CD47 Blockade Accelerates Blood Clearance and Alleviates Early Brain Injury After Experimental Subarachnoid Hemorrhage.

Aims: Subarachnoid hemorrhage (SAH) is a devastating stroke subtype. Following SAH, erythrocyte lysis contributes to cell death and brain injuries. Blockage of the anti-phagocytic receptor Cluster of Differentiation 47 (CD47) enhances phagocyte clearance of erythrocytes, though it has not been well-studied post-SAH. The current study aims to determine whether anti-CD47 treatment can enhance blood clearance after experimental SAH. Methods: The prechiasmatic blood injection model of SAH was used in mice. Mice were either treated with the CD47-blocking antibody or IgG as control. The effect of the anti-CD47 antibody on blood clearance and neurological function following SAH was determined. Neuroinflammation and neuronal injury were compared between the treatment and control samples on day 1 and day 7 after SAH using flow cytometry, immunofluorescence, Fluoro-Jade C, and Nissl staining, RT-PCR, and Western blot analysis. Results: CD47-blocking antibody sped-up blood clearance after SAH, and resulted in less neuronal injury and neurological deficits than control samples. Microglia played a role in the anti-CD47 blockade. Following SAH Following SAH, CD47 antibody-treated mice had less neuroinflammation and lower levels of apoptosis compared to controls and both one and 7 days. Conclusions: CD47 antibody treatment has a neuroprotective effect following SAH, by increasing blood clearance rate and reducing brain injury. These findings suggest CD47 antibody treatment may improve SAH patient outcomes.

Comparision of Mechanical Thrombectomy With Contact Aspiration or Stent Retriever in Patients With Large-vessel Occlusion in Acute Ischemic Stroke.

OBJECTIVES: Whether the direct aspiration approach of thrombectomy for recanalization in patients with acute ischemic stroke has a similar efficacy and safety compared to the stent-retriever still remains uncertain. METHODS: A retrospective data analysis was performed to identify patients with large cerebral artery acute ischemic stroke treated with endovascular thrombectomy. The study was conducted between January 2018 and December 2019 in a single stroke center. RESULTS: Twenty patients met inclusion criteria for this study with a mean age 66.64 ±â€Š17.92 years' old. The symptom occurred on the left side were in 13, and the right side in 7. The location of occlusion was 8 in M1 of the middle cerebral artery of M2, and 6 in internal carotid artery. Nine patients were randomized to first-line treatment with contact aspiration and eleven to first-line treatment with a stent retriever. The mean time from admission time to groin puncture was 55.51 ±â€Š31.03 minutes. The average time from groin puncture to maximal revascularizion after mechanical thrombectomy was 50.9 ±â€Š22.5 minutes in contact aspiration group, but this time was 71.37 ±â€Š25.45 minutes in the group of stent retriever. The overall successful revascularization rate (TICI 2b-3) was 88.9% in contact aspiration (TICI2a = 1, TICI 2b = 4 patients, TICI 3 = 4 patients), and 90.1% in stent retriever (TICI2a = 1, TICI 2b = 6 patients, TICI 3 = 4 patients). DISCUSSION: First-line thrombectomy with contact aspiration did not result in a higher successful revascularization rate at the end of the procedure but had a short time from groin puncture to maximal revascularizion.

Endovascular thrombectomy can be beneficial to acute ischemic stroke patients with large infarcts.

OBJECTIVE: This study aimed to assess whether patients with acute ischemic stroke (AIS) and large infarct lesions benefit from reperfusion management. To determine the efficacy of different recanalization managements on AIS patients with Alberta Stroke Program Early CT Score (ASPECTS) < 6, the authors retrospectively analyzed hospitalized patients with AIS. METHODS: Eighty-nine patients with AIS and ASPECTS < 6 were screened from 13,285 hospitalized patients treated by thrombolysis, thrombectomy, or conventional care in two stroke medical centers. Logistic regression or Fisher's exact test was performed for comparison of the outcome and risk events between patients treated by thrombectomy (or thrombolysis) and conventional care. The modified Rankin Scale (mRS) score was used to assess the major clinical outcome of patients 3 months after disease onset. Disease outcome was also examined by analyzing symptom improvement at discharge. In particular, mortality and symptomatic intracranial hemorrhage (sICH) were evaluated as risk factors. RESULTS: This study included 21 patients who received thrombolysis, 36 patients receiving thrombectomy, and 32 patients receiving conventional treatment. Among these 3 treatments, only the thrombectomy group clearly showed the most encouraging clinical outcome (mRS score 0-2; p < 0.05, Fisher's exact test) and marked improvement (OR 25.84, 95% CI 2.44-273.59) compared with conventional treatment. It is noteworthy that the mortality rate of the thrombectomy and thrombolysis group was similar to that of the conventional group, and thrombectomy and thrombolysis increased the risk of sICH in comparison with conventional care (p < 0.05, Fisher's exact test). CONCLUSIONS: Patients with AIS and ASPECTS < 6 definitely benefited from thrombectomy with higher sICH risk, whereas thrombolysis management showed similar efficacy to the control group.

Neuroprotective Effects of Valproic Acid on Blood-Brain Barrier Disruption and Apoptosis-Related Early Brain Injury in Rats Subjected to Subarachnoid Hemorrhage Are Modulated by Heat Shock Protein 70/Matrix Metalloproteinases and Heat Shock Protein 70/AKT Pathways.

BACKGROUND: Blood-brain barrier (BBB) disruption and neural apoptosis are thought to promote early brain injury (EBI) after subarachnoid hemorrhage (SAH). Previous studies have demonstrated that valproic acid (VPA) decreased brain injury in a prechiasmatic injection model of SAH in mice. It should be noted that the beneficial effects of VPA and the underlying mechanisms have not been fully elucidated. OBJECTIVE: To characterize the effects of VPA on BBB disruption and neural apoptosis and to determine mechanisms involved in EBI after SAH. METHODS: An endovascular perforation model was used to induce SAH in rats. VPA (300 mg/kg) was promptly administered after SAH induction, and the same dose was given 12 hours later. Quercetin (100 mg/kg), an inhibitor of heat shock protein 70 (HSP70), was injected into the peritoneum 2 hours before SAH induction. Mortality, SAH grades, neurological function, Evans Blue extravasation, brain edema, transmission electron microscopy, Western blot, double fluorescence labeling, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling staining also were used. RESULTS: VPA treatment decreased BBB disruption and brain edema, attenuated neural apoptosis, and improved neurobehavioral functions in EBI after SAH. Double fluorescence labeling indicated that matrix metallopeptidase 9 (MMP-9) was located predominately in neurons and endothelial cells. VPA upregulated the expression of HSP70, effectively decreased the expression and activity of MMP-9, and reduced claudin-5 and occludin degradation. Meanwhile, VPA also upregulated the expression of phosphorylated Akt and bcl-2. Both the anti-BBB disruption and antiapoptotic effects of VPA were abolished by quercetin. CONCLUSION: VPA prevented BBB disruption and alleviated neural apoptosis after SAH. The action of VPA appeared to be mediated though the HSP70/MMPs and HSP70/Akt pathways. ABBREVIATIONS: BBB, blood-brain barrierEBI, early brain injuryHSP, heat shock proteinMMP, matrix metalloproteinasePBS, phosphate-buffered salineSAH, subarachnoid hemorrhageTUNEL, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelingVPA, valproic acid.

Induction of autophagic cell death in the rat brain caused by iron.

BACKGROUND: The accumulation of iron in the brain is a hallmark of hemorrhagic stroke and several neurodegenerative diseases. Iron overload has been reported to induce brain injury through necrotic and apoptotic mechanisms. This study was taken to examine whether iron in the brain contributes to autophagic cell death. METHODS: Sprague-Dawley rats received an intracerebral ventricular injection of either ferrous chloride or saline. The expression levels of autophagic markers were measured by Western blot analysis. Immunofluorescent double labeling was used to identify the cell types expressing Beclin 1. Transmission electron microscopy was performed to examine the ultrastructural changes in neural cells 1 day after ferrous iron injection. RESULTS: Western blot analysis showed that the ratios of LC3-II to LC3-I and ATG5 levels were significantly upregulated at 6 hours and 1 day after ferrous iron injection. Beclin 1 expression was markedly elevated as early as 6 hours, reaching a peak at 24 hours and remaining elevated at 3 days after the injection. Beclin 1 immunoreactivity was located in both neurons and astrocytes under confocal microscopy. Induction of autophagic cell death was manifested by accumulation of autophagic vacuoles in the contralateral parietal cortex under transmission electron microscopy. CONCLUSIONS: Our data showed that increased ferrous iron levels in the brain induced autophagic cell death. These results also suggest that autophagy form of programmed cell death may be a mechanism of brain injury in iron overload disorders.

[Acute insular infarct increases risk of electrocardiogram changes and sudden cardiac death].

OBJECTIVE: To investigate the influence of location and size of acute insular infarct on stroke-related electrocardiogram (ECG) changes and cardiovascular events. METHODS: Ninety-nine cases admitted to hospital from October 2007 to June 2009, who were diagnosed as acute middle cerebral artery territory infarct within 48 h after onset and without the history of cardiac diseases, were included in the study. The patients were further divided into three groups: major insular infarct, minor insular infarct and control group, according to the infarct size on MRI diffusion-weighted image. The clinical data, ECG changes and cardiovascular events were compared between left and right insular infarct. Logistic regression was applied to determine the independent risk factors of ECG changes and cardiovascular events. RESULT: Large artery atherosclerosis was the main cause of acute insular infarct (71.8 %), which was associated with higher NIHSS score compared to the control group (P < 0.01). Comparing the left and right insular infarct, the frequencies of sinus bradycardia and sudden cardiac death were significantly higher in left insular infarct (P < 0.01 and P < 0.05), while there was a trend that the frequency of atrial fibrillation was higher in right insular infarct (P = 0.079). With the larger size of insular infarct, the frequency of sinus bradycardia, new atrial fibrillation and sudden cardiac death (P<0.01, P<0.05 and P<0.05, respectively) became much higher. Logistic regression analysis showed that major insular infarct was related to the higher frequency of sinus bradycardia (OR = 4.660, 95% CI: 1.646 ~ 13.195; P = 0.004). CONCLUSION: Acute insular infarct is associated with the stroke-related ECG changes and sudden cardiac death. Left insular infarct is related to sinus bradycardia, possibly due to the enhanced parasympathetic tone. It deserves clinical attention that the incidence of cardiac autonomic disturbance becomes higher with the enlarged insular infarct size.

Delayed substantia nigra damage and leukoencephalopathy after hypoxic-ischemic injury.

Delayed post-anoxic encephalopathy has rarely been reported, and has most commonly been associated with carbon monoxide poisoning. The underlying pathophysiological mechanism is unknown. We describe a patient with a delayed neurologic decline after a good initial recovery from a hypoxic-ischemic event precipitated by acute blood loss. MRI revealed early globus pallidus necrosis followed by delayed substantia nigra damage and leukoencephalopathy. We suggest that anemia might play a role in this pattern of hypoxic-ischemic brain injury.