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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.

BACKGROUND AND PURPOSE This study was undertaken to screen the circular RNAs (circRNAs) influencing matrix metalloproteinase 9 (MMP9) through the competing endogenous RNA (ceRNA) network and evaluate the prognostic value of these circRNAs for acute ischemic stroke. METHODS A total of 220 ischemic stroke patients and 62 healthy subjects were included in this study. RNA was isolated from blood collected in PAXgene tubes. Illumina sequencing, quantitative real-time polymerase chain reaction (qRT-PCR) validation, and luciferase reporter assay were explored to construct and verify the existence of a circRNA-microRNA (miRNA)-matrix metalloproteinase-9 (MMP9) network. The 215 ischemic stroke patients were recruited in a prognostic cohort. They were prospectively followed up for 3 months after stroke onset, and a poor functional outcome was defined as a major disability or death. RESULTS After Illumina sequencing, six circRNAs were predicted to bind miRNAs and then regulate MMP9 messenger RNA (mRNA). qRT-PCR showed that only circSKA3 was significantly increased in ischemic stroke patients compared to healthy controls and positively associated with MMP9 mRNA expression. Luciferase reporter assay further verified a direct interaction between circSKA3, MMP9, and hsa-miR-6796-5p. Patients in the top tertile of circSKA3 had a 2.672-fold (p

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.)

Objective: It has been demonstrated that Triad1 (2 RING fingers and double RING finger linked 1) negatively regulates myeloid cell growth and induces cell apoptosis. However, its functions in intracerebral hemorrhage (ICH) disease have not been conducted. In this study, the role of Triad1 in rat model of ICH was explored.Methods: We observe an increasing expression of Triad1 in areas adjacent to hematoma after ICH. Immunofluorescence shows that Triad1 is colocalized with neurons, while not microglia or astrocyte, indicates its correlation with neuronal activities following ICH.Results: As neuronal apoptosis is the most crucial event in ICH disease, the expression of active caspase-3 and p53 is also enhanced around the hematoma, which is consistent with Triad1 in expression tendency. In turn, Triad1 depletion in primary cortical neurons decreased the apoptosis of neurons after using Triad1 shRNA.Conclusion: We conclude that inhibition of Triad1 expression might protect the brain from secondary damage following ICH.

Objectives The prognostic role of baseline platelet count (PLT) in acute ischemic stroke patients with large vessel occlusion undergoing endovascular thrombectomy is unclear. Whether PLT modifies alteplase treatment effect on clinical outcome in those patients is also uncertain. Methods We derived data from a multicenter randomized clinical trial (DIRECT-MT) comparing intravenous alteplase before endovascular treatment vs. endovascular treatment only. The 654 patients with available PLT data were included. Primary outcome was the ordinal modified Rankin Scale (mRS) score evaluated at 90 days. We also assessed various secondary and safety outcomes. Results After adjusting for confounding factors, patients in the top tertile of PLT had a significantly lower risk of a worse shift in the distribution of mRS score (Odds Ratio: 0.671, 95% Confidence Interval: 0.473–0.953, p for trend=0.025), major disability and death (Odds Ratio: 0.617, 95% Confidence Interval: 0.393–0.97, p for trend=0.037) as well as death (Odds Ratio: 0.544, 95% Confidence Interval: 0.313–0.947, p for trend=0.031), respectively, compared with the bottom one. Among patients in the bottom tertile of PLT, combination therapy was associated with a better imaging outcome of eTICI score of 2b, 2c or 3 on final angiogram (Odds Ratio: 3.23, 95% Confidence Interval: 1.49–7.002) with a marginally significant interaction effect. Conclusions Participants with higher baseline PLT had a decreased risk of poor functional outcomes. Low baseline PLT modified alteplase treatment effect on the eTICI score on final angiogram. Combination therapy was beneficial for patients with low baseline PLT to have a better reperfusion status.

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.

Recent studies have shown that Cab45s, belonging to the CREC family, can fight against apoptosis in the cancer cell lines. Here, we report that Cab45s may involve in neuronal apoptosis at the early stage of intracerebral hemorrhage (ICH) in pathophysiology. We found that expression of Cab45s was enhanced in areas contiguous to hematoma following ICH in adult rats, and that so were the expressions of Glucose-regulated protein 78 (GRP78), pro-apoptotic Bcl-2-associated X protein (Bax) and active caspase-3. In vitro, coimmunoprecipitation analysis indicated the interaction between Cab45s and GRP78. Depletion of Cab45s attenuated the expression of GRP78, but increased the expressions of Bax and caspase-3 in PC12 cells treated with hemin, which finally promoted apoptosis. Together, these results reveal that Cab45s might exert its anti-apoptotic function against neuronal apoptosis. Thus, the study may provide evidences for regulating Cab45s as a potentially reliable treatment for the secondary damage following ICH.

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.

Background: Recent studies have suggested that omentin-1 plays a critical role in the development of cardiovascular disease. However, reported findings are inconsistent, and no study has evaluated the association between omentin-1 levels and a poor functional outcome after ischemic stroke onset. Methods: A total of 266 acute ischemic stroke patients were included in this study. All patients were prospectively followed up for 3 months after acute ischemic stroke onset and a poor functional outcome was defined as a major disability or death occurring during the follow-up period. A multivariable logistic model was used to evaluate the association between serum omentin-1 levels and the functional outcome of ischemic stroke patients at 3 months. Results: Ischemic stroke patients with poor functional outcome had significantly lower levels of serum omentin-1 than patients without poor functional outcome at the 3-month follow-up (50.2 [40.2–59.8] vs. 58.3 [44.9–69.6] ng/mL, p Conclusions: Higher omentin-1 levels at baseline were negatively associated with poor functional outcome among ischemic stroke patients. Omentin-1 may represent a biomarker for predicting poor functional outcome of acute ischemic stroke patients.

Prior studies suggested that ischemic stroke patients with high omentin-1 concentrations were at a decreased risk of unstable carotid plaque and 3-month poor functional outcome. We aim to evaluate the association between serum omentin-1 and 1-y mortality after ischemic stroke.A total of 303 ischemic stroke patients were prospectively followed up at 1 y. Outcome was defined as death occurred during the follow-up period. A multivariable Cox model was used to evaluate the association between serum omentin-1 concentrations and 1-y mortality among ischemic stroke patients.From lowest to highest tertile of serum omentin-1, the 1-y cumulative death rate was 12%, 3.7% and 2.1%, respectively (P = 0.006). The hazard ratio (95% confidence interval) of the highest tertile compared with the lowest tertile was 0.19 (0.04-0.88) for mortality after multivariable adjustment (P for trend 0.01). The net reclassification index and integrated discrimination improvement were significantly improved in predicting 1-y mortality when omentin-1 data was added to the multivariable Cox regression model.Among patients with ischemic stroke, high baseline serum omentin-1 was associated with a decreased risk of 1-y mortality. These findings, if confirmed by clinical trials, suggest that increasing omentin-1 concentrations may lower the risk of mortality among 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)

Skin-derived precursors (SKPs) are self-renewing and pluripotent adult stem cell sources that have been successfully obtained and cultured from adult tissues of rodents and humans. Skin-derived precursor Schwann cells (SKP-SCs), derived from SKPs when cultured in a neuro stromal medium supplemented with some appropriate neurotrophic factors, have been reported to play a neuroprotective effect in the peripheral nervous system. This proves our previous studies that SKP-SCs' function to bridge sciatic nerve gap in rats. However, the function of SKP-SCs in Parkinson disease (PD) remains unknown. This study was aimed to investigate the possible neuroprotective effects of SKP-SCs in 6-OHDA-induced Parkinson's disease (PD) model. Our results showed that the treatment with SKP-SCs prevented SH-SY5Y cells from 6-OHDA-induced apoptosis, accompanied by modulation of apoptosis-related proteins (Bcl-2 and Bax) and the decreased expression of active caspase-3. Furthermore, we confirmed that SKP-SCs might exert protective effects and increase the mitochondrial membrane potential (MMP) through PI3K/AKT/Bcl-2 pathway. Taken together, our results demonstrated that SKP-SCs protect against 6-OHDA-induced cytotoxicity through PI3K/AKT/Bcl-2 pathway in PD model in vitro, which provides a new theoretical basis for the treatment of PD.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease characterized by severe dyskinesia due to a progressive loss of dopaminergic neurons along the nigro-striatal pathway. The current focus of treatment is to relieve symptoms through administration of levodopa, such as L-3,4-dihydroxy phenylalanine replacement therapy, dopaminergic agonist administration, functional neurosurgery, and gene therapy, rather than preventing dopaminergic neuronal damage. Hence, the application and development of neuroprotective/disease modification strategies is absolutely necessary. Currently, stem cell therapy has been considered for PD treatment. As for the stem cells, mesenchymal stem cells (MSCs) seem to be the most promising. In this review, we analyze the mechanisms of action of MSCs in Parkinson's disease, including growth factor secretion, exocytosis, and attenuation of neuroinflammation. To determine efficacy and protect patients from possible adverse effects, ongoing rigorous and controlled studies of MSC treatment will be critical.

Summary Background Previous randomised trials have shown an overwhelming benefit of mechanical thrombectomy for treating patients with stroke caused by large vessel occlusion of the anterior circulation. Whether endovascular treatment is beneficial for vertebrobasilar artery occlusion remains unknown. In this study, we aimed to investigate the safety and efficacy of endovascular treatment of acute strokes due to vertebrobasilar artery occlusion. Methods We did a multicentre, randomised, open-label trial, with blinded outcome assessment of thrombectomy in patients presenting within 8 h of vertebrobasilar occlusion at 28 centres in China. Patients were randomly assigned (1:1) to endovascular therapy plus standard medical therapy (intervention group) or standard medical therapy alone (control group). The randomisation sequence was computer-generated and stratified by participating centres. Allocation concealment was implemented by use of sealed envelopes. The primary outcome was a modified Rankin scale (mRS) score of 3 or lower (indicating ability to walk unassisted) at 90 days, assessed on an intention-to-treat basis. The primary safety outcome was mortality at 90 days. Secondary safety endpoints included the rates of symptomatic intracranial haemorrhage, device-related complications, and other severe adverse events. The BEST trial is registered with ClinicalTrials.gov , NCT02441556 . Findings Between April 27, 2015, and Sept 27, 2017, we assessed 288 patients for eligibility. The trial was terminated early after 131 patients had been randomly assigned (66 patients to the intervention group and 65 to the control group) because of high crossover rate and poor recruitment. In the intention-to-treat analysis, there was no evidence of a difference in the proportion of participants with mRS 0–3 at 90 days according to treatment (28 [42%] of 66 patients in the intervention group vs 21 [32%] of 65 in the control group; adjusted odds ratio [OR] 1·74, 95% CI 0·81–3·74). Secondary prespecified analyses of the primary outcome, done to assess the effect of crossovers, showed higher rates of mRS 0–3 at 90 days in patients who actually received the intervention compared with those who received standard medical therapy alone in both per-protocol (28 [44%] of 63 patients with intervention vs 13 [25%] of 51 with standard therapy; adjusted OR 2·90, 95% CI 1·20–7·03) and as-treated (36 [47%] of 77 patients with intervention vs 13 [24%] of 54 with standard therapy; 3·02, 1·31–7·00) populations. The 90-day mortality was similar between groups (22 [33%] of 66 patients in the intervention vs 25 [38%] of 65 in the control group; p=0·54) despite a numerically higher prevalence of symptomatic intracranial haemorrhage in the intervention group. Interpretation There was no evidence of a difference in favourable outcomes of patients receiving endovascular therapy compared with those receiving standard medical therapy alone. Results might have been confounded by loss of equipoise over the course of the trial, resulting in poor adherence to the assigned study treatment and a reduced sample size due to the early termination of the study. Funding Jiangsu Provincial Special Program of Medical Science.

Recently, NIX, a pro-apoptotic BH3-only protein, was found to be a novel p75 neurotrophin receptor (p75NTR) binding protein by screening a human fetal brain two-hybrid library in our laboratory. We further study the interaction of these two proteins and the possible roles of p75NTR and NIX in intracerebral hemorrhage (ICH)-induced neuronal death. Using the split-ubiquitin yeast two-hybrid system, we found that the “Copper” domain in p75NTR and the TM region in NIX were sufficient for the interaction of these two proteins. Co-immunoprecipitation and in vitro binding assays demonstrated the direct interaction between p75NTR and NIX. NIX protein was stabilized by p75NTR at post-translational levels. Moreover, p75NTR was able to work together with NIX to promote apoptosis and affected the NIX-induced JNK-p53-Bax pathway in neuronal PC12 cells. Previous work has indicated that p75NTR and NIX are induced in neurons in human ICH and the rat ICH model, respectively. We confirm that both p75NTR and NIX levels were up-regulated in glutamate-treated primary cortical neurons (a cellular in vitro model for ICH) and in the rat ICH model. Glutamate exposure increased the association between p75NTR and NIX and elevated the activation of the JNK-p53-Bax pathway and neuronal apoptosis; all of these observations were similar in the rat ICH model. Importantly, p75NTR and NIX appeared to be involved in cortical neuronal apoptosis, because knockdown of p75NTR or NIX not only inhibited the JNK pathway but also impaired neuronal apoptosis. Thus, p75NTR and NIX may play critical roles in ICH-induced neuronal apoptosis in vitro and in vivo.

PRDM5 (PR domain containing 5) belongs to PRDM family which consists of transcriptional regulators that modulate cellular processes such as cell growth, differentiation and apoptosis. However, the function of PRDM5 in central nervous system (CNS) inflammatory response is unknown. In recent study, an adult rat neuroinflammation model via lipopolysaccharide (LPS) lateral ventricle injection was constructed. PRDM5 expression was increased in activated astrocytes and apoptotic neurons of the adult rat cerebral cortex after LPS injection. In vitro studies showed that the remarkable upregulation of PRDM5 might be involved in rat primary astrocyte proliferation and rat primary neuronal apoptosis in the cerebral cortex following LPS administration. In addition, using PRDM5 RNA interference both in rat primary asrtocytes and neurons, further indicated that PRDM5 was required for astrocyte proliferation and neuronal apoptosis induced by LPS. Our findings on the cellular signaling pathway may provide a new therapeutic strategy against neuroinflammation in the CNS.

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.

Cyclin-dependent kinase-5 (CDK5), a serine/threonine kinase which can be activated by its neuron-specific activator p35, or its truncated form p25, plays an important role in a variety of neuronal events, including neuronal migration, synaptic transmission, and neuronal death. Accumulating evidence has shown that abnormal activation of CDK5 was a critical neuronal pro-death signal in central nervous system (CNS) diseases. However, it remains unclear how CDK5 functions upon neuronal apoptosis following intracerebral hemorrhage (ICH). In the present study, we established ICH models by injecting autologous whole blood into the right basal ganglia of adult rats and assessed their neurological deficits by behavioral tests. CDK5 protein levels and kinase activities were upregulated adjacent to the hematoma following ICH. Immunofluorescent staining showed CDK5 was mainly localized in neurons, rather than in astrocytes or oligodendrocytes. Furthermore, active caspase-3, an apoptotic marker, showed a temporally parallel expression with the protein levels/kinase activities of CDK5 following ICH. Meantime, myocyte enhancer factor 2D (MEF2D), a pro-survival transcription factor which could be phosphorylated inactivation by CDK5, also exhibited high phosphorylation levels following ICH. In vitro, we obtained a consistent upregulation of CDK5 kinase activity in primary cortical neurons after thrombin treatment. Knocking down CDK5 kinase activity suppressed neuronal apoptosis and coupled with reduced MEF2D phosphorylation at ser(444) residues. Thus, we speculated that CDK5 might exert an important function in the regulation of neuronal apoptosis following ICH.

Pyrroloquinoline quinone (PQQ), a redox cofactor in the mitochondrial respiratory chain, has been shown to protect neurons against glutamate-induced damage both in vitro and in vivo. In this study, specific inhibitors to each of the mitochondrial complexes were used to find out which reactive oxygen species (ROS)-generating sites could be affected by PQQ. Then we established an in vitro model of Parkinson's disease (PD) by exposing cultured SH-SY5Y dopaminergic cells to rotenone, a complex I inhibitor. The neuroprotective effects of PQQ were observed by pretreatment of SH-SY5Y cells with PQQ before rotenone injury, and the possible involvement of certain signaling pathways were investigated. PQQ pretreatment prevented SH-SY5Y cells from rotenone-induced apoptosis in a concentration-dependent manner. PQQ neuroprotection was associated with inhibition of intracellular ROS production, modulation of the expression of apoptosis-related Bcl-2 and Bax, and regulation of the level of superoxide dismutase, glutathione, and malondialdehyde. Meanwhile, PQQ up-regulated the gene expression of Ndufs 1, 2, and 4 (complex I subunits), and increased mitochondrial viability and mitochondrial DNA content. Furthermore, PQQ pretreatment activated ERK1/2 phosphorylation in rotenone-injured SH-SY5Y cells, while ERK1/2 inhibition suppressed PQQ neuroprotection. All the results suggested that PQQ could protect SH-SY5Y cells against rotenone injury by reducing ROS production and maintaining mitochondrial functions through activation of ERK1/2 pathway.

EHD2, a member of the Eps15 homology domain (EH domain) family, is important for protein interactions during vesicular trafficking. Previous studies have proved that EHD2 can regulate trafficking from the plasma membrane in the process of endocytosis. However, its function in central nervous system diseases is still with limited understanding. In this frame, we found that EHD2 expression was upregulated in the perihematomal caudate in adult rats after intracerebral hemorrhage (ICH). Double immunofluorescence staining revealed that EHD2 was colocalized with neurons and activated microglias after ICH. Besides, we detected that neuronal apoptosis markers (TUNEL and caspase-3), and microglial activation marker (CD68), also known as a marker of macrophage, were colocated with EHD2. The vitro study also indicated that EHD2 was linked with neuronal apoptosis and microglial phagocytosis. All our findings suggested that EHD2 might be involved in the pathophysiology of ICH.

SYF2, known as CCNDBP1-interactor or p29, is likely involved in pre-mRNA splicing and cell cycle progression. The present study was designed to elucidate dynamic changes in SYF2 expression and distribution in the cerebral cortex in a lipopolysaccharide (LPS)-induced neuroinflammation rat model. It was found that SYF2 expression was induced strongly in active astrocytes after LPS injection. In vitro studies showed that the upregulation of SYF2 might be involved in the activation of C6 cells after LPS challenge and the neuronal apoptosis after conditioned media challenge. In addition, with silencing of SYF2 in C6 and PC12 cells by siRNA, the results indicated that SYF2 was required for astrocyte activation and neuronal apoptosis induced by LPS. Our findings on the cellular signaling pathway may provide a new therapeutic strategy against neuroinflammation in the CNS.

Wild type p53-induced phosphatase 1 (Wip1) is a phosphatase which belongs to protein phosphatase type 2C family, which have been predominantly linked to cell growth and to cellular stress signaling. Numerous downstream targets of Wip1 have been identified, and genetic studies confirm that some play a part in tumorigenesis. Recent evidence highlights a new role for Wip1 in the regulation of NF-κB p65, which indicated that it might play a critical role in immune system. However, its regulation role in central nervous system (CNS) remains poorly understood. To elaborate whether Wip1 was involved in CNS injury, we performed a neuroinflammatory model by lipopolysaccharide (LPS) lateral–ventral injection in adult rats. Wip1 expression was strongly upregulated in active astrocytes in inflamed brain cortex. In vitro studies indicated that the upregulation of Wip1 may be involved in the subsequent astrocytic activation following LPS exposure, and knockdown of Wip1 in primary astrocytes by siRNA showed that Wip1 inhibited the synthesis of TNF-α. Collectively, these results suggested that Wip1 may be important in host defense in CNS immune response, which might provide a potent therapeutic target of neuroinflammation.

Chronic administration of d -galactose ( d -gal) is widely used to mimic the process of brain aging; however, the neural mechanisms are still poorly understood. In this study, we investigated the effect of long-term d -gal treatment on the number of GABA-immunoreactive neurons in rat cerebral cortex and the behavioral correlates. After eight weeks of daily subcutaneous injection of d -gal (100 mg/ml/kg), rats showed reduced exploratory activity and lower ambulation in the open field compared to controls. There was no significant reduction in total neurons in the cortex, but there was a marked decrease in the number of GABA-immunoreactive neurons in all cortical layers of d -gal-treated rats. The ratio of GABA-immunoreactive neurons to total neurons was significantly lower in all cortical layers of d -gal-treated rats, with greatest reductions in output layers III (39.9% reduction), V (46.3%), and VI (48.4%). Our study provides the first evidence that chronic d -gal treatment may decrease cortical GABAergic neurotransmission, especially in cerebral output layers. The reduction in GABA-immunoreactive cell number likely disrupts the intracortical excitatory/inhibitory balance and may contribute to the behavioral deficits observed in this aging model.

To investigate possible protective effects of pyrroloquinoline quinone (PQQ) on the rat cortex with glutamate injection and to understand the mechanisms linking the in vivo neuroprotection of PQQ. Adult Sprague-Dawley rats received glutamate injection into the rat cortex. Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling assay was performed to observe influences of co-treatment with PQQ (simultaneous injection with PQQ and glutamate) on neural cell apoptosis in the rat cortex. The production of reactive oxygen species (ROS) in the rat cortex was detected by flow cytometry using 2',7'-dichlorofluorescin diacetate labeling, and the activity of superoxide dismutase, glutathione and malondialdehyde was respectively determined. Real time quantitative RT-PCR and Western blot were applied to measure the mRNA and protein expressions of Nrf1, Nrf2, HO-1 and GCLC in the rat cortex. Western blot was used to detect the phosphorylation of Akt and GSK3β in the rat cortex. Co-treatment with PQQ protected neural cells in the rat cortex from glutamate-induced apoptosis. PQQ decreased the ROS production induced by glutamate injection. PQQ increased the mRNA and protein expressions of Nrf2, HO-1 and GCLC and the phosphorylation of Akt and GSK3β in the cortex of glutamate-injected rats. PQQ could produce neuroprotective effects on the rat cortex. The antioxidant properties of PQQ and PQQ-induced activation of Akt/GSK3β signal pathway might be responsible for the in vivo neuroprotection of PQQ.

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.

αB-crystallin (αBC) is involved in diverse cellular activities. Previous studies demonstrated that αBC had anti-apoptotic and proliferation-promoting effects in multiple diseases. Here, we explored the αBC's roles in the pathophysiology of intracerebral hemorrhage (ICH). An ICH rat model was established and assessed by behavioral tests. Using Western blot and immunohistochemistry, significant up-regulation of αBC was found in neurons and astrocytes in brain areas surrounding the hematoma following ICH. Increase of αBC expression was found to be accompanied by the increased expression of proliferating cell nuclear antigen (PCNA), p53, Bax, and active-caspase-3. αBC was co-localized with PCNA in astrocytes or active-caspase-3 in neurons, suggesting its role in astrocyte proliferation and neuronal apoptosis. Our in vitro study, using αBC RNA interference in PC12 cells, indicated that αBC might exert its anti-apoptotic function in neuronal apoptosis. Thus, αBC may play a role in protecting the brain from secondary damage following ICH.

Heat shock protein A12B (HSPA12B) is the newest member of a recently defined subfamily of proteins distantly related to the 70-kDa family of heat shock proteins (HSP70) family. HSP70s play a crucial role in protecting cells, tissues, organs and animals from various noxious conditions. Here we studied the dynamic expression changes and localization of HSPA12B after middle cerebral artery occlusion (MCAO) with reperfusion induced ischemic insult processes in adult rats. Apoptosis, as indicated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, was also increased in the peri-ischemic cortex compared to non-ischemic hemisphere. The expression of HSPA12B was strongly induced in the ischemic hemisphere of MCAO reperfusion rats in vivo. In vitro studies indicated that the up-regulation of HSPA12B may be involved in oxygen-glucose deprivation-induced PC12 cell death. And knockdown of HSPA12B in cultured differentiated PC12 cells by siRNA showed that HSPA12B inhibited the expression of active caspase-3. Collectively, these results suggested that HSPA12B may be required for protecting neurons from ischemic insults.

OTUB1 is a member of deubiquitinating enzymes, which was shown as a proteasome-associated DUB to be involved in the proteins Ub-dependent degradation. Previous studies have indicated that OTUB1 was expressed in brain. But its distribution and function in the brain remain unclear. In this study, we explored the roles of OTUB1 protein in the pathophysiology of intracerebral hemorrhage (ICH). From the results of Western blot, immunohistochemistry, and immunofluorescence, we found an obvious up-regulation of OTUB1 in neurons adjacent to the hematoma after ICH. Furthermore, we also found that the increase of OTUB1 expression was accompanied by the enhanced expression of Bax and active caspase-3, and decreased expression of Bcl-2 in the pathological process of rat ICH. What's more, our in vitro study, using OTUB1 RNA interference in PC12 cells, suggested that OTUB1 might exert its anti-apoptotic function in neuronal apoptosis. Therefore, OTUB1 may play a role in protecting the brain from secondary damage following ICH.

Contrary to cell cycle-associated cyclin-dependent kinases, CDK5 is best known for its regulation of signaling processes in regulating mammalian CNS development. Studies of CDK5 have focused on its phosphorylation, although the diversity of CDK5 functions in the brain suggests additional forms of regulation. Here we expanded on the functional roles of CDK5 glycosylation in neurons. We showed that CDK5 was dynamically modified with O-GlcNAc in response to neuronal activity and that glycosylation represses CDK5-dependent apoptosis by impairing its association with p53 pathway. Blocking glycosylation of CDK5 alters cellular function and increases neuronal apoptosis in the cell model of the ICH. Our findings demonstrated a new role for O-glycosylation in neuronal apoptosis and provided a mechanistic understanding of how glycosylation contributes to critical neuronal functions. Moreover, we identified a previously unknown mechanism for the regulation of activity-dependent gene expression, neural development, and apoptosis.

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.

Background and purpose Hyperintense vessels (HV) on fluid-attenuated inversion recovery (FLAIR) images were assumed to be explained by slow antegrade or retrograde leptomeningeal collateral flow related to extracranial or intracranial artery steno-occlusion. The aim of this study was to investigate the effect of recanalization after endovascular therapy of symptomatic internal carotid artery (ICA) occlusion on the presence of HV. Methods Eleven patients with symptomatic ICA occlusion were retrospectively enrolled. Changes in the HV on FLAIR images were examined in affected hemisphere of each patient after successful treatment with endovascular recanalization (angioplasty, n =3; stent-assisted angioplasty, n =8). The relationship between postoperative changes in the HV and Thrombolysis In Cerebral Ischemia (TICI) scale (I-III) was assessed. Results After operation, HV of the 11 affected hemispheres were showed to be decreased ( n =3) or disappeared ( n =8) in treated side. The median interval between pre- and postoperative MRI examinations was 97.0h (range, from 69. to 48.7h). Of the 8 patients with disappeared HV, 7 achieved high TICI grade flow (III) and 1 had relatively low TICI grade flow (IIc) in treated side. However, all the 3 patients with decreased HV were found to be relatively low TICI grade flow (IIc). Conclusion Our data indicate that endovascular recanalization of ICA occlusion was effective for decreasing HV. Postoperative decrease in HV can be considered as a marker for hemodynamic improvement.

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.

The present study was designed to investigate the neuroprotective effect of ginseng total saponins (GTSs) and its underlying mechanisms in a rat model of traumatic brain injury (TBI). Rats were injected with GTSs (20 mg/kg, i.p.) or vehicle for 14 days after TBI. Neurological functions were determined using beam balance and prehensile traction tests at 1-14 days after trauma. Brain samples were extracted at 1 day after trauma for determination of water content, Nissl staining, enzyme-linked immunosorbent assay, immunohistochemistry, terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick end labeling, and measurement of oxidative stress variables and inflammatory cytokines. Moreover, the dose response of the neuroprotective effect and time window of the efficacy of GTSs were also determined. We found that treatment of GTSs 1) improved the neurological function with an effective dosage of 5-80 mg/kg and an efficacy time window of 3-6 hr after TBI; 2) reduced brain water content and neuronal loss in the hippocampal CA3 area; 3) increased the activity of superoxide dismutase and decreased the activity of nitric oxide synthase and the amount of malondialdehyde and nitric oxide; 4) down-regulated interleukin-1β, interleukin-6, and tumor necrosis factor-α and upregulated interleukin-10 in the cortical area surrounding the injured core; and 5) inhibited the apoptotic cell death and expression of caspase-3 and bax and raised the expression of bcl-2. These findings suggest that administration of GTSs after TBI could reduce the secondary injury through inhibiting oxidative and nitrative stress, attenuating inflammatory response, and reducing apoptotic cell death.