatien group, inserting suture was omitted. After ischemia for 1 hour and reperfusion for 2 hours, suspension of phycocyanin was intragastdcaUy administrated into the rats of the phycocyanin-treated group at 100 mg/kg , and the same volume of normal saline was isochrenously administrated into the rats of control group as the same. ② Six rats were chosen respectively from the control group and phycocyanin-treated group, then neurologic impairment degrees of rats were evaluated according to Bederson＇s grading. ③ Six rats were chosen respectively from the control and phycocyanin-treated groups. The isolated brain tissue was stained with tdphenyltetrazolium chloride, and then the size of cerebral infarction was calculated with HPIAS-1000 image analytical system by calculating the ratio of cerebral infarction size at each layer and contralateral hemisphere size of the same layer. ④ Twenty--eight rats were chosen respectively from the control and phycocyanin-treated groups, Brain tissue was harvested at reperfusion for 6,12,24 hours and for 2,3,7 and 14 days after ischemia for 1 hour, respectively, 4 rats at each time point. Brain tissue of 4 rats of sham-opera- tion group was harvested at the 24^th hour after operation. Brain tissue sections were performed in situ hybridization detection of Cespase-3 mRNA. MAIN OUTCOME MEASURES： Comparison of neurologic impairment degree, cerebral infarction size and the expression of brain tissue Caspase-3 mRNA of rats between two groups RESULTS： Totally 84 rats entered the stage of result analysis. ① Bederson＇s scores at ischemia and reperfusion for 24 and 48 hours were significantly lower in the phycocyanin-treated group than in the control group（P 〈 0.05）. ② After brain ischemia and reperfusion, the infarction area was the largest in the 3^rc layer in both control and phycocyanin-treated group, which was（25.23±0,47）% and（23.09±120） %, respectively, and the size of infarction area in the 2^nd layer to the 5^th layer was significantly smaller in the phycocyanin-treated group than in the control group （P 〈 0.05）. ③Positive cell counts of brain tissue Caspase-3 mRNA： The number of positive cells of Caspase-3 mRNA of control group was increased from cerebral ischemia and reperfusion 6 hours, reached the peak at ischemia and reperfusion 24 hours, began to decrease 2 days later and positive cells of Caspese-3 mRNA were still expressed on the 14^th day after reperfusion. At ischemia and reperfusion 6,12 and 24 hours as well as 2,3,7 and 14 days, positive cell counts of Caspase-3 at peripheral ischemic area were significantly lower in the phycocyanin-treated greup[（70.67 ±3.65）, （85.06±4.79）, （119.54±5.37）,（74.26±2.19）, （62.06±3.34）, （23.11±1.89）, （10.75±2.63）/visual field] than in the control group [（94.38±8 28）, （108.81 ±16.11）, （140.88±14.47）, （98.13±11.31）, （81.03±9.31）, （31.22±8.86）, （16.06±5.96）Nisual field] （ P 〈 0.05）; and those at central ischemic area were also significantly lower in the phycocyanin-treated group [（33.86±4.01）, （39.51±3.46）, （50.96 ±2.53）, （43.07±4.09）, （36.25 ±3.72）, （9.03±3.87）, （4.91±5.59）/visual field ]than in the control group [（51.35±2.13）, （54.87±3.42）, （61.77±4.94）, （55.69±6.06）, （49.01 ±5.73） ,（12.84±3.37）, （7.32±2.39）/visual field]（P 〈 0.05）. CONCLUSION ： Phycocyanin can obviously improve the neurologic function, reduce the size of brain infarction and down-regulate the expression of Caspase-3 mRNA of rats with ischemia and reperfusion injury, thus protect brain.

Protective effect of ultrashortwave versus radix salviae miltiorrhizae on brains of rats with cerebral ischemia-reperfusion injury

BACKGROUND： HOW to control the effect of oxygen-derived free radicals on development of cerebral injury and cerebral edema is a key factor for treating cerebral ischemia-reperfusion injury. OBJECTIVE： To observe and compare the protective effects, synergistic action and mechanisms of ultrashortwave （USW） and radix salviae miltiorrhizae （RSM） on the focal cerebral ischemia-reperfusion injuries in rats. DESIGN： Randomized controlled animal study SEI-FING： Department of Rehabilitation Medicine, First Hospital affiliated to China Medical University MATERIALS： A total of 160 healthy Wistar rats of both genders and aged 18-20 weeks weighing 250-300 g of clean grade were selected in this study. 5 mL/ampoule RSM injection fluid was produced by the First Pharmaceutical Corporation of Shanghai （batch number： 011019, 0.01 mug）. The USW therapeutic device was produced by Shanghai Electronic Device Factory with the frequency of 40.68 MHz and the maximal export power of 40 W. The first channel of power after modulation was 11 W. METHODS： The experiment was carried out in the Rehabilitation Medicine Department of the First Hospital affiliated to China Medical University from May 2002 to January 2003. Focal ischemia-reperfusion model was established in rats by reversible right middle cerebral artery occlusion with filament. Right cerebral ischemia was for 2 hours and then with 24 hours reperfusion. The scores of neurological deficits were evaluated by 0 to 4 scales. After surgery, 64 successful rats models were divided into four groups according to digital table： control group, USW group, RSM group and RSM ＋ USW group with 16 cases in each group. Rats in control group were intraperitoneally injected with the same volume of saline （0.1 mL/g）; rats in USW group were given small dosage of USW on head for 10 minutes at 6 hours after reperfusion; rats in RSM group were intraperitoneally injected with 0.01 mL/g RSM solution at 30 minutes before reperfusion; rats in RSM ＋ USW group were intraperitoneally injected with 0.01 mL/g RSM parenteral solution at 30 minutes before reperfusion and given small dosage of USW on head for 10 minutes once at 6 hours after reperfusion; sixteen rats in sham operation group did not receive any treatment. All 80 rats were taken brains at 24 hours after reperfusion to measure wet and dry weights to calculate water content： Cerebral water content （%） = （1-dry/wet weight） × 100%. Superoxide dismutase （SOD） activity was measured by hydroxylamine method and malondialdehyde （MDA） content was measured by TBA photometric method. MAIN OUTCOME MEASURES ： Cerebral water content, SOD activity and MDA content RESULTS： All 160 rats except 80 failing in modeling were involved in the final analysis. （① The cerebral water content of left hemisphere made no significant difference （P 〉 0.05）. The cerebral water content of right hemisphere in the control group and the three treatment groups was obviously higher than that of the sham operation group [（81.26±0.77）%, （79.74±0.68）%, （79.76±0.81）%, （79.61±0.79）%, （77.43±0.61）%, P 〈 0.05]. The cerebral water content of right hemisphere in the three treatment groups was obviously lower than that of the control group （P〈 0.05）. There was no significant difference among the three treatment groups （P 〉 0.05）. ② Compared with the control group, SOD activity （right） of the control group decreased obviously （P 〈 0.05）, while MDA content increased obviously （P 〈 0.05）. SOD activity in the three therapeutic groups increased obviously, while MDA content decreased obviously （P 〈 0.05）; there was no significant difference among the three treatment groups （P 〉 0.05）. CONCLUSION： ① USW and RSM therapy have neuroprotective effects against focal cerebral ischemia-reperfusion injuries by means of decreasing cerebral water content and MDA and increasing the activity of SOD. ② Synergistic action was not observed between these two therapeutic methods.

Selective brain hypothermia-induced neuroprotection against focal cerebral ischemia/reperfusion injury is associated with Fis1 inhibition

Selective brain hypothermia is considered an effective treatment for neuronal injury after stroke,and avoids the complications of general hypothermia.However,the mechanisms by which selective brain hypothermia affects mitochondrial fission remain unknown.In this study,we investigated the effect of selective brain hypothermia on the expression of fission 1 (Fis1) protein,a key factor in the mitochondrial fission system,during focal cerebral ischemia/reperfusion injury.Sprague-Dawley rats were divided into four groups.In the sham group,the carotid arteries were exposed only.In the other three groups,middle cerebral artery occlusion was performed using the intraluminal filament technique.After 2 hours of occlusion,the filament was slowly removed to allow blood reperfusion in the ischemia/reperfusion group.Saline,at 4℃ and 37℃,were perfused through the carotid artery in the hypothermia and normothermia groups,respectively,followed by restoration of blood flow.Neurological function was assessed with the Zea Longa 5-point scoring method.Cerebral infarct volume was assessed by 2,3,5-triphenyltetrazolium chloride staining,and apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining.Fis1 and cytosolic cytochrome c levels were assessed by western blot assay.Fis1 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction.Mitochondrial ultrastructure was evaluated by transmission electron microscopy.Compared with the sham group,apoptosis,Fis1 protein and mRNA expression and cytosolic cytochrome c levels in the cortical ischemic penumbra and cerebral infarct volume were increased after reperfusion in the other three groups.These changes caused by cerebral ischemia/reperfusion were inhibited in the hypothermia group compared with the normothermia group.These findings show that selective brain hypothermia inhibits Fis1 expression and reduces apoptosis,thereby ameliorating focal cerebral ischemia/reperfusion injury in rats.Experiments were authorized by the Ethics Committee of Qingdao Municipal Hospital of China (approval No.2019008).

Protective effects of acupuncture on brain tissue following ischemia/reperfusion injury

BACKGROUND： In patients with cerebrovascular disease, by means of the neuroendocrine system, acupuncture supports the transformation of a local pathological status into a physiological status. Recently, great progress has been made in studying the protective effects of acupuncture on brain ischemia/reperfusion injury. OBJECTIVE： To summarize research advances in the protective effects of acupuncture on brain ischemia/reperfusion injury. RETRIEVAL STRATEGY： Using the terms ＂acupuncture, transcutaneous electrical acupoint stimulation, cerebral ischemia/reperfusion injury, and cerebral protection＂, we retrieved articles from the PubMed database published between January 1991 and June 1994. Meanwhile, we searched the China National Knowledge Infrastructure with the same terms. Altogether, 114 articles and their results were analyzed. Inclusive criteria： studies that were closely related to the protective effects of acupuncture on brain ischemia/reperfusion injury, or studies, whose contents were in the same study field and were published recently, or in the authorized journals. Exclusive criteria： repetitive studies. LITERATURE EVALUATION： Thirty articles that related to the protective effects of acupuncture on brain ischemia/reperfusion injury were included. Among them, 7 were clinical studies, and the remaining 23 articles were animal experimental studies. DATA SYNTHESIS： ① Animal experimental studies have demonstrated that acupuncture improves brain blood perfusion and brain electrical activity, influences pathomorphological and ultramicrostructural changes in ischemic brain tissue, is beneficial in maintaining the stability of intracellular and extracellular ions, resists free radical injury and lipid peroxidation, and influences cytokine, neurotransmitter, brain cell signal transduction, and apoptosis-regulating genes. ② Clinical studies have demonstrated that acupuncture not only promotes nutritional supply to local brain tissue in patients with cerebral infarction, but also increases brain blood flow and attenuates inflammatory reactions of injured brain tissue. ③ At present, the mechanisms underlying the protective effects of acupuncture on brain ischemia/reperfusion injury have been greatly studied. Some conclusions, however, are not sufficient or comprehensive, and remain as primarily isolated incidents. CONCLUSION： Studies that focused on mechanisms that influence the protective effects of acupuncture on brain ischemia/reperfusion injury have provided results; however, several mechanisms are still poorly understood. The goals for studying the mechanistic actions of acupuncture are to not only investigate the various protective effects of acupuncture on ischemic brain injury, but to also understand the internal associations between the various protective effects and their common mechanistic actions.

Expression of netrin-1 and its receptors, deleted in colorectal cancer and uncoordinated locomotion-5 homolog B, in rat brain following focal cerebral ischemia reperfusion injury

Netrin-1 is currently one of the most highly studied axon guidance factors. Netrin-1 is widely expressed in the embryonic central nervous system, and together with the deleted in colorectal cancer and uncoordinated locomotion-5 homolog B receptors, netrin-1 plays a guiding role in the construction of neural conduction pathways and the directional migration of neuronal cells. In this study, we established a rat middle cerebral artery ischemia reperfusion model using the intraluminal thread technique. Immunofluorescence microscopy showed that the expression of netrin-1 and deleted in colorectal cancer in the ischemic penumbra was upregulated at 1 day after reperfusion, reached a peak at 14 days, and decreased at 21 days. There was no obvious change in the expression of uncoordinated locomotion-5 homolog B during this time period. Double immunofluorescence labeling revealed that netrin-1 was expressed in neuronal cells and around small vessels, but not in astrocytes and microglia, while deleted in colorectal cancer was localized in the cell membranes and protrusions of neurons and astrocytes. Our experimental findings indicate that netrin-1 may be involved in post-ischemic repair and neuronal protection via deleted in colorectal cancer receptors.

Buyanghuanwu decoction promotes angiogenesis after cerebral ischemia/reperfusion injury：mechanisms of brain tissue repair

Buyanghuanwu decoction has been shown to protect against cerebral ischemia/reperfusion injury,but the underlying mechanisms remain unclear.In this study,rats were intragastrically given Buyanghuanwu decoction,15 m L/kg,for 3 days.A rat model of cerebral ischemia/reperfusion injury was established by middle cerebral artery occlusion.In rats administered Buyanghuanwu decoction,infarct volume was reduced,serum vascular endothelial growth factor and integrin αvβ3 levels were increased,and brain tissue vascular endothelial growth factor and CD34 expression levels were increased compared with untreated animals.These effects of Buyanghuanwu decoction were partially suppressed by an angiogenesis inhibitor（administered through the lateral ventricle for 7 consecutive days）.These data suggest that Buyanghuanwu decoction promotes angiogenesis,improves cerebral circulation,and enhances brain tissue repair after cerebral ischemia/reperfusion injury.

Mapping Changes of Whole Brain Blood Flow in Rats with Myocardial Ischemia/Reperfusion Injury Assessed by Positron Emission Tomography

l8F-labeled fluorodeoxyglucose positron emission tomography (l8F-FDG PET) is the most sensitive tool for studying brain metabolism in vivo.We investigated the image patterns of 18F-FDG PET during reperfusion injury and correlated changes of whole brain blood flow utilizing a rat myocardial ischemia/reperfiision injury (MIRI) model.The results assessed by echocardiography indicated resultant cardiac dysfunction after ischemia-reperfusion in the rat heart.It was found that the average standardized uptake value (SUVaverage) of the whole brain was significantly decreased in model rats,and the glucose uptake of different brain regions including accumbens core/shell (Acb),left caudate putamen (LCPu),hippocampus (HIP),left hypothalamus (LHYP),olfactory (OLF),superior colliculus (SC),right midbrain (RMID),ventral tegmental area (VTA),inferior colliculus (IC) and left thalamus whole (LTHA) was significantly decreased in MIRI rats whereas no significant difference was found in the SUVaverage of amygdala (AMY),right Cpu,RHYP,right HYP,left MID,right THA,pons and medulla oblongata (MO).These l8F-FDG PET data provide a reliable identification method for brain metabolic changes in rats with MIRI.

The action mechanism by which C1q/tumor necrosis factor-related protein-6 alleviates cerebral ischemia/reperfusion injury in diabetic mice

Studies have shown that C1q/tumor necrosis factor-related protein-6 (CTRP6) can alleviate renal ischemia/reperfusion injury in mice. However, its role in the brain remains poorly understood. To investigate the role of CTRP6 in cerebral ischemia/reperfusion injury associated with diabetes mellitus, a diabetes mellitus mouse model of cerebral ischemia/reperfusion injury was established by occlusion of the middle cerebral artery. To overexpress CTRP6 in the brain, an adeno-associated virus carrying CTRP6 was injected into the lateral ventricle. The result was that oxygen injury and inflammation in brain tissue were clearly attenuated, and the number of neurons was greatly reduced. In vitro experiments showed that CTRP6 knockout exacerbated oxidative damage, inflammatory reaction, and apoptosis in cerebral cortical neurons in high glucose hypoxia-simulated diabetic cerebral ischemia/reperfusion injury. CTRP6 overexpression enhanced the sirtuin-1 signaling pathway in diabetic brains after ischemia/reperfusion injury. To investigate the mechanism underlying these effects, we examined mice with depletion of brain tissue-specific sirtuin-1. CTRP6-like protection was achieved by activating the sirtuin-1 signaling pathway. Taken together, these results indicate that CTRP6 likely attenuates cerebral ischemia/reperfusion injury through activation of the sirtuin-1 signaling pathway.

Gut microbial regulation of innate and adaptive immunity after traumatic brain injury

Acute care management of traumatic brain injury is focused on the prevention and reduction of secondary insults such as hypotension,hypoxia,intracranial hypertension,and detrimental inflammation.However,the imperative to balance multiple clinical concerns simultaneously often results in therapeutic strategies targeted to address one clinical concern causing unintended effects in other remote organ systems.Recently the bidirectional communication between the gastrointestinal tract and the brain has been shown to influence both the central nervous system and gastrointestinal tract homeostasis in health and disease.A critical component of this axis is the microorganisms of the gut known as the gut microbiome.Changes in gut microbial populations in the setting of central nervous system disease,including traumatic brain injury,have been reported in both humans and experimental animal models and can be further disrupted by off-target effects of patient care.In this review article,we will explore the important role gut microbial populations play in regulating brain-resident and peripheral immune cell responses after traumatic brain injury.We will discuss the role of bacterial metabolites in gut microbial regulation of neuroinflammation and their potential as an avenue for therapeutic intervention in the setting of traumatic brain injury.

Treatment with β-sitosterol ameliorates the effects of cerebral ischemia/reperfusion injury by suppressing cholesterol overload, endoplasmic reticulum stress, and apoptosis

β-Sitosterol is a type of phytosterol that occurs naturally in plants.Previous studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unknown whetherβ-sitosterol treatment reduces the effects of ischemic stroke.Here we found that,in a mouse model of ischemic stroke induced by middle cerebral artery occlusion,β-sitosterol reduced the volume of cerebral infarction and brain edema,reduced neuronal apoptosis in brain tissue,and alleviated neurological dysfunction;moreover,β-sitosterol increased the activity of oxygen-and glucose-deprived cerebral cortex neurons and reduced apoptosis.Further investigation showed that the neuroprotective effects ofβ-sitosterol may be related to inhibition of endoplasmic reticulum stress caused by intracellular cholesterol accumulation after ischemic stroke.In addition,β-sitosterol showed high affinity for NPC1L1,a key transporter of cholesterol,and antagonized its activity.In conclusion,β-sitosterol may help treat ischemic stroke by inhibiting neuronal intracellular cholesterol overload/endoplasmic reticulum stress/apoptosis signaling pathways.

The effect of hyperglycemia on blood brain barrier of rats with focal cerebral ischemia/reperfusion injury

Objective： To determine whether hyperglycemia could aggravate the microvascular damage in ischemic stroke. Methods： Hyperglycemia model was made by injection of streptozocin through subcutaneous injection in wistar rats. Using the suture model, the rats were subjected to 3h of focal ischemia and different times of reperfusion, including 6,12,24,48,96h and 7d. TIC dyeing was used to Show the infarction area of rats. The infarctive volume of rats were calculated by computer imaging analysis system;Matrix metalloproteinase （MMP-2） and （MMP-9）were detected by immunohistochemistly and in situ hybridization histochemistly in Wistar rats. Results： The infarctive volume was siginificantly larger in hyperglycemic rats than that of nonhyperglycemic rats. The level of MMP-2, MMP-9 expression in the group of hyperglycemic rats was higher than that of nonhyperglycemic rats. Conclusion： Hyperglycemia aggravated the injury of focal ischmia-repeffusion in wistar rats and the higher expression of MMP-2,MMP-9 might be one of the mechanism in aggravation of focal ischemia/repeffusion injury.

Connecting cellular mechanisms and extracellular vesicle cargo in traumatic brain injury

Traumatic brain injury is followed by a cascade of dynamic and complex events occurring at the cellular level. These events include: diffuse axonal injury, neuronal cell death, blood-brain barrier break down, glial activation and neuroinflammation, edema, ischemia, vascular injury, energy failure, and peripheral immune cell infiltration. The timing of these events post injury has been linked to injury severity and functional outcome. Extracellular vesicles are membrane bound secretory vesicles that contain markers and cargo pertaining to their cell of origin and can cross the blood-brain barrier. These qualities make extracellular vesicles intriguing candidates for a liquid biopsy into the pathophysiologic changes occurring at the cellular level post traumatic brain injury. Herein, we review the most commonly reported cargo changes in extracellular vesicles from clinical traumatic brain injury samples. We then use knowledge from animal and in vitro models to help infer what these changes may indicate regrading cellular responses post traumatic brain injury. Future research should prioritize labeling extracellular vesicles with markers for distinct cell types across a range of timepoints post traumatic brain injury.