Systolic blood pressure and early neurological deterioration in minor stroke: A post hoc analysis of ARAMIS trial.

BACKGROUND: Systolic blood pressure (SBP) was a predictor of early neurological deterioration (END) in stroke. We performed a secondary analysis of ARAMIS trial to investigate whether baseline SBP affects the effect of dual antiplatelet versus intravenous alteplase on END. METHODS: This post hoc analysis included patients in the as-treated analysis set. According to SBP at admission, patients were divided into SBP ≥140 mmHg and SBP <140 mmHg subgroups. In each subgroup, patients were further classified into dual antiplatelet and intravenous alteplase treatment groups based on study drug actually received. Primary outcome was END, defined as an increase of ≥2 in the NIHSS score from baseline within 24 h. We investigated effect of dual antiplatelet vs intravenous alteplase on END in SBP subgroups and their interaction effect with subgroups. RESULTS: A total of 723 patients from as-treated analysis set were included: 344 were assigned into dual antiplatelet group and 379 into intravenous alteplase group. For primary outcome, there was more treatment effect of dual antiplatelet in SBP ≥140 mmHg subgroup (adjusted RD, -5.2%; 95% CI, -8.2% to -2.3%; p < 0.001) and no effect in SBP <140 mmHg subgroup (adjusted RD, -0.1%; 95% CI, -8.0% to 7.7%; p = 0.97), but no significant interaction between subgroups was found (adjusted p = 0.20). CONCLUSIONS: Among patients with minor nondisabling acute ischemic stroke, dual antiplatelet may be better than alteplase with respect to preventing END within 24 h when baseline SBP ≥140 mmHg.

Intra-arterial tenecteplase during thrombectomy for acute stroke (BRETIS-TNK II): rationale and design.

BACKGROUND: Our recent pilot study suggests intra-arterial tenecteplase (TNK) during the first pass of endovascular treatment (EVT) seems safe, may increase first-pass reperfusion and good outcome in acute ischaemic stroke (AIS) patients with large-vessel occlusion (LVO). AIMS: To determine the efficacy and safety of intra-arterial TNK administration during EVT in AIS-LVO patients presenting up to 24 hours from symptom onset. SAMPLE SIZE ESTIMATES: A maximum of 380 patients are required to test the superiority hypothesis with 80% power according to a two-side 0.05 level of significance, stratified by age, gender, baseline systolic blood pressure, prestroke modified Rankin Scale (mRS), baseline National Institute of Health stroke scale, baseline ASPECTS, time from onset to groin puncture, intravenous thrombolysis before EVT, stroke territory and stroke aetiology. DESIGN: Intra-arterial TNK during thrombectomy for acute stroke (BRETIS-TNK II) study is a prospective, randomised, adaptive enrichment, open-label, blinded end point, multicentre study. Eligible AIS-LVO patients are randomly assigned into the experimental group and control group with a ratio of 1:1. The experimental group will be treated with intra-arterial infusion of TNK during EVT. The control group will be treated with standard EVT. OUTCOME: The primary end point is a favourable outcome, defined as an mRS score of 0-2 at 90 days. The primary safety end point is symptomatic intracranial haemorrhage within 48 hours, which is defined as an increase in the National Institutes of Health Stroke Scale score of ≥4 points as a result of the intracranial haemorrhage. CONCLUSIONS: The results of BRETIS-TNK II will provide evidence for the efficacy and safety of intra-arterial TNK administration during EVT in AIS patients with LVO.

Cellular and molecular mechanisms in vascular repair after traumatic brain injury: a narrative review.

Traumatic brain injury (TBI) disrupts normal brain function and is associated with high morbidity and fatality rates. TBI is characterized as mild, moderate or severe depending on its severity. The damage may be transient and limited to the dura matter, with only subtle changes in cerebral parenchyma, or life-threatening with obvious focal contusions, hematomas and edema. Blood vessels are often injured in TBI. Even in mild TBI, dysfunctional cerebral vascular repair may result in prolonged symptoms and poor outcomes. Various distinct types of cells participate in vascular repair after TBI. A better understanding of the cellular response and function in vascular repair can facilitate the development of new therapeutic strategies. In this review, we analyzed the mechanism of cerebrovascular impairment and the repercussions following various forms of TBI. We then discussed the role of distinct cell types in the repair of meningeal and parenchyma vasculature following TBI, including endothelial cells, endothelial progenitor cells, pericytes, glial cells (astrocytes and microglia), neurons, myeloid cells (macrophages and monocytes) and meningeal lymphatic endothelial cells. Finally, possible treatment techniques targeting these unique cell types for vascular repair after TBI are discussed.

Intra-arterial tenecteplase is safe and may improve the first-pass recanalization for acute ischemic stroke with large-artery atherosclerosis: the BRETIS-TNK trial.

Background and purpose: The first-pass recanalization of endovascular treatment (EVT) is closely correlated with clinical outcome of patients with large vessel occlusion (LVO) stroke. The aim of the study was to explore whether intra-arterial tenecteplase (TNK) during the first pass of EVT can increase first-pass successful reperfusion and improve the neurological outcome in AIS-LVO patients. Materials and methods: The BRETIS-TNK trial (ClinicalTrials.gov Identifier: NCT04202458) was a prospective, single-arm, single center study. Twenty-six eligible AIS-LVO patients with large-artery atherosclerosis etiology were consecutively enrolled from December 2019 to November 2021. Intra-arterial TNK (4 mg) after microcatheter navigation through the clot was administered, followed by TNK (0.4 mg/min) given continuously for 20 min after the first retrieval attempt of EVT without confirmation of the reperfusion status by DSA. The 50 control patients comprised of a historical cohort before the BRETIS-TNK trial (from March 2015 to November 2019). Successful reperfusion was defined as modified Thrombolysis In Cerebral Infarction (mTICI) ≥2b. Results: The first-pass successful reperfusion rate was higher in the BRETIS-TNK vs. control group (53.8% vs. 36%, p = 0.14), and the difference became statistically significant after propensity score matching (53.8% vs. 23.1%, p = 0.03). There was no difference in symptomatic intracranial hemorrhage between the BRETIS-TNK and control groups (7.7% vs. 10.0%, p = 0.92). There was a trend toward higher proportion of functional independence at 90 days in the BRETIS-TNK comparing with the control group (50% vs. 32%, p = 0.11). Conclusion: This is the first study to report that intra-arterial TNK during the first pass of EVT seems safe and feasible in AIS-LVO patients.

Predicting symptomatic intracranial hemorrhage in anterior circulation stroke patients with contrast enhancement after thrombectomy: the CAGA score.

BACKGROUND: The aim of the study was to establish a reliable scoring tool to identify the probability of symptomatic intracranial hemorrhage (sICH) in anterior circulation stroke patients with contrast enhancement (CE) on brain non-contrast CT (NCCT) after endovascular thrombectomy (EVT). METHODS: We retrospectively reviewed consecutive patients with acute ischemic stroke (AIS) who had CE on NCCT immediately after EVT for anterior circulation large vessel occlusion (LVO). We used the Alberta stroke program early CT score (ASPECTS) scoring system to estimate the extent and location of CE. Multivariable logistic regression was performed to derive an sICH predictive score. The discrimination and calibration of this score were assessed using the area under the receiver operator characteristic curve, calibration curve, and decision curve analysis. RESULTS: In this study, 194 of 322 (60.25%) anterior circulation AIS-LVO patients had CE on NCCT. After excluding 85 patients, 109 patients were enrolled in the final analysis. In multivariate regression analysis, age ≥70 years (adjusted OR (aOR) 9.23, 95% CI 2.43 to 34.97, P＜0.05), atrial fibrillation (AF) (aOR 4.17, 95% CI 1.33 to 13.12, P＜0.05), serum glucose ≥11.1 mmol/L (aOR 9.39, 95% CI 2.74 to 32.14, P＜0.05), CE-ASPECTS ＜5 (aOR 3.95, 95% CI 1.30 to 12.04 P＜0.05), and CE at the internal capsule (aOR 3.45, 95% CI 1.03 to 11.59, P＜0.05) and M1 region (aOR 3.65, 95% CI 1.13 to 11.80, P＜0.05) were associated with sICH. These variables were incorporated as the CE-age-glucose-AF (CAGA) score. The CAGA score demonstrated good discrimination and calibration in this cohort, as well as the fivefold cross validation. CONCLUSION: The CAGA score reliably predicted sICH in patients with CE on NCCT after EVT treatment.

Association between collaterals, cerebral circulation time and outcome after thrombectomy of stroke.

OBJECTIVE: Cerebral circulation time (CCT) and collateral score (CS) are associated with functional outcomes in acute ischemic stroke (AIS) patients after endovascular treatment (EVT), and may be related to each other. We aim to determine the relationship between CS and CCT on functional outcomes. METHODS: We retrospectively enrolled consecutive patients with anterior circulation large vessel occlusion (LVO) AIS who received EVT. CS and CCT were measured based on digital subtraction angiography (DSA). We defined CS 0-2 and 3-4 as poor and good collateral status, respectively, and used change of CCT (cCCT), which was defined as the change of stroke side CCT (sCCT) versus healthy side CCT (hCCT). Mediating analysis was used to evaluate the influence of cCCT on the association between CS and functional outcomes, and ROC curves were further used to explore the predictive ability of the interaction between cCCT and CS for functional outcomes. RESULTS: A total of 100 patients were enrolled in the final analysis. A higher cCCT (r = -0.239; p = 0.017) was associated with lower CS, and cCCT mediated the association of CS with functional outcome. Logistic regression analysis found that CS, cCCT and cCCT-CS interactions were independently associated with functional outcome, and cCCT-CS interaction has better predictive performance, with a higher area under curve value than CS or cCCT alone (0.79 vs. 0.75 or 0.75). INTERPRETATION: To our knowledge, this study provides the first report of the association of collateral status with cCCT, and their interaction effect on functional outcome in AIS-LVO patients receiving EVT.

Changes in blood gas values and electrolytes in the occluded artery predict outcomes after endovascular treatment in ischemic stroke.

BACKGROUND AND PURPOSE: Endovascular treatment (EVT) is the best treatment for acute ischemic stroke with large vessel occlusion (LVO) and makes it possible to analyze the blood contents from the occluded vascular compartments. In this study, we attempted to evaluate regional changes in blood gas values and electrolytes in the occluded vessels, aiming to determine whether these changes can predict outcomes in LVO patients receiving EVT. MATERIALS AND METHODS: We prospectively observed 45 consecutive ischemic stroke patients with LVO of the anterior circulation who underwent EVT. We collected the arterial blood proximal to the occlusion site before and after EVT, and the blood within the core of the occluded vascular compartment (distal to the thrombus) and evaluated the labs for blood gas values and electrolytes. Femoral samples were obtained under physiological flow conditions to represent systemic arterial blood. RESULTS: Compared with the femoral arterial blood samples, significant decreases in K+, Ca2+, HCO3-, BE, HCT, tHbc, and TCO2 levels were observed in the proximal luminal blood before EVT. Decreases in K+ and Ca2+ levels were also observed in the proximal luminal blood after EVT. Proximal/femoral ratio of pH and Na+ was associated with short-term clinical outcomes at 72 hours after EVT. A higher proximal/femoral Na+ ratio was associated with successful recanalization. Further analysis after propensity score matching showed significant changes in blood gas and electrolyte among different arterial locations in ICA and MCA LVO participants. Linear regression analyses indicated that the proximal/femoral ratio of pH, Na+, pCO2, HCO3, and TCO2 before EVT were associated with decrease in NIHSS score at 72 hours in ICA-LVO group. CONCLUSIONS: Obvious changes in several parameters of arterial blood gas and electrolyte from the ischemic vasculature occur during hyperacute stroke. Proximal/femoral pH and Na+ ratio before EVT may be associated with short-term clinical outcome, which deserve to be further investigated.

Toll-Like Receptor 4 Signaling in Neurons Mediates Cerebral Ischemia/Reperfusion Injury.

In microglia, Toll-like receptor 4 (TLR4) is well known to contribute to neuroinflammatory responses following brain ischemia. TLR4 is also expressed in neurons and can mediate the conduction of calcium (Ca2+) influx, but the mechanistic link between neuronal TLR4 signaling and brain ischemic injury is still poorly understood. Here, primary neuronal cell cultures from TLR4 knockout mice and mice with conditional TLR4 knockout in glutamatergic neurons (TLR4cKO) were used to establish ischemic models in vitro and in vivo, respectively. We found that deleting TLR4 would reduce the neuronal death and intracellular Ca2+ increasement induced by oxygen and glucose deprivation (OGD) or lipopolysaccharide treatment. Infarct volume and functional deficits were also alleviated in TLR4cKO mice following cerebral ischemia/reperfusion (I/R). Furthermore, TLR4 and N-methyl-D-aspartate receptor subunit 2B (NMDAR2B) were colocalized in neurons. Deletion of TLR4 in neurons rescued the upregulation of phosphorylated NMDAR2B induced by ischemia via Src kinase in vitro and in vivo. Downstream of NMDAR2B signaling, the interaction of neuronal nitric oxide synthase (nNOS) with postsynaptic density protein-95 (PSD-95) was also disrupted in TLR4cKO mice following cerebral I/R. Taken together, our results demonstrate a novel molecular neuronal pathway in which TLR4 signaling in neurons plays a crucial role in neuronal death and provide a new target for neuroprotection after ischemic stroke.

The effect of head-down tilt in experimental acute ischemic stroke.

BACKGROUND: Collateral therapeutics exert a promising protective effect on the outcome of acute ischemic stroke. Cerebral blood flow (CBF) may be modulated by different head positioning. The current study aimed to determine the effect of head-down tilt (HDT) on stroke in a rodent model. METHODS: The model of middle cerebral artery occlusion and reperfusion (MCAO/R) was used in this study. Neurological deficit scoring, 2,3,5-triphenyltetrazolium chloride staining, brain water content, perivascular aquaporin protein-4 (AQP4) localization, pericyte marker platelet-derived growth factor receptor ß (PDGFRß), and CBF velocity were evaluated at 24 h after MCAO/R and HDT treatment. RESULTS: In the rat model of MCAO/R, brain infarct volume and neurological deficit score were significantly alleviated in the -30° and -60° groups compared to those in the lying flat (0°) group. Compared with the 0° group, an increase in CBF velocity was detected in the -30° group through two-photon microscopy imaging at 24 h after MCAO/R. Compared with the SHAM group, a decrease in PDGFRß was observed in both the MCAO/R and HDT treatment (-30°) groups. The integrated optical density of PDGFRß was found to be higher in the HDT treatment (-30°) group than in the MCAO/R group. An impairment in perivascular AQP4 polarity and an increase in brain water content were observed after MCAO/R, which were not exacerbated by HDT treatment (-30°). CONCLUSIONS: Our findings suggest that HDT treatment at certain degrees may exert a neuroprotective effect after MCAO/R through improving CBF velocity and the protection of pericytes.

Effect of head-down tilt on clinical outcome and cerebral perfusion in ischemic stroke patients: A case series.

Background: The effect of head position on stroke is not clear. The current study aimed to observe the effect of head-down tilt on acute ischemic stroke (AIS) patients with large vessel occlusion. Methods: We observed the influence of head-down tilt position on clinical outcomes, myocardial enzymogram and N-terminal pro b-type Natriuretic Peptide in 4 AIS patients who suffered early neurological deterioration (END). Cerebral perfusion imaging was performed in 3 patients using arterial spin labeling. Results: In series of AIS patients with END, head down tilt (-20°) prevented further neurological deterioration and improved clinical outcomes. An increase in cerebral blood flow was observed by arterial spin labeling after head down tilt treatment. No obvious adverse events occurred. Conclusion: The case series suggest that head-down tilt may improve clinical outcome in AIS patients through increasing the cerebral perfusion with no obvious adverse events. The finding needs to be confirmed in future clinical trials.

Contrast enhancement by location and volume is associated with long-term outcome after thrombectomy in acute ischemic stroke.

Contrast enhancement (CE) on brain non-contrast computed tomography (NCCT) is common after endovascular thrombectomy (EVT) in patients with acute ischemic stroke (AIS), but its association with clinical outcomes is not well established. The current study aimed to investigate this relationship. We retrospectively reviewed consecutive patients with acute ischemic stroke who had hyperdensity on NCCT immediately after EVT for anterior circulation large vessel occlusion (LVO) from January 2016 to December 2019. We used ASPECTS combined with volume measurement by 3D reconstruction to estimate the extent and location of CE. Multivariable regression analysis was conducted to explore the risk factors associated with clinical outcome. In this study, 113 of 158 (71.52%) anterior circulation AIS-LVO patients had hyperdensity on brain NCCT. After strict inclusion and exclusion criteria, a total of 64 patients were enrolled in the final analysis. In logistic regression analysis, CE-ASPECTS, CE volume, CE at the caudate nucleus, M4 and M6 region were associated with 3-month poor functional outcome after adjusting for confounding factors. The conventional variable model was used for reference, including age, initial NIHSS, the procedure time, stent retriever passes, recanalization status and baseline ASPECTS, with AUC of 0.73. When combined with the above-named variables (conventional variables + CE-ASPECTS + CE volume + CE at caudate nucleus + CE at M4 region + CE at M6 region), the predictive power was significantly improved, with AUC of 0.87 (95% CI 0.78-0.95). The spatial location and volume of CE on NCCT obtained immediately after EVT were independent and strong predictors for poor outcome at 3-months in patients with AIS after excluding definite hemorrhage by 24-h follow up CT.

Cerebral Circulation Time After Thrombectomy: A Potential Predictor of Outcome After Recanalization in Acute Stroke.

Background Despite successful recanalization, up to half of patients with acute ischemic stroke caused by large-vessel occlusion treated with endovascular treatment (EVT) do not recover to functional independence. We aim to evaluate the role of cerebral circulation time (CCT) as outcome predictor after EVT. Methods and Results We retrospectively enrolled consecutive patients with acute ischemic stroke-large-vessel occlusion undergoing EVT. Three categories of CCT based on digital subtraction angiography were studied: CCT of the stroke side, CCT of the healthy side), and change of CCT of the stroke side versus CCT of the healthy side. Dramatic clinical recovery was defined as a 24-hour National Institutes of Health Stroke Scale score ≤2 or ≥8 points drop. A modified Rankin Scale score ≤2 at 3 months was considered a favorable outcome. Logistic regression analysis was performed to evaluate the prediction of CCT on prognosis. One hundred patients were enrolled, of which 38 (38.0%) experienced a dramatic clinical recovery and 43 (43.0%) achieved a favorable outcome. Logistic regression analysis found that shorter change of CCT of the stroke side versus CCT of the healthy side and CCT of the stroke side were independent positive prognostic factors for dramatic clinical recovery (odds ratio [OR], 0.189; P=0.033; OR, 0.581; P=0.035) and favorable outcomes (OR, 0.142; P=0.020; OR, 0.581; P=0.046) after adjustment for potential confounders. A model including the change of CCT of the stroke side versus CCT of the healthy side also had significantly higher area under the curve values compared with the baseline model in patients with dramatic clinical recovery (0.780 versus 0.742) or favorable outcome (0.759 versus 0.713). Conclusions To our knowledge, this is the first report that CCT based on digital subtraction angiography data exhibits an independent predictive performance for clinical outcome in patients with acute ischemic stroke-large-vessel occlusion after EVT. Given that this readily available CCT can provide alternative perfusion information during EVT, a prospective, multicenter trial is warranted.

NLRP3 Inflammasome-Dependent Increases in High Mobility Group Box 1 Involved in the Cognitive Dysfunction Caused by Tau-Overexpression.

Tau hyperphosphorylation is a characteristic alteration present in a range of neurological conditions, such as traumatic brain injury (TBI) and neurodegenerative diseases. Treatments targeting high-mobility group box protein 1 (HMGB1) induce neuroprotective effects in these neuropathologic conditions. However, little is known about the interactions between hyperphosphorylated tau and HMGB1 in neuroinflammation. We established a model of TBI with controlled cortical impacts (CCIs) and a tau hyperphosphorylation model by injecting the virus encoding human P301S tau in mice, and immunofluorescence, western blotting analysis, and behavioral tests were performed to clarify the interaction between phosphorylated tau (p-tau) and HMGB1 levels. We demonstrated that p-tau and HMGB1 were elevated in the spatial memory-related brain regions in mice with TBI and tau-overexpression. Animals with tau-overexpression also had significantly increased nucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome activation, which manifested as increases in apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), activating caspase-1 and interleukin 1 beta (IL-1ß) levels. In addition, NLRP3-/- mice and the HMGB1 inhibitor, glycyrrhizin, were used to explore therapeutic strategies for diseases with p-tau overexpression. Compared with wild-type (WT) mice with tau-overexpression, downregulation of p-tau and HMGB1 was observed in NLRP3-/- mice, indicating that HMGB1 alterations were NLRP3-dependent. Moreover, treatment with glycyrrhizin at a late stage markedly reduced p-tau levels and improved performance in the Y- and T-mazes and the ability of tau-overexpressing mice to build nests, which revealed improvements in spatial memory and advanced hippocampal function. The findings identified that p-tau has a triggering role in the modulation of neuroinflammation and spatial memory in an NLRP3-dependent manner, and suggest that treatment with HMGB1 inhibitors may be a better therapeutic strategy for tauopathies.

Outcomes of general anesthesia versus conscious sedation for Stroke undergoing endovascular treatment: a meta-analysis.

BACKGROUND: The impact of anesthesia strategy on the outcomes of acute ischemic stroke (AIS) patients undergoing endovascular treatment is currently controversy. Thus, we performed this meta-analysis to compare the differences of clinical and angiographic outcomes between general anesthesia (GA) and conscious sedation (CS). METHODS: A literature search in PubMed, Embase, and Web of Knowledge databases through February 2019 was conducted for related records on GA and CS of AIS undergoing endovascular treatment. The results of the studies were pooled and meta-analyzed with fixed- or random-effect model based on heterogeneity test in total and subgroup analyses. RESULTS: Twenty-three studies including 6703 patients were analyzed in this meta-analysis. We found that patients in the GA group have lower odds of favorable functional outcome (mRS scores ≤2) compared with the CS group (odds ratio [OR] = 0.62, 95% confidence interval [CI]: 0.49-0.77), and higher risk of mortality (OR = 1.68, 95% CI: 1.49-1.90), pneumonia (OR = 1.78, 95% CI: 1.40-2.26), symptomatic intracranial hemorrhage (OR = 1.64, 95% CI: 1.13-2.37). However, no significant differences were seen between the groups in the rate of recanalization (OR = 1.07, 95% CI: 0.89-1.28), vessel dissection or perforation (OR = 1.00, 95% CI: 0.98-1.03) and asymptomatic intracranial hemorrhage (OR = 1.19, 95% CI: 0.96-1.47). While in the RCT subgroup analysis, we found patients in the GA group does not show lower rate of favorable functional outcome compared with the CS group (OR = 1.84, 95% CI: 1.17-2.89). And there was no significant difference in the rate of mortality between GA and CS groups during RCT subgroup analysis (OR = 0.74, 95% CI: 0.43-1.27). CONCLUSIONS: AIS patients performed endovascular treatment under GA compared with CS was associated with worse functional outcome and increased rate of mortality, but differences in worsened outcomes do not exist when one looks into the GA vs. CS RCTs. Moreover, these findings are mainly based on the retrospective studies and additional multi-center randomized controlled trials to definitively address these issues is warranted.

A novel rat model of cerebral artery occlusion complicated with prior venous stagnation.

BACKGROUND: To establish a novel rat model of middle cerebral artery occlusion (MCAO) complicated with prior venous stagnation, and to investigate the role of cerebral venous drainage in neural injury after acute cerebral infarction. NEW METHOD: Eighteen SD rats were randomly divided into two groups: control group and jugular vein ligation group. The left jugular vein ligation was performed to produce the jugular venous stagnation. In the control group, the jugular vein was exposed but not ligated. Cerebral blood flow (CBF) was measured through laser speckle imaging before and after the surgery. At 1 week after the surgery, CBF was again measured and then a left MCAO was performed in both groups. At 24 h after MCAO, neurological deficit scoring was performed and the infarct volume was measured by 2,3,5-triphenyltetrazolium chloride staining. RESULTS: Compared with the control group, a significant decrease in the CBF level was observed immediately after the ligation. A moderate recovery in CBF level was observed at 1 week after the ligation. The neurological deficit scores were significantly higher in the ligation group than in the control group at 24 h after the MCAO. Additionally, the volume of cerebral infarction increased significantly in the ligation group compared with that in the control group at the 24 h after MCAO. COMPARISON WITH EXISTING METHOD(S) AND CONCLUSIONS: The novel rat model of cerebral artery occlusion complicated with long-term unilateral venous stagnation indicates cerebral venous drainage impairment may aggravate behavioral impairment and increase infarct volume after cerebral infarction.

Caffeine attenuates brain injury but increases mortality induced by high-intensity blast wave exposure.

Caffeine is a substance that is consumed worldwide, and it may exert neuroprotective effects against various cerebral insults, including neurotrauma, which is the most prevalent injury among military personnel. To investigate the effects of caffeine on high-intensity blast wave-induced severe blast injury in mice, three different paradigms of caffeine were applied to male C57BL/6 mice with severe whole body blast injury (WBBI). The results demonstrated that chronic caffeine treatment alleviated blast-induced traumatic brain injury (bTBI); however, both chronic and acute caffeine treatments exacerbated blast-induced lung injuries and, more importantly, increased both the cumulative and time-segmented mortalities postinjury. Interestingly, withdrawing caffeine intake preinjury resulted in favorable outcomes in mortality and lung injury, similar to the findings in water-treated mice, and had the trend to attenuate brain injury. These findings demonstrated that although drinking coffee or caffeine preparations attenuated blast-induced brain trauma, these beverages may place personnel in the battlefield at high risk of casualties, which will help us re-evaluate the therapeutic strategy of caffeine application, particularly in multiple-organ-trauma settings. Furthermore, these findings provided possible strategies for reducing the risk of casualties with caffeine consumption, which may help to change the coffee-drinking habits of military personnel.

Time dependent neuroprotection of dexamethasone in experimental focal cerebral ischemia: The involvement of NF-κB pathways.

We propose that the neuroprotective effect of glucocorticoid in ischemic damage may be time dependent. The present study was designed to test the proposal and its possible mechanismin cerebral ischemia/reperfusion (I/R) injury model. Reperfusion injury was induced after 120 min of middle cerebral artery occlusion (MCAO) in male Sprague-Dawley rats. Atdifferenttimepoints after MCAO, rats were treated with high dose dexamethasone (10 mg/kg), and neurological deficit and infarct sizes were measured 2 h, 24 h after MCAO. The expression of NF-κB target genes, including inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), were determined by western blot analysis and ELISA. Dexamethasone delivered 30 min (but not 60 min, 120 min) after MCAO markedly decreased the infarct size, improved neurological deficits in I/R injury model. Dexamethasone delivered 30 min (but not 60 min) after MCAO significantly inhibited NF-κB p65 expression and phosphorylation, compared with I/R group. The expression of iNOS, COX-2, TNF-α and IL-1ß, were also suppressed by dexamethasone delivered 30 min (but not 60 min) after MCAO. The results imply that neuroprotective action of dexamethasone in focal ischemic stroke model may be time dependent and attributed to inhibiting inflammation-related NF-κB p65 pathways.

Intra-arterial human urinary kallidinogenase alleviates brain injury in rats with permanent middle cerebral artery occlusion through PI3K/AKT/FoxO1 signaling pathway.

An urgent need exists to develop intra-arterial treatment for acute ischemic stroke in animal study. This study aimed to explore the beneficial effects of intra-arterial administration of human urinary kallidinogenase (HUK) on brain injury after permanent middle cerebral artery occlusion (pMCAO) in a rat model, and the potential underlying molecular mechanisms. Brain injury induced by pMCAO was evaluated through measuring neurological deficit scores, neuropathological changes, and inflammatory factors. Neurological deficits were observed 24 h after pMCAO and were alleviated by intra-arterial HUK treatment obviously. Inhibition of PI3K by LY294002 blocked the beneficial effect of HUK on neurological functions. In contrast to the pMCAO group, the intra-arterial HUK treatment group showed relatively more regularly arranged neurons and fewer pyknosis. Neurodegeneration, necrosis, infarct area and markers for brain injury were all ameliorated by intra-arterial HUK treatment. Moreover, a lower expression of inflammatory factors including interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α, and a higher expression of IL-10 were observed in the intra-arterial HUK treatment group than that in the pMCAO group. Additionally, when comparing with pMCAO group, a lower level of caspase-3, bax, and apoptotic rate, and a higher level of bcl-2, p-PI3K, p-AKT and p-FoxO1were observed in the pMCAO + HUK group. These results suggest that intra-arterial administration of HUK is a promising therapeutic strategy against pMCAO induced brain injury, and PI3K/AKT/FoxO1 signaling pathway may be involved in this process.

Impaired autophagic flux is associated with the severity of trauma and the role of A2AR in brain cells after traumatic brain injury.

Recent studies have shown that after traumatic brain injury (TBI), the number of autophagosomes is markedly increased in brain cells surrounding the wound; however, whether autophagy is enhanced or suppressed by TBI remains controversial. In our study, we used a controlled cortical impact system to establish models of mild, moderate and severe TBI. In the mild TBI model, the levels of autophagy-related protein 6 (Beclin1) and autophagy-related protein 12 (ATG12)-autophagy-related protein 5 (ATG5) conjugates were increased, indicating the enhanced initiation of autophagy. Furthermore, the level of the autophagic substrate sequestosome 1 (SQSTM1) was decreased in the ipsilateral cortex. This result, together with the results observed in tandem mRFP-GFP-LC3 adeno-associated virus (AAV)-infected mice, indicates that autophagosome clearance was also increased after mild TBI. Conversely, following moderate and severe TBI, there was no change in the initiation of autophagy, and autophagosome accumulation was observed. Next, we used chloroquine (CQ) to artificially impair autophagic flux in the injured cortex of the mild TBI model and found that the severity of trauma was obviously exacerbated. In addition, autophagic flux and trauma severity were significantly improved in adenosine A2A receptor (A2AR) knockout (KO) mice subjected to moderate TBI. Thus, A2AR may be involved in regulating the impairment of autophagic flux in response to brain injury. Our findings suggest that whether autophagy is increased after TBI is associated with whether autophagic flux is impaired, and the impairment of autophagic flux exacerbates the severity of trauma. Furthermore, A2AR may be a target for alleviating the impairment in autophagic flux after TBI.

Perivascular AQP4 dysregulation in the hippocampal CA1 area after traumatic brain injury is alleviated by adenosine A2A receptor inactivation.

Traumatic brain injury (TBI) can induce cognitive dysfunction due to the regional accumulation of hyperphosphorylated tau protein (p-tau). However, the factors that cause p-tau to concentrate in specific brain regions remain unclear. Here, we show that AQP4 polarization in the perivascular astrocytic end feet was impaired after TBI, which was most prominent in the ipsilateral brain tissue surrounding the directly impacted region and the contralateral hippocampal CA1 area and was accompanied by increased local p-tau, changes in dendritic spine density and morphology, and upregulation of the adenosine A2A receptor (A2AR). The critical role of the A2AR signaling in these pathological changes was confirmed by alleviation of the impairment of AQP4 polarity and accumulation of p-tau in the contralateral CA1 area in A2AR knockout mice. Given that p-tau can be released to the extracellular space and that the astroglial water transport via AQP4 is involved in tau clearance from the brain interstitium, our results suggest that regional disruption of AQP4 polarity following TBI may reduce the clearance of the toxic interstitial solutes such as p-tau and lead to changes in dendritic spine density and morphology. This may explain why TBI patients are more vulnerable to cognitive dysfunction.