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Richmond agitation-sedation scale (RASS) is a simple and widely used tool for evaluating sedation and agitation in adult ICU patients. Early deep sedation has been shown to be an important independent predictor of death, however, studies on the role of RASS in the prognostic assessment of neurocritical patients are lacking. The purpose of this study was to investigate the relationship between RASS and in-hospital mortality in neurocritical patients, and to develop and validate an effective predictive model based on this. This was a retrospective study of neurocritical patients from a large clinical database. A total of 2651 patients were collected, including general demographic characteristics, past medical history, biochemical test data and physical examination within 24 h of admission, and related medical records. Univariate and multivariate logistic regression analyses were used to screen out significant variables. Finally, 11 significant predictors were included into the logistic regression to establish the nomogram. The area under the curve (AUC) of the nomogram was 0.9087(0.8950–0.9224) and the corrected c index was 0.9043, which gave the model better discriminatory ability compared with critical care related scales, such as SOFA and SAPSII scores. Besides, tools including calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC) were used to verify that the model had good discrimination, calibration, and clinical applicability. RASS score was an independent prognostic predictor of in-hospital death in neurocritical patients, and patients who are deeply sedated have a worse prognosis. RASS-related nomogram could be applied to predict the prognosis of neurocritical patients and to take effective intervention measures in early stage.

Autophagy has been shown to play an important role in Parkinson's disease. We hypothesized that skin-derived precursor cells exhibit neuroprotective effects in Parkinson's disease through affecting autophagy. In this study, 6-hydroxydopamine-damaged SH-SY5Y cells were pretreated with a culture medium containing skin-derived precursors differentiated into Schwann cells (SKP-SCs). The results showed that the SKP-SC culture medium remarkably enhanced the activity of SH-SY5Y cells damaged by 6-hydroxydopamine, reduced excessive autophagy, increased tyrosine hydroxylase expression, reduced α-synuclein expression, reduced the autophagosome number, and activated the PI3K/AKT/mTOR pathway. Autophagy activator rapamycin inhibited the effects of SKP-SCs, and autophagy inhibitor 3-methyladenine had the opposite effect. These findings confirm that SKP-SCs modulate the PI3K/AKT/mTOR pathway to inhibit autophagy, thereby exhibiting a neuroprotective effect in a cellular model of Parkinson's disease. This study was approved by the Animal Ethics Committee of Laboratory Animal Center of Nantong University (approval No. S20181009-205) on October 9, 2018.

Background and Purpose: Whether imaging parameters would independently predict stroke recurrence in low-risk minor ischemic stroke (MIS) or transient ischemic attack (TIA) according to traditional score system (such as ABCD 2 score, which was termed on the basis of the initials of the five factors: age, blood pressure, clinical features, duration, diabetes) remains unclear. We sought to evaluate the association between imaging parameters and 1-year stroke recurrence in patients with TIA or MIS in different risk stratum stratified by ABCD 2 score. Methods: We included patients with TIA and MIS (National Institutes of Health Stroke Scale score ≤3) with complete baseline vessel and brain imaging data from the Third China National Stroke Registry III. Patients were categorized into different risk groups based on ABCD 2 score (low risk, 0–3; moderate risk, 4–5; and high risk, 6–7). The primary outcome was stroke recurrence within 1 year. Multivariable Cox proportional-hazards regression models were used to assess whether imaging parameters (large artery stenosis, infarction number) were independently associated with stroke recurrence. Results: Of the 7140 patients included, 584 patients experienced stroke recurrence within 1 year. According to the ABCD 2 score, large artery stenosis was associated with higher stroke recurrence in both low-risk (adjusted hazard ratio, 1.746 [95% CI, 1.200–2.540]) and moderate-risk group (adjusted hazard ratio, 1.326 [95% CI, 1.042–1.687]) but not in the high-risk group ( P >0.05). Patients with multiple acute infarctions or single acute infarction had a higher risk of recurrent stroke than those with no infarction in both low- and moderate-risk groups, but not in the high-risk group. Conclusions: Large artery stenosis and infarction number were independent predictors of 1-year stroke recurrence in low-moderate risk but not in high-risk patients with TIA or MIS stratified by ABCD 2 score. This finding emphasizes the importance of early brain and vascular imaging evaluation for risk stratification in patients with TIA or MIS.

Background and Purpose: We aimed to evaluate the impact of cortical microinfarcts (CMIs) on functional outcome after endovascular treatment in patients with acute ischemic stroke. Methods: In a multicenter registration study for RESCUE-RE (a registration study for Critical Care of Acute Ischemic Stroke After Recanalization), eligible patients with large vessel occlusion stroke receiving endovascular treatment, who had undergone 3T magnetic resonance imaging on admission or within 24 hours after endovascular treatment were analyzed. We evaluated the presence and numbers of CMIs with assessment of axial T1, T2-weighted images, and fluid-attenuated inversion recovery images. The primary outcome was functional dependence or death defined as modified Rankin Scale scores of 3 to 6 at 90 days. Secondary outcomes included early neurological improvement, any intracranial hemorrhage, symptomatic intracranial hemorrhage, and mortality. We investigated the independent associations of CMIs with the outcomes using multivariable logistic regression in overall patients and in subgroups. Results: Among 414 patients (enrolled from July 2018 to May 2019) included in the analyses, 96 (23.2%) patients had at least one CMI (maximum 6). Patients with CMI(s) were more likely to be functionally dependent or dead at 90 days, compared with those without (55.2% versus 37.4%; P P =0.04) and multiple CMIs (CMIs ≥2; adjusted odds ratio, 7.41 [95% CI, 2.48−22.17]; P Conclusions: Acute large vessel occlusion stroke patients receiving endovascular treatment with CMI(s) were more likely to have a poor functional outcome at 90 days, independent of patients’ characteristics. Such associations may be dose-dependent. Registration: URL: http://www.chictr.org.cn ; Unique identifier: ChiCTR1900022154.

BACKGROUND In acute ischemic stroke, there is uncertainty regarding the benefit and risk of administering intravenous alteplase before endovascular thrombectomy. METHODS We conducted a trial at 41 academic tertiary care centers in China to evaluate endovascular thrombectomy with or without intravenous alteplase in patients with acute ischemic stroke. Patients with acute ischemic stroke from large-vessel occlusion in the anterior circulation were randomly assigned in a 1:1 ratio to undergo endovascular thrombectomy alone (thrombectomy-alone group) or endovascular thrombectomy preceded by intravenous alteplase, at a dose of 0.9 mg per kilogram of body weight, administered within 4.5 hours after symptom onset (combination-therapy group). The primary analysis for noninferiority assessed the between-group difference in the distribution of the modified Rankin scale scores (range, 0 [no symptoms] to 6 [death]) at 90 days on the basis of a lower boundary of the 95% confidence interval of the adjusted common odds ratio equal to or larger than 0.8. We assessed various secondary outcomes, including death and reperfusion of the ischemic area. RESULTS Of 1586 patients screened, 656 were enrolled, with 327 patients assigned to the thrombectomy-alone group and 329 assigned to the combination-therapy group. Endovascular thrombectomy alone was noninferior to combined intravenous alteplase and endovascular thrombectomy with regard to the primary outcome (adjusted common odds ratio, 1.07; 95% confidence interval, 0.81 to 1.40; P=0.04 for noninferiority) but was associated with lower percentages of patients with successful reperfusion before thrombectomy (2.4% vs. 7.0%) and overall successful reperfusion (79.4% vs. 84.5%). Mortality at 90 days was 17.7% in the thrombectomy-alone group and 18.8% in the combination-therapy group. CONCLUSIONS In Chinese patients with acute ischemic stroke from large-vessel occlusion, endovascular thrombectomy alone was noninferior with regard to functional outcome, within a 20% margin of confidence, to endovascular thrombectomy preceded by intravenous alteplase administered within 4.5 hours after symptom onset. (Funded by the Stroke Prevention Project of the National Health Commission of the People’s Republic of China and the Wu Jieping Medical Foundation; DIRECT-MT Clinical-Trials.gov number, NCT03469206.)

Intracerebral hemorrhage (ICH) refers to hemorrhage caused by spontaneous rupture of blood vessels in the brain. Brain injury due to ICH leads to catastrophic effects resulting from the formation of hematoma and oxidative stress caused by components of lysed erythrocytes. However, not all neurons in the area surrounding the hematoma die immediately: A number of neurons remain in a critical, but reversible, state; however, the genes involved in this critical state remain poorly understood. Gene chip technology was used identify changes in the area surrounding the hematoma associated with the upregulation of 210 and downregulation of 173 genes. Gene Ontology functional annotation revealed changes in the gene expression profile in the peripheral region of hematoma following ICH, which were primarily associated with the external stimulation received by the organism, the transmission of harmful information to the cell through the transport of cell membrane proteins, and the regulation of a series of biological processes. Protein interaction network analysis revealed that 11 up-[secreted phosphoprotein 1, dual specificity phosphatase 9, catechol-O-methyltransferase, BAR/IMD domain-containing adaptor protein 2-like 1, plakophilin 2, homer scaffold protein 3, ret proto-oncogene (RET), KIT proto-oncogene, receptor tyrosine kinase, hepsin, connector enhancer of kinase suppressor of Ras 2 and kalirin RhoGEF kinase] and four downregulated genes (transcription factor AP-2β, peptidylprolyl isomerase A, SHOC2 leucine rich repeat scaffold protein and synuclein α) may serve a significant role in the area around hematoma following ICH. Reverse transcription-quantitative PCR was used to verify that these genes were differentially expressed in the ICH compared with the control group. Causal network analysis suggested that the Achaete-scute homolog 1-RET signaling axis served a key role in the repair of nerve injury in the peripheral region of hematoma following ICH. Additionally, in vivo experiments revealed that RET expression was upregulated and co-localized with neurons. Taken together, these results suggested that the changes in the gene expression profile in the area around hematoma following ICH were primarily associated with the repair of damage caused to the nervous system.

Background Prostaglandin E1 (PGE1) exerts various pharmacological effects such as membrane stabilization, anti-inflammatory functions, vasodilation, and platelet aggregation inhibition. We have previously demonstrated that PGE1 has a beneficial impact on patients suffering from intracerebral hemorrhage (ICH). The related mechanism underlying PGE1's beneficial effect on ICH treatment needs further exploration. Methods The present study elucidates the mechanism of PGE1 on ICH treatment using a neuronal apoptosis model in vitro. The mouse primary cortical neurons were pretreated with different concentrations of PGE1, followed by the treatment with hemin, the main catabolite in whole blood, to mimic the clinical ICH. Results Comparing with the vehicle-treated group, PGE1 prevented cultured cortical neurons from the accumulation of inhibited intracellular levels of reactive oxygen species (ROS), amelioration of mitochondrial membrane potential, and hemin-induced apoptosis. The reduction of ROS and apoptosis were associated with the up-regulation of Heme oxygenase-1 (HO-1) expression. Knockdown of nuclear transcription factor erythroid 2-related factor (Nrf2) by siRNA attenuated the upregulation of HO-1 as well as the protective effect of PGE1. Conclusions Our work suggests that the Nrf2/HO-1 molecular pathway may play a crucial role in treating ICH patients with PGE1 and may represent novel molecular targets, resulting in discovering new drugs for ICH treatment.

Supplemental Digital Content is available in the text., Background and Purpose: Among patients with a transient ischemic attack or minor ischemic strokes, those with ipsilateral atherosclerotic stenosis of cervicocranial vasculature have the highest risk of recurrent vascular events. Methods: In the double-blind THALES (The Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death) trial, we randomized patients with a noncardioembolic, nonsevere ischemic stroke, or high-risk transient ischemic attack to ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2–30) or placebo added to aspirin (300–325 mg on day 1 followed by 75–100 mg daily for days 2–30) within 24 hours of symptom onset. The present paper reports a prespecified analysis in patients with and without ipsilateral, potentially causal atherosclerotic stenosis ≥30% of cervicocranial vasculature. The primary end point was time to the occurrence of stroke or death within 30 days. Results: Of 11 016 randomized patients, 2351 (21.3%) patients had an ipsilateral atherosclerotic stenosis. After 30 days, a primary end point occurred in 92/1136 (8.1%) patients with ipsilateral stenosis randomized to ticagrelor and in 132/1215 (10.9%) randomized to placebo (hazard ratio 0.73 [95% CI, 0.56–0.96], P=0.023) resulting in a number needed to treat of 34 (95% CI, 19–171). In patients without ipsilateral stenosis, the corresponding event rate was 211/4387 (4.8%) and 230/4278 (5.4%), respectively (hazard ratio, 0.89 [95% CI, 0.74–1.08]; P=0.23, Pinteraction=0.245). Severe bleeding occurred in 4 (0.4%) and 3 (0.2%) patients with ipsilateral atherosclerotic stenosis on ticagrelor and on placebo, respectively (P=NS), and in 24 (0.5%) and 4 (0.1%), respectively, in 8665 patients without ipsilateral stenosis (hazard ratio=5.87 [95% CI, 2.04–16.9], P=0.001). Conclusions: In this exploratory analysis comparing ticagrelor added to aspirin to aspirin alone, we found no treatment by ipsilateral atherosclerosis stenosis subgroup interaction but did identify a higher absolute risk and a greater absolute risk reduction of stroke or death at 30 days in patients with ipsilateral atherosclerosis stenosis than in those without. In this easily identified population, ticagrelor added to aspirin provided a clinically meaningful benefit with a number needed to treat of 34 (95% CI, 19–171). Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03354429.

Aims: Omentin-1 was proved to be associated with ischemic stroke clinical functional outcome. It also predicted carotid atherosclerosis among metabolic syndrome subjects and type 2 diabetes patients. Our aim was to examine the association of omentin-1 levels with carotid plaque instability and stenosis degree among ischemic stroke patients. Methods: A total of 173 acute ischemic stroke patients were included in this study. Serum omentin-1 levels were assayed. Carotid ultrasound examinations were performed to evaluate the carotid plaque instability and stenosis degree. Multivariable logistic analyses were used to examine the association of serum omentin-1 levels with carotid plaque instability and stenosis degree. Results: Ischemic stroke patients with unstable carotid plaque had significantly lower levels of serum omentin-1 than patients with stable plaque (53 [40.2–64.1] vs 61.8 [52.4–77.2] ng/ml, P < 0.01). Subjects in the highest tertile of serum omentin-1 levels had a 0.31-fold risk of having unstable plaque compared with those in the lowest tertile (P < 0.05), and its trend test was significant (P for trend = 0.03). The integrated discrimination improvement was significantly improved in predicting carotid plaque instability when omentin-1 data was added to the multivariable logistic regression model. No significant association was detected between omentin-1 and moderate-severe carotid stenosis or occlusion. Conclusions: Among ischemic stroke patients, higher omentin-1 levels were inversely associated with carotid plaque instability, but not associated with moderate-severe carotid stenosis or occlusion. Omentin-1 may represent a biomarker for predicting carotid plaque instability of acute ischemic stroke patients.

OBJECTIVE The RECO flow restoration (FR) device is a new stent retriever designed for rapid flow restoration in acute ischemic stroke (AIS) caused by large vessel occlusion (LVO). Here, the authors compared the efficacy and safety of the RECO device with the predicate Solitaire FR stent retriever. METHODS The RECO Flow Restoration Device Versus Solitaire FR With the Intention for Thrombectomy Study (REDIRECT) was a multicenter, prospective, open randomized controlled trial. Patients with acute LVO at 7 Chinese stroke centers participated in the study. The primary efficacy endpoint was defined as a modified thrombolysis in cerebral infarction (mTICI) reperfusion grade ≥ 2 within three passes. The primary safety endpoint comprised any serious adverse device effect, symptomatic intracerebral hemorrhage (sICH), and any serious adverse event (SAE; defined as cerebral palsy or death) within 24 hours after the procedure. The secondary efficacy endpoints consisted of functional independence (modified Rankin Scale score 0–2), procedure duration, and 90-day all-cause mortality. RESULTS Between January 2014 and August 2016, 67 patients were randomly allocated to the RECO group and 69 patients to the Solitaire FR group. The primary efficacy endpoint (mTICI grade ≥ 2 within three passes) was similar in the two treatment groups (91% vs 87%, respectively, p = 0.5861), and the rate of reperfusion with an mTICI grade 2b/3 was 87% versus 75% (p = 0.1272). There were no serious adverse device effects in any patient. The rates of sICH (1.5% vs 7.2%, p = 0.1027) and SAEs (6.0% vs 1.4%, p = 0.2050) within 24 hours after the procedure were similar in the two treatment groups. There was no significant difference in the rate of functional independence (63% vs 46%, p = 0.0609) or 90-day all-cause mortality (13% vs 23%, p = 0.1848) or in procedure duration (85.39 ± 47.01 vs 89.94 ± 53.34 minutes, p = 0.5986) between the two groups. CONCLUSIONS The RECO stent retriever is effective and safe as a mechanical thrombectomy device for AIS due to LVO. Clinical trial registration no.: NCT01983644 (clinicaltrials.gov)

Objective SSTR2 is a member of superfamily of SST receptor (SSTR), and widely expressed in the brain; however, the knowledge of its functions in area adjacent to hematoma after intracerebral hemorrhage (ICH) is still limited. Method The role of SSTR2 in the processes of ICH was explored by conducting an ICH rat model. Western blot and immunohistochemistry were employed to examine the level of SSTR2 in area adjacent to hematoma after ICH. Immunofluorescent staining was used to observe the spatial correlation of SSTR2 with cellular types adjacent to hematoma after ICH. RNA interference specific to SSTR2 was adopted in PC12 cells to clarify the causal correlation between SSTR2 and neuronal activities. Results Increased expression of SSTR2 was observed and restricted to the neurons adjacent to hematoma following ICH. Immunofluorescent staining showed that SSTR2 was significant increased in neurons, but not astrocytes or microglia. Increasing SSTR2 level was found to be accompanied by the up-regulation of activated caspase-3 and the down-expression of p-Akt in a time-dependent manner. What's more, using SSTR2 RNA interference (SSTR2-RNAi) in PC12 cells, we indicated that SSTR2 might have a pro-apoptotic role in neurons. Conclusion We speculated that SSTR2 might exert its pro-apoptotic function in neurons through inhibiting Akt activity following ICH.

O-Linked N-acetylglucosamine, or O-GlcNAc, is a dynamic post-translational modification that cycles on and off serine and threonine residues of nucleocytoplasmic and mitochondrial proteins. In addition to cancer and inflammation diseases, O-GlcNAc modification appears to play a critical role during cell apoptosis and stress response, although the precise mechanisms are still not very clear. Here we found that nitric oxide synthase adaptor (NOS1AP), which plays an important part in glutamate-induced neuronal apoptosis, carries the modification of O-GlcNAc. Mass spectrometry analysis identified Ser47, Ser183, Ser204, Ser269, Ser271 as O-GlcNAc sites. Higher O-GlcNAc of NOS1AP was detected during glutamate-induced neuronal apoptosis. Furthermore, with O-GlcNAc sites of NOS1AP mutated, the interaction of NOS1AP and neuronal nitric oxide syntheses (nNOS) decreases. Finally, during glutamate-induced neuronal apoptosis, decreasing the O-GlcNAc modification of NOS1AP results in more severe neuronal apoptosis. All these results suggest that O-GlcNAc modification of NOS1AP exerts protective effects during glutamate-induced neuronal apoptosis.

Traumatic brain injury (TBI) triggers a complex series of neurochemical and signaling changes that lead to neuronal dysfunction and overreactive astrocytes. In the current study, we showed that interactions between SCYL1-bp1 and Pirh2 are involved in central nervous system (CNS) injury and repair. Western blot and immunohistochemical analysis of an acute traumatic brain injury model in adult rats revealed significantly increased levels of SCYL1-bp1 and Pirh2 in the ipsilateral brain cortex, compared to contralateral cerebral cortex. Immunofluorescence double-labeling analyses further revealed that SCYL1-bp1 is mainly co-expressed with NeuN. Terminal deoxynucleotidyl transferase-mediated biotinylated-dUTP nick-end labeling staining data supported the involvement of SCYL1-bp1 and Pirh2 in neuronal apoptosis after brain injury. We additionally examined the expression profiles of active caspase-3, which were altered in correlation with the levels of SCYL1-bp1 and Pirh2. Notably, both SCYL1-bp1 and Pirh2 were colocalized with active caspase-3, and all three proteins participated in neuronal apoptosis. Immunoprecipitation experiments further revealed interactions of these proteins with each other in the pathophysiology process. To our knowledge, this is the first study to report interactions between SCYL1-bp1 and Pirh2 in traumatic brain. Our data collectively indicate that SCYL1-bp1 and Pirh2 play important roles in CNS pathophysiology after TBI.

The members of high-temperature requirement (HtrA) family are evolutionarily conserved serine proteases that combine a trypsin-like protease domain with at least one PDZ interaction domain. HtrA2, a special one, is mainly located in mitochondria and required for maintaining homeostasis. Once released into cytoplasm, HtrA2 contributes to apoptosis via caspase-dependent and -independent pathways. Accumulating evidence has showed its pro-apoptotic effect in cancers and central nervous system (CNS) diseases. However, the distribution and function of HtrA2 in CNS diseases remains to be further explored. To investigate HtrA2's roles in the pathophysiology of intracerebral hemorrhage (ICH), an ICH rat model was established and assessed by behavioral tests. Western blot and immunohistochemistry revealed a remarkable up-regulation of HtrA2 surrounding the hematoma after ICH; and immunofluorescence showed HtrA2 was strikingly increased in neurons, but not in astrocytes and oligodendrocytes. Terminal deoxynucleotidyl transferase-mediated biotinylated-dUTP nick-end labeling staining suggested the involvement of HtrA2 in neuronal apoptosis after ICH. Additionally, HtrA2 co-localized with active-caspase-3 around the hematoma and the expression of active-caspase-3 was parallel with that of HtrA2 in a time-dependent manner. Furthermore, hemin was used to stimulus a neuronal cell line PC12 to mimic ICH model in vitro. We analyzed the relationship of HtrA2 with X-linked inhibitor of apoptosis protein (XIAP) in PC12 cells by Western blot, immunofluorescence and co-immunoprecipitation. The connection of HtrA2 with XIAP was strengthened in apoptotic cells after hemin treatment. Thus, we speculated that HtrA2 might exert an important function in regulating caspase-dependent neuronal apoptosis through interacting with XIAP following ICH.

Tropomyosin (TM), is a coiled-coil dimmer which modulates actin filament properties, has been implicated in the control of actin filament dynamics during cell migration, morphogenesis, and cytokinesis. However, the expressions and possible functions of tropomyosin in central nervous system (CNS) lesion remain unknown. In this study, we found the expression of tropomyosin gradually increased in rat brains subjected to traumatic brain injury (TBI). Double immunofluorescence staining showed tropomyosin was expressed in neurons and reactive astrocytes following TBI but not in quiescent astrocytes in normal brains. Furthermore, we detected that proliferating cell nuclear antigen (PCNA) had the co-localization with GFAP, and tropomyosin. In conclusion, this was the first description of tropomyosin expression in rat traumatic brain. Our date suggested that tropomyosin might be involved in the astrocytes proliferation following TBI.

Glycine acts as a co-agonist for the activation of N-methyl-D-aspartate receptors (NMDARs) by binding to glycine sites, thus potentiating glutamate-elicited responses and inhibiting NMDAR desensitization in a dose-dependent manner. The present study aimed to characterize the glycine-dependent inactivation of NMDARs and to explore its pathophysiological significance.Primary hippocampal cell cultures from embryonic days 17-18 rats were treated with NMDA or NMDA plus glycine. Patch-clamp recording and intracellular Ca(2+) imaging were performed to test the effects of glycine on NMDA-activated currents and increase of intracellular free Ca(2+) respectively. Immunofluorescence staining was conducted to examine NR1 internalization. Cell damage was tested with MTT method and lactate dehydrogenase leakage.Glycine reduced the peak current and Ca(2+) influx elicited by NMDA application at concentrations ≥ 300 μmol/L. This is a novel suppressive influence of glycine on NMDAR function, since it occurs via the NMDAR glycine-binding site, in contrast to the classic suppression, which occurs through the binding of glycine to glycine receptors. The level of membrane NMDARs was measured to evaluate whether internalization was involved. Immunohistochemical labeling showed that incubation with high concentrations of NMDA plus glycine did not change the expression of NMDARs on the cell surface when compared to the expression without glycine; hence the possibility of NMDAR internalization primed by glycine binding was excluded.In summary, the novel suppressive effect of glycine on NMDARs was mediated via binding to the glycine site of the NMDAR and not by activation of the strychnine-sensitive glycine-receptor-gated chloride channel or by the internalization of NMDARs. The inhibitory influence of glycine on NMDARs adds a new insight to our knowledge of the complexity of synaptic transmission.

BAG-1 protein was initially identified as a Bcl-2-binding protein. It was reported to enhance Bcl-2 protection from cell death, suggesting that BAG-1 represents a new type of anti-cell death gene. Moreover, recent study has shown that BAG-1 can enhance the proliferation of neuronal precursor cells, attenuate the growth inhibition induced by siah1. However, its function and expression in the central nervous system lesion are not been understood very well. In this study, we performed a traumatic brain injury (TBI) model in adult rats and investigated the dynamic changes of BAG-1 expression in the brain cortex. Double immunofluorescence staining revealed that BAG-1 was co-expressed with NEURON and glial fibrillary acidic protein (GFAP). In addition, we detected that proliferating cell nuclear antigen had the co-localization with GFAP, and BAG-1. All our findings suggested that BAG-1 might involve in the pathophysiology of brain after TBI.

Background and Purpose— We aimed to develop a risk score (intracerebral hemorrhage–associated pneumonia score, ICH-APS) for predicting hospital-acquired stroke-associated pneumonia (SAP) after ICH. Methods— The ICH-APS was developed based on the China National Stroke Registry (CNSR), in which eligible patients were randomly divided into derivation (60%) and validation (40%) cohorts. Variables routinely collected at presentation were used for predicting SAP after ICH. For testing the added value of hematoma volume measure, we separately developed 2 models with (ICH-APS-B) and without (ICH-APS-A) hematoma volume included. Multivariable logistic regression was performed to identify independent predictors. The area under the receiver operating characteristic curve (AUROC), Hosmer–Lemeshow goodness-of-fit test, and integrated discrimination index were used to assess model discrimination, calibration, and reclassification, respectively. Results— The SAP was 16.4% and 17.7% in the overall derivation (n=2998) and validation (n=2000) cohorts, respectively. A 23-point ICH-APS-A was developed based on a set of predictors and showed good discrimination in the overall derivation (AUROC, 0.75; 95% confidence interval, 0.72–0.77) and validation (AUROC, 0.76; 95% confidence interval, 0.71–0.79) cohorts. The ICH-APS-A was more sensitive for patients with length of stay >48 hours (AUROC, 0.78; 95% confidence interval, 0.75–0.81) than those with length of stay P =0.20) and validation ( P =0.66) cohorts. Similarly, a 26-point ICH-APS-B was established. The ICH-APS-A and ICH-APS-B were not significantly different in discrimination and reclassification for SAP after ICH. Conclusion— The ICH-APSs are valid risk scores for predicting SAP after ICH, especially for patients with length of stay >48 hours.

Depression is a major psychiatric disorder affecting nearly 21% of the world population and imposes a substantial health burden on society. Current available antidepressants are not adequate to meet the clinical needs. Here we report that auraptenol, an active component of the traditional Chinese medicine, angelicae dahuricae radix, had antidepressant-like effects in mice models of depression. In mouse forced swimming test and tail suspension test, two validated models of depression, auraptenol dose-dependently decreased the immobility duration within the dose range of 0.05–0.4 mg/kg. In addition, the antidepressant-like effects of auraptenol was significantly averted by a selective serotonin 5-HT1A receptor antagonist WAY100635 (1 mg/kg). These doses that affected the immobile response did not affect locomotor activity. In summary, this study for the first time identified an active component from the herbal medicine angelicae dahuricae radix that possesses robust antidepressant-like efficacy in mice. These data support further exploration for the possibility of developing auraptenol as a novel antidepressant agent in the treatment of major depression disorders.

SGTB (Small glutamine-rich tetratricopeptide repeat (TPR)-containing, β) plays a critical role in protein–protein interactions. The interaction between SGTB and heat shock cognate protein (Hsc70)/heat shock protein (Hsp70) has aroused much attention in recent years. The present study was designed to elucidate dynamic changes in SGTB expression and distribution in the cerebral cortex in a lipopolysaccharide (LPS)-induced neuroinflammation rat model. It was found that SGTB expression was increased significantly in apoptotic neurons after LPS injection. The result of our in vitro study suggested that SGTB up-regulation might be associated with neuronal apoptosis after H2O2 challenge. In addition, silencing of SGTB in cultured PC12 (Pheochromocytoma) by siRNA indicated that SGTB was required for neuronal apoptosis induced by oxidative stress. Our finding about the cellular signal pathway may provide a new strategy against neuronal apoptosis in neuroinflammation in CNS.

Introduction: L-serine plays critical roles in neuronal development and function. We have recently reported that L-serine protected against ischemic neuronal injury in vivo and in vitro. The mechanism underlying the neuroprotective effect of L-serine remains unclear. L-serine has been documented to induce a fall in mean arterial pressure through activation of small- and intermediate-conductance calcium-activated potassium channels on the endothelium. Such vasodilating action of L-serine in cerebral blood vessels has not been investigated. Hypothesis: Improving regional cerebral blood flow (rCBF) by L-serine contributes to its neuroprotection on the brain after permanent middle cerebral artery occlusion (pMCAO). Methods: Adult male Sprague-Dawley rats were randomly assigned to sham, vehicle or L-serine-treated groups. pMCAO was induced while monitoring rCBF. The neurological deficit scores, brain infarct volumes and physiological parameters were assessed. L-serine and D-serine content in the cortex was measured with high performance liquid chromatography. Results: Compared to vehicle treatment, administration of L-serine improved rCBF in the ischemic cortex and reduced the neurological deficits, infarct volume and cortical neuronal loss in a dose- and time-dependent manner. The improvement of rCBF and neuroprotective effect of L-serine were abolished by apamin plus charybdotoxin, which blocks the calcium-activated potassium channels on the endothelium, but not influenced by strychnine, an antagonist of glycine receptors. HPLC results shows that L-serine treatment increased the content of both L-serine and D-serine in the ischemic cortex. However, inhibiting the conversion of L-serine to D-serine by aminooxyacetic acid did not affect the L-serine-afforded protection, suggesting that the neuroprotective efficacy of L-serine is not related to the conversion of L-serine to D-serine. Conclusions: L-serine displayed a neuroprotective effect in the ischemic brain, at least partly due to an elevation in rCBF through cerebral blood vessel dilation mediated by the calcium-activated potassium channels on the endothelial cells. L-serine may be a potential novel therapy for ischemic brain injury.

Bnip3L, also known as NIX, is a homolog of the E1B 19K/Bcl-2 binding and pro-apoptotic protein Bnip3 which can bind to Bcl-2 to elaborate that effect. In tumor cells, Bnip3L played a role in tumor growth inhibition, but some studies argued hypoxia-induced autophagy via Bnip3L was a survival mechanism that promoted tumor progression. In heart muscle, it related to decreased myocardial function. However, its function in intracerebral hemorrhage (ICH) is still not clear. In this frame, we found the Bnip3L expression increased in the perihematomal region in adult rats after performed ICH. Double immunofluorenscence staining manifested that Bnip3L co-located with neurons, not astrocytes or oligodendrocytes. Furthermore, we detected that neuronal apoptosis marker active caspase-3 had colocalizations with Bnip3L. In addition, colocalizations and co-immunoprecipitation between Bnip3L and Bcl-2, consistent with previous study, were also found. All our findings suggested that Bnip3L might be involved in the pathophysiology of ICH.

CBLL1 (Casitas B-lineage lymphoma-transforming sequence-like protein 1) also known as Hakai, was originally identified as an E3 ubiquitin-ligase for the E-cadherin complex. Recent data have provided evidences for novel biological functional role of CBLL1 during tumor progression and other diseases. However, its distribution and function in the central nervous system (CNS) remains unclear. In this study, we found CBLL1 was significant up-regulation in cerebral cortex after LPS administration and immunofluorescent labeling indicated that CBLL1 was localized striking in the neurons. We also investigated co-staining of CBLL1 and active-caspase-3 and cyclin D1 in the cerebral cortex following LPS administration. Based on our data, we speculated that CBLL1 might play an important role in neuronal apoptosis following LPS administration and might provide a basis for the further study on its role in cell cycle re-entry in neuroinflammation in CNS.

SKIP (Ski-interacting protein), is part of nuclear regulatory complexes and interacts with factors involved in preinitiation, splicing and polyadenylation, potentiates the activity of important transcription factors, involved in an increasing number of signaling cascades. However, its distribution and function in the central nervous system remains poorly understood. In this study, western blot analysis, RT-PCR and immunohistochemistry showed a significant up-regulation of SKIP in ipsilateral peritrauma cortex compared with the sham group. Immunofluorescent labeling indicated that SKIP was localized striking in the neurons, but not astrocytes and oligodendrocytes; co-localization of SKIP and active caspase-3 and PCNA in the ipsilateral cortex. In addition, the expression patterns of active caspase-3 and PCNA were parallel with that of SKIP. Based on our data, we speculated that SKIP might play an important role in neuronal apoptosis following TBI; and might provide a basis for the further study on its role in cell cycle re-entry in traumatic brain injury.

CtBP2 (C-terminal binding protein 2), which is widely expressed during developmental processes and differentiation, acts as a transcriptional repressor following recruitment to target promoters through repressors or other co-repressor proteins. In this study, we elucidated the dynamic expression changes and localization of CtBP2 in lipopolysaccharide (LPS)-induced neuroinflammatory processes in adult rats. CtBP2 expression was strongly induced in active glia cells (microglia and astrocytes) in inflamed spinal cord. In vitro studies indicated that the up-regulation of CtBP2 may be involved in the subsequent microglia activation following LPS exposure. And the knock-down of CtBP2 in microglia cell line HAPI by siRNA showed that CtBP2 increased the activation of microglia induced by LPS. Collectively, these results suggested CtBP2 may be important in host defense in microglia-mediated immune response. Understanding the cell signal pathway may provide a novel strategy against inflammatory and immune reaction in neuroinflammation in central nervous system.