Role of SIRT1 in regulating endoplasmic reticulum stress in early brain injury after subarachnoid hemorrhage / 国际生物医学工程杂志

Objective:To investigate the effect of Sirtuin 1 (SIRT1) on subarachnoid hemorrhage (SAH) and its possible mechanism.Methods:A mouse model of SAH was constructed by internal carotid artery puncture. The protein and mRNA expression levels of SIRT1 at 0, 3, 6, 12, 24, 48, and 72 h were detected by Western Blot and qRT-PCR. A Western Blot assay was used to examine SIRT1 and the expression levels of endoplasmic reticulum stress-related markers GRP78, p-PERK/PERK, p-eIF2α/eIF2α, and CHOP after administration of a SIRT1 inhibitor or SIRT1 si-RNA. At 24 h after SAH, subarachnoid hemorrhage volume, neurological function score, brain water content, and blood-brain barrier integrity were measured.Results:The highest expression of SIRT1 protein and mRNA was observed at 24 h compared with other time points, and the differences were statistically significant (all P < 0.001). Inhibition of SIRT1 expression leads to increased expression of endoplasmic reticulum stress-related proteins GRP78, p-PERK/PERK, p-eIF2α/eIF2α, and CHOP, exacerbating hemorrhage and brain water content, disrupting blood-brain barrier integrity, and significantly reducing neurological function scores. Conclusions:Inhibition of SIRT1 expression significantly increased the endoplasmic reticulum response to excitation and exacerbated early brain injury after SAH.

Protective effects of histone deacetylase 6 specific inhibitor tubastatin A on subarachnoid hemorrhage in rats and the underlying mechanisms / 中南大学学报(医学版)

OBJECTIVES@#Subarachnoid hemorrhage (SAH) is a serious cerebrovascular disease. Early brain injury (EBI) and cerebral vasospasm are the main reasons for poor prognosis of SAH patients. The specific inhibitor of histone deacetylase 6 (HDAC6), tubastatin A (TubA), has been proved to have a definite neuroprotective effect on a variety of animal models of acute and chronic central nervous system diseases. However, the neuroprotective effect of TubA on SAH remains unclear. This study aims to investigate the expression and localization of HDAC6 in the early stage of SAH, and to evaluate the protective effects of TubA on EBI and cerebral vasospasm after SAH and the underlying mechanisms.@*METHODS@#Adult male SD rats were treated with modified internal carotid artery puncture to establish SAH model. In the first part of the experiment, rats were randomly divided into 6 groups: a sham group, a SAH-3 h group, a SAH-6 h group, a SAH-12 h group, a SAH-24 h group, and a SAH-48 h group. At 3, 6, 12, and 24 h after SAH modeling, the injured cerebral cortex of rats in each group was taken for Western blotting to detect the expression of HDAC6. In addition, the distribution of HDAC6 in the cerebral cortex of the injured side was measured by immunofluorescence double staining in SAH-24 h group rats. In the second part, rats were randomly divided into 4 groups: a sham group, a SAH group, a SAH+TubAL group (giving 25 mg/kg TubA), and a SAH+TubAH group (giving 40 mg/kg TubA). At 24 h after modeling, the injured cerebral cortex tissue was taken for Western blotting to detect the expression levels of HDAC6, endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS), terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining to detect apoptosis, and hematoxylin and eosin (HE) staining to detect the diameter of middle cerebral artery.@*RESULTS@#The protein expression of HDAC6 began to increase at 6 h after SAH (P<0.05), peaked at 24 h (P<0.001), and decreased at 48 h, but there was still a difference compared with the sham group (P<0.05). HDAC6 is mainly expressed in the cytoplasm of the neurons. Compared with the sham group, the neurological score was decreased significantly and brain water content was increased significantly in the SAH group (both P<0.01). Compared with the SAH group, the neurological score was increased significantly and brain water content was decreased significantly in the SAH+TubAH group (both P<0.05), while the improvement of the above indexes was not significant in the SAH+TubAL group (both P>0.05). Compared with the sham group, the expression of eNOS was significantly decreased (P<0.01) and the expressions of iNOS and HDAC6 were significantly increased (P<0.05 and P<0.01, respectively) in the SAH group. Compared with the SAH group, the expression of eNOS was significantly increased, and iNOS and HDAC6 were significantly decreased in the SAH+TubA group (all P<0.05). Compared with the SAH group, the number of TUNEL positive cells was significantly decreased and the diameter of middle cerebral artery was significantly increased in the SAH+TubA group (both P<0.05) .@*CONCLUSIONS@#HDAC6 is mainly expressed in neurons and is up-regulated in the cerebral cortex at the early stage of SAH. TubA has protective effects on EBI and cerebral vasospasm in SAH rats by reducing brain edema and cell apoptosis in the early stage of SAH. In addition, its effect of reducing cerebral vasospasm may be related to regulating the expression of eNOS and iNOS.

Schisandrin B Inhibits NLRP3 Inflammasome Pathway and Attenuates Early Brain Injury in Rats of Subarachnoid Hemorrhage / 中国结合医学杂志

OBJECTIVE@#To determine whether Schisandrin B (Sch B) attenuates early brain injury (EBI) in rats with subarachnoid hemorrhage (SAH).@*METHODS@#Sprague-Dawley rats were divided into sham (sham operation), SAH, SAH+vehicle, and SAH+Sch B groups using a random number table. Rats underwent SAH by endovascular perforation and received Sch B (100 mg/kg) or normal saline after 2 and 12 h of SAH. SAH grading, neurological scores, brain water content, Evan's blue extravasation, and terminal transferase-mediated dUTP nick end-labeling (TUNEL) staining were carried out 24 h after SAH. Immunofluorescent staining was performed to detect the expressions of ionized calcium binding adapter molecule 1 (Iba-1) and myeloperoxidase (MPO) in the rat brain, while the expressions of B-cell lymphoma 2 (Bcl-2), Bax, Caspase-3, nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), apoptosis-associated specklike protein containing the caspase-1 activator domain (ASC), Caspase-1, interleukin (IL)-1β, and IL-18 in the rat brains were detected by Western blot.@*RESULTS@#Compared with the SAH group, Sch B significantly improved the neurological function, reduced brain water content, Evan's blue content, and apoptotic cells number in the brain of rats (P<0.05 or P<0.01). Moreover, Sch B decreased SAH-induced expressions of Iba-1 and MPO (P<0.01). SAH caused the elevated expressions of Bax, Caspase-3, NLRP3, ASC, Caspase-1, IL-1β, and IL-18 in the rat brain (P<0.01), all of which were inhibited by Sch B (P<0.01). In addition, Sch B increased the Bcl-2 expression (P<0.01).@*CONCLUSION@#Sch B attenuated SAH-induced EBI, which might be associated with the inhibition of neuroinflammation, neuronal apoptosis, and the NLRP3 inflammatory signaling pathway.

Baicalin Reduces Early Brain Injury after Subarachnoid Hemorrhage in Rats / 中国结合医学杂志

OBJECTIVE@#To evaluate the effect of baicalin on subarachnoid hemorrhage (SAH) in rats and explore the potential mechanisms.@*METHODS@#Sprague-Dawley rats underwent experimental SAH and received treatment with baicalin at 10 or 50 mg/kg after 2 and 12 h of SAH. Neurological scores, brain water content, Evans-blue extravasation, and levels of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), myeloperoxidase (MPO), and malondialdehyde (MDA) were measured 24 h after SAH. Expression of nuclear factor erythroid-related factor 2 (Nrf2), NAD(P)H: quinone oxidoreductase 1 (NQO1), matrix metalloproteinase-9 (MMP-9), aquaporin 4 (AQP4), occludin, and zonulaoccludens-1 (ZO-1) were detected in the brain by Western blot. Heme oxygenase-1 (HO-1) was detected by quantitative polymerase chain reaction, and tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were assessed by enzyme-linked immunosorbent assay.@*RESULTS@#Baicalin attenuated EBI 24 h after SAH in rats (P<0.05). Baicalin elevated neurological scores, GSH-Px, SOD, and increased the expression of Nrf2, NQO1, HO-1, occludin, and ZO-1 in SAH rats (P<0.05 or P<0.01). Baicalin reduced MPO, MDA, and the expression of MMP-9, AQP4, TNF-α, and IL-1β (P<0.05 or P<0.01).@*CONCLUSION@#Baicalin reduced SAH-induced EBI, partially via activation of the Nrf2/HO-1 pathway and inhibition of MMP-9 and AQP4.

The role of toll-like receptor 4 in early brain injury in rats with subarachnoid hemorrhage and its effect on the autophagy of neurons in the hippocampus / 西安交通大学学报(医学版)

Objective: To investigate the role of Toll-like receptor 4 (TLR4) in early brain injury in rats with subarachnoid hemorrhage and its effect on autophagy in hippocampus CA1 area. Methods: Totally 192 SD rats were randomly divided into sham operation group, SAH model group (model group), SAH+DMSO solvent group (solvent group), and SAH+TLR4 inhibitor group (CLI-095 group). Each group was divided into 24 h and 48 h 2 time points. The SAH model was established by internal carotid artery puncture. The drug-administered group was injected with 10 μL of DMSO solution or 100 μg/mL of CLI-095 solution of 10 μL before the preparation of SAH model. The behavioral changes of the rats were detected by Garcia score; the cerebral edema was detected by wet and dryweight method. The morphology of hippocampal CA1 neurons was observed by HE staining. Immunohistochemistry and immunoblotting were used to detect the expressions of TLR4, LC3 and Beclin1 in the hippocampus CA1 area. Results: Compared with the sham group, Garcia score was reduced at each time point (P<0.05). The degree of brain edema was increased and the number of viable neurons was reduced (P<0.05). The expressions of TLR4, LC3 and Beclin1 were increased in the hippocampus CA1 area in the model group (P<0.05). Compared with the model group, the Garcia score was increased at each time point (P<0.05). The degree of brain edema was reduced and the number of viable neurons was increased (P<0.05). The expressions of TLR4, LC3 and Beclin1 were reduced in the hippocampus CA1 area in the CLI-095 group (P<0.05). Conclusion: TLR4 may participate in the regulation of SAH-induced autophagy and aggravate the process of secondary brain injury in SAH.

Effect of Gastrodin on Early Brain Injury and Neurological Outcome After Subarachnoid Hemorrhage in Rats / 神经科学通报·英文版

Gastrodin is a phenolic glycoside that has been demonstrated to provide neuroprotection in preclinical models of central nervous system disease, but its effect in subarachnoid hemorrhage (SAH) remains unclear. In this study, we showed that intraperitoneal administration of gastrodin (100 mg/kg per day) significantly attenuated the SAH-induced neurological deficit, brain edema, and increased blood-brain barrier permeability in rats. Meanwhile, gastrodin treatment significantly reduced the SAH-induced elevation of glutamate concentration in the cerebrospinal fluid and the intracellular Ca overload. Moreover, gastrodin suppressed the SAH-induced microglial activation, astrocyte activation, and neuronal apoptosis. Mechanistically, gastrodin significantly reduced the oxidative stress and inflammatory response, up-regulated the expression of nuclear factor erythroid 2-related factor 2, heme oxygenase-1, phospho-Akt and B-cell lymphoma 2, and down-regulated the expression of BCL2-associated X protein and cleaved caspase-3. Our results suggested that the administration of gastrodin provides neuroprotection against early brain injury after experimental SAH.

A study on the relationship between placental inflammation, prenatal corticosteroids and early brain injury of preterm infants / 中国新生儿科杂志

Objective To study the correlation between histological chorioamnionitis (HCA),prenatal corticosteroids and early brain injury of preterm infants.Method From December 2014 to December 2016,preterm infants with gestational age ≤ 34 weeks admitted to our hospital and umbilical cord blood samples taken immediately after birth were reviewed.According to the results of pathological examination of their mother's placenta and the use of glucocorticoids (GCs),they were assigned into HCA+ GCs + group,HCA + GCs-group,HCA-GCs-group,and HCA-GCs +group.The levels of lnterleukin-6 (IL-6),hepcidin,erythropoietin (EPO),human activin A (ACV-A),S-100β protein,and CC-chemokine ligand 18 (CCL18) in premature infants' umbilical cord blood in each group were tested using ELISA method.The incidences of premature infants' early brain injury and the correlation with inflammatory factors in each group were analyzed.The ROC curve was used to analyze the sensitivity and specificity of S-100β protein and IL-6 level in predicting early brain injury in preterm infants with placenta inflammation.Result A total of 343 infants with gestational age ≤ 34 weeks and their umbilical cord blood samples were tested.Among the 343 premature infants,47.1％ suffered from early brain injury (98/208) in the HCA+ group;while 27.4％ suffered from early brain injury (37/135) in the HCA-group,the difference was statistically significant between the two groups (P ＜ 0.001).A total of 142 cases received prenatal GCs treatment,and 41 (28.9％) cases had early brain injury.201 cases didn't receive prenatal GCs treatment,and 94 (46.8％) had early brain injury.The differences between the two groups were also statistically significant (P=0.001).The incidence of early brain injury in the HCA+GCs-group was significantly higher than the HCA+GCs+ group,HCA-GCs-group and HCA-GCs+ group(P＜0.05).The S-100β protein and IL-6 level in umbilical cord blood of the HCA+GCs-group and HCA+GCs+ group were higher than the HCA-GCs-group(P＜0.05).The area under the ROC curve for IL-6 predicting early brain injury in preterm infants was 0.732 (95％CI 0.675～0.789,P＜0.05).The cut-off value of 213.45 pg/ml of IL-6 (was selected to predict the risk of early brain injury with the sensitivity of 41.9 ％ and the specificity 99.0 ％.The area under the ROC curve for S-100β protein was 0.511 (95％CI 0.449～0.574,P=0.723).Conclusion Placental inflammation and insufficient prenatal glucocorticoids treatment are closely related to the occurrence of early brain injury in preterm infants.S-100β protein and IL-6 in umbilical cord blood may play an important role in early brain injury of premature infants.The IL-6 level has a higher predictive value for early brain injury,while S-100β protein level has a less predictive value.

Tristetraprolin attenuates subarachnoid hemorrhage-induced early brain injury in rats / 中国病理生理杂志

AIM:To explore the expression level of tristetraprolin(TTP)in rats after subarachnoid hemor-rhage(SAH)as well as the potential role of TTP in the early brain injury(EBI)after SAH in rats.METHODS:In the first experiment setting,total 56 adult male SD rats were randomly divided into sham group and SAH group.The SAH mod-el was performed by endovascular perforation.The brain tissues were taken out after SAH at 5 different time points(0,12, 24,48,72 h and 1 week).The expression of TTP in the brain tissues was detected by Western blot.In the second experi-ment,a total of 60 SD rats were divided into 4 groups: sham group, SAH group, SAH +vector group and SAH +TPP group.Neurological score,brain water content and blood-brain barrier were evaluated at 48 h after SAH.TUNEL staining was performed to detect cell apoptosis in the rat brain tissue.ELISA method was used for quantitative detection of interleu-kin-6(IL-6)and tumor necrosis factor-α(TNF-α).The protein levels of TTP,Bax,Bcl-2 and cleaved caspase-3 in the rat brain tissue were detected by Western blot.RESULTS:The protein expression of TTP in the brain was downregulated markedly from 12 h after SAH,reached the lowest level at 48 h,and then had an upward trend.After modeling for 48 h, Garcia neurological score was significantly reduced,and brain water content and Evans blue(EB)content of the brain tis-sue of the rats in SAH group were significantly higher than those in sham group(P<0.05).SAH induced significant in-creases in IL-6 and TNF-αlevels in the brain tissue(P<0.05).The number of TUNEL-stained cells was increased in the subcortical brain region after SAH compared with sham group.In addition,a lower level of Bcl-2 and higher levels of Bax and cleaved caspase-3 in the rat brains were observed at 48 h after SAH.However,the neurological deficit score was signif-icantly increased,and the brain water content and EB content in the rat brains were significantly reduced in SAH +TTP group in comparison with SAH +vector group(P<0.05).Over-expression of TTP dramatically suppressed the levels of IL-6 and TNF-αin the rat brains,and reduced the number of TUNEL positive cells.Furthermore,upregulation of TTP signifi-cantly decreased the levels of cleaved caspase-3 and Bax, and evidently enhanced the expression of Bcl-2(P<0.01). CONCLUSION:The expression of TTP is significantly decreased in early period after SAH, and enhancing the level of TTP effectively inhibits EBI following SAH in rats.

The influence of U0126 of ERK signaling pathway inhibitor on early brain inj ury and neurons autophagy in SAH rats / 西安交通大学学报(医学版)

ABSTRACT:Objective To explore role of U0126,the specific inhibitor of ERK signaling pathway,in early brain injury (EBI)and the autophagy of nerve cells in hippocampus area in subarachnoid hemorrhage (SAH). Methods A total of 48 male adult SD rats were randomly divided into control group,SAH group,DMSO+SAH group,and U0126+SAH group,with 12 in each.We established SAH rat model by the puncture of internal carotid artery.The same amount of saline water,DMSO and U0126 solution of 0.5 mL per rat was injected respectively into the rats of different groups 30 min before modeling.The rats were killed at 24 h.To measure brain water content by Wet and dry method after 24 h,the morphological changes of hippocampus CA1 neural cells were observed by microscopy;the expression levels of ERK,Beclin-1 and LC3 were detected by using immunohistochemical method. Results Compared with that in sham group,brain water content increased obviously in SAH model group.The density of surviving neurons in SAH group was significantly lower than that in control group (P<0 .0 5 ).ERK signaling pathway was activated obviously,the expressions of Beclin 1 and LC3-Ⅱ were significantly higher than those in control group (P<0.05).Compared with SAH model group,in U0126 group brain water content increased obviously.Compared with those in SAH group,the density of surviving neurons was significantly lower (P<0.05), ERK signaling pathway was suppressed,the expressions of Beclin-1 and LC3-Ⅱ were significantly lower (P<0.05). Conclusion The U0126,the ERK signaling pathway inhibitor,can inhibit neuron autophagy and increase EBR of SAH.

Protective effect of mitochondria-targeted antioxidant SS31 on early brain injury following subarachnoid hemorrhage in rats / 中南大学学报(医学版)

Objective:To evaluate protective effects of SS31 on early brain injury (EBI) induced by subarachnoid hemorrhage (SAH) in rats.Methods:A total of 96 Sprague-Dawley rats were randomly divided into 4 groups:A sham group,an SAH group,an SAH+vehicle group (SAH+V),and an SAH+SS31 group.The SAHinduced prechiasmatic cistern rat model was established in this study.Neurological deficit scores were evaluated at 24 h after SAH.The SS31 (5 mg/kg) as well as equal volume of vehicle were administrated intraperitoneally at 2 h after SAH.The neurological scores,brain edema,blood-brain barrier (BBB) permeability,apoptosis,malondialdehyde (MDA),glutathione peroxidase (GPx) activity,superoride dismutase (SOD) activity,and the expression ofcytosolic cytochrome c (Cyt C) and Bax were analyzed at 24 h after SAH.Results:Treatment with SS31 could significantly reduce MDA levels,and restored the activities of GPx and SOD in the cortex following SAH when compared with the SAH+V group.In addition,Bax SS31 trearment increased or decreased the levels of mitochondrial Cyt C or Bax,respectively.Moreover,SS31 treatment ameliorated brain edema and Evans blue dye extravasation,improved neurological deficits,and decreased neuronal apoptosis at 24 h after SAH.Conclusion:SS31 could alleviate EBI after SAH through its antioxidant property and ability in inhibition of neuronal apoptosis.

Effect of Extracellular Regulated Protein Kinases Signaling Pathway on Early Brain Injury and Neurons Autoph-agy in Rats with Subarachnoid Hemorrhage / 中国康复理论与实践

Objective To explore the effect of extracellular regulated protein kinases (ERK) signaling pathway on early brain injury and autophagy of nerve cell in hippocampus area in rats with subarachnoid hemorrhage (SAH). Methods Forty-eight adult male Sprague-Daw-ley rats were randomly divided into sham group, SAH group, SAH+dimethyl sulfoxide (DMSO) group and SAH+U0126 group, with 12 rats in each group. The SAH model was established with puncture of internal carotid artery. The SAH+U0126 group was injected with U0126 0.05 mg/kg;the sham group and SAH group were injected with normal saline, and the SAH+DMSO group was injected with DMSO 30 min-utes before modeling. They were sacrificed 24 hours after modeling. The brain water content was measured with wet and dry method. The morphology changes of neural cells in hippocampus CA1 were observed by HE staining. The expression of phosphorylation ERK (p-ERK), Beclin-1 and LC3-Ⅱwere detected with immunohistochemical method and Western blotting. Results Compared with the sham group, the brain water content increased (P0.05). Conclusion The activation of ERK signaling pathway may alleviate early brain injury after SAH by regulation of autophagy.

Downregulation of thioredoxin-interacting protein attenuates early brain injury after subarachnoid hem- orrhage of rats / 中国神经精神疾病杂志

Objective To explore the possible mechanism by which thioredoxin-interacting protein (TXNIP) par?ticipated in early brain injury (EBI) of subarachnoid hemorrhage (SAH) via examination of the expression of TXNIP and its downstream apoptotic factors before and after intervention. Methods Subarachnoid Hemorrhage (SAH) was performed by endovascular perforation. Total 97 adult male SD rats were randomly divided into 6 groups:sham-operation (17), SAH (32), control siRNA (12), TXNIP siRNA (12), resveratrol control (12) and resveratrol injection (12). Western blot was used to examine the expression of TXNIP, p-ASK-1, Caspase-3 before and after intervention. Laser scanning confocal microscopy (LSCM) was used to detect the expression of TXNIP in neurons. The co-localization of TXNIP with apoptotic cells was examined by using fluorescent TUNEL. Mortality, behavior score and cerebral edema were also evaluated. Re?sults Mortality, behavior scores and brain edema were improved after TXNIP siRNA and resveratrol injection(P<0.05). LSCM showed that TXNIP was widely expressed in brain and mainly located in cytoplasm of neurons in SAH rats. Fluo?rescent TUNEL revealed the co-localization of TXNIP with apoptotic cells. The expression level of TXNIP was signifi?cantly higher in SAH group than in sham operation (P<0.05, n=3). The expression level of TXNIP gradually increased at 12h and still remained at high level at 72h (P<0.05). This increase was simultaneously accompanied by the increase in downstream apoptosis factors, p-ASK-1 and Caspase-3. Inhibition of TXNIP by siRNA or resveratrol significantly re?duced the expression of TXNIP, p-ASK-1 and Caspase-3 (P<0.05, n=3). Conclusion TXNIP gradually increases in ear?ly period after SAH and aggravates brain damage through activation of ASK-1 apoptosis signaling pathway, whereas inhi?bition of TXNIP may attenuate EBI through reduction of p-ASK-1 and Caspase-3 after SAH.

Role of glucose-regulated protein 78 in early brain injury after experimental subarachnoid hemorrhage in rats / 华中科技大学学报（医学）（英德文版）

Early brain injury (EBI) plays a key role in the pathogenesis of subarachnoid hemorrhage (SAH). This study investigated the role of glucose-regulated protein 78 (GRP78) in EBI after SAH. Male Sprague-Dawley rats (n=108) weighing 260±40 g were divided into control, sham-operated, and operated groups. Blood was injected into the prechiasmatic cistern of rats in the operated group. Neurological scores, ultrastructures of neurons, apoptosis, and GRP78 expression in the hippocampus were examined using Garcia scoring system, transmission electron microscopy, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling, and Western blotting at 1, 6, 12, 24, 48, and 72 h after SAH, respectively. The results showed that neurological scores were significantly decreased in the operated group as compared with those in control and sham-operated groups at 12, 24, 48, and 72 h. Metachromatin, chromatin pyknosis at the edge, endoplasmic reticulum swelling, and invagination of nuclear membrane were observed at 24 h in the operated group, indicating the early morphological changes of apoptosis. The number of apoptotic cells was significantly increased in the operated group as compared with that in control and sham-operated groups at 6, 12, 24, 48, and 72 h. The GRP78 protein expression levels in the operated group were significantly elevated at all time points and reached the peak at 12 h. GRP78 expression was positively associated with apoptosis cells and negatively with neurological scores. In conclusion, EBI was demonstrated to occur after SAH and GRP78 was involved in the development of EBI after SAH.

Research progress of early brain injury mechanism after subarachnoid hemorrhage / 医学研究生学报

Subarachnoid hemorrhage ( SAH) especially aneurismal SAH is a deadly cerebrovascular disorder with very high mortality and morbidity rates, but there is still no effective treatment in clinical practice.In recent years, more and more studies have suggested that early brain injury ( EBI) may be the main factor for poor prognosis of SAH.The pathogenesis of EBI after SAH includes a series of complicated pathophysiological changes.This paper reviews the related progress of EBI after SAH from the aspects of acute cerebral ischemia, the disruption of blood brain barrier, apoptosis, autophagy, oxidative stress, inflammation, and so on.

Aminoguanidine alleviates early brain injury after subarachnoid hemorrhage in rats / 医学研究生学报

Objective Recent studies have indicated that early brain injury is the leading cause of death in patients with subarachnoid hemorrhage ( SAH) .Our study investigated the role of aminoguanidine ( AG) in early brain injury after SAH . Methods Sixty-eight male SD rats were equally randomized into four groups of equal number :control, sham, SAH, and AG.The animals in the sham group were injected with isotonic saline solution , while those of the latter two groups with femoral artery blood ( FAB) and FAB+AG, respectively, into the pre-chiasmatic cistern to induce SAH. At 24 hours after modeling , all the rats were killed for HE staining , obtainment of behavioral neurological assessment ( BNA ) scores by Garcia, measurement of the apoptosis of neurons by TUNEL , and de-termination of the expressions of the iNOS and NSE proteins by West-ern blot. Results The results of HE staining showed the presence of more red blood cells in the subarachnoid cavity of the rats in the SAH group, with a significantly decreased BNA score ( 14.47 ± 0.62) as compared with those in the control (17.94 ±0.24), sham (17.59 ±0.51), and AG group (15.71 ±0.47) (P<0.05). The rate of positive cells was remarkably higher in the SAH group ([42.38 ±2.38]%) than in the control ([6.35 ±0.94]%), sham ([6.85 ±0.69]%), and AG group ([30.48 ±2.89]%) ( P<0.01), with significant differences among the latter three groups (P<0.05).The expressions of iNOS and NSE were markedly higher in the SAH group ([3.86 ±0.07] and [1.59 ±0.06]) than in the control (0 and[0.35 ±0.09]), sham ([2.96 ±0.34] and [0.38 ±0.08]), and AG group ([3.41 ±0.04] and [0.70 ±0.12]) ( P<0.05).Both the expression levels of iNOS and NSE were positively correlated with the rate of positive cells (r=0 .879 and 0.935, P<0.01). Conclusion AG can alleviate early brain injury after SAH in SD rats by improving the neuro-ethologic function , suppressing the apoptosis of neurons , and reducing the expressions of iNOS and NSE .

Effects of DETA/NO on capillary spasm and early brain inj ury after subarachnoid hemorrhage in rats / 西安交通大学学报(医学版)

Objective To explore the effects of diethylenetriamine/nitric oxide (DETA/NO)on capillary spasm and early brain injury (EBI)after subarachnoid hemorrhage (SAH)in rats.Methods Sixty-nine male Sprague-dawley rats were randomized into three groups:sham group,SAH group and DETA/NO group.SAH model was established by wearing out the willis ring with thread and then Garcia neurological score was observed in the general animals.The expressions of alpha smooth muscle actin (αSMA)and PDGFRβwere detected by dual immunofluorescence staining;nitric oxide kit was used for detecting brain tissue NO concentration.Changes in the hemoglobin-stimulated capillaries were observed in rat slices.Results Three days after surgery,neurological deficit score was remarkably improved in DETA/NO group compared with that in SAH group (P<0 .0 5 ). Immunofluorescence results showed that the expressions of peri-capillaryαSMA and PDGFRβwere significantly increased after SAH (P<0.05 ),and that DETA/NO could down-regulate the expressions (P<0.05 ).NO concentration was greatly reduced about 3 hours after SAH and then gradually increased;DETA/NO could maintain the concentration of NO at an early stage (P<0 .0 5 ).The capillary contraction was observed in slices perfused with hemoglobin;DETA/NO could alleviate capillary spasm.Conclusion DETA/NO can alleviate the severity of capillary spasm and EBI after SAH in rats.

Nrf2 knockout and brain injury following subarachnoid hemorrhage in mice / 医学研究生学报

Objective Subarachnoid hemorrhage ( SAH) is a devastating disease with a high mortality.This study was to in-vestigate the effect of Nrf2 on secondary brain injury following SAH and its action mechanism in mice. Methods SAH models were established in wild-type ( WT) and Nrf2 knockout ( KO) ICR male mice by injecting fresh blood drawn from the femoral artery into the pre-chiasmatic cistern.The animals were divided into four groups, WT sham, WT SAH, KO sham, and KO SAH.At 24 hours after modeling, the expression levels of malondialdehyde ( MDA) , GSH/GSSG, TNF-αand IL-1β, the volume of brain water, and content of Evans blue were measured, the activity scores obtained, and cerebral vasospasm of the anterior and middle cerebral arteries ( ACA and MCA) detected. Results At 24 hours, the expressions of MDA, TNF-α, and IL-1βwere (3.299 ±0.335), (1.187 ± 0.436), and (59.330 ±21.787) mg/g in the WT sham group, (4.339 ±0.328), (2.432 ±0.434), and (121.584 ±21.675) mg/g in the WT SAH group, (3.488 ±0.634), (1.170 ±0.312), and (58.497 ±15.608) mg/g in the KO sham group, and (5.335 ±0.499), (3.132 ±0.548), and (171.117 ±50.479) mg/g in the KO SAH group, markedly increased in the SAH groups as compared with the sham controls (P<0.05), while the GSH/GSSG levels were significantly higher in the former two groups than in the latter (0.553 ±0.100 and 0.375 ±0.068 vs 0.714 ±0.091, 0.761 ±0.114, P<0.01).The contents of brain water and Evans blue were (0.784 ±0.005) and (7.055 ±1.046) μg/g in the WT sham group, (0.808 ±0.004) and (7.230 ±1.192) μg/g in the WT SAH group, (0.784 ±0.004) and (9.620 ±1.290) μg/g in the KO sham group, and (0.819 ±0.004) and (11.628 ±1.040)μg/g in the KO SAH group, remarkably increased in the SAH groups in comparison with the sham groups (P<0.05).The apoptosis rate 8.916 and 82.100 ±6.870 vs 70.833 ±8.750 and 51.767 ±13.006), ACA radius/wall thickness value (13.885 ±3.360 and 14.212 ±3.2545 vs 8.024 ±2.780 and 6.861 ±2.702), MCA radius/wall thickness value (18.648 ±2.893 and 19.435 ±2.775 vs 6.337 ±3.993 and 5.107 ±3.805), and activity score (2.733 ±0.450 and 2.767 ±0.430 vs 1.967 ±0.928 and 1.433 ±0.679) (all P<0.01). Conclusion Nrf2 knockout increases oxidative stress and inflammatory reaction following SAH and consequently aggravates secondary brain injury.Nrf2 has a protective effect against SAH-induced brain injury.

Expression of Claudin-5 and ZO-1 in Early Brain Injury after Subarachnoid Hemorrhage in Rats / 中国医科大学学报

Objective Aimed to clarify the molecular mechanism after subarachnoid hemorrhage （SAH） by investigating the expression of tight junction protein Claudin-5 and ZO-1 and the effects of SP600125 on them. Methods Seventy-five male Sprague Dawley rats （300 to 350 g） were randomly divided into sham,SAH,SAH ＋ DMSO （dimethyl sufoxide） solution,SAH ＋SP600125 （C-Jun N-terminal kinase inhibitor）10 mg/kg,and SAH ＋SP600125 30 mg/kg groups. The standard endovaseular perforation was performed to produce experimental SAH. The JNK inhibitor SP600125 was intraperitoneally administered at 1 hour before and 6 hours after SAH. Results At 24 hours after SAH,signs of microvessels injury were observed in brain cortex. Compared with the sham group,expression of Claudin-5 and ZO-1 was sig- nificantly decreased （P 〈 0.05 ）. JNK inhibitior SP600125 suppressed the decrease of Claudin-5 and ZO-1 expression, attenuated blood-brain barrier disruption in rats after SAH. Conclusions The blood-brain barrier disruption is an important mechanism of early brain injury after SAH. JNK inhibitor SP600125 improves neurological outcomes and provides neuropmtecfion against acute events after SAH such as bloodbrain barrier disruption and cell apoptosis.