Recombinant human brain natriuretic peptide attenuates ischemic brain injury in mice by inhibiting oxidative stress and cell apoptosis via activation of PI3K/AKT/Nrf2/HO-1 pathway.

Ischemic stroke followed by cerebral artery occlusion is a main cause of chronic disability worldwide. Recombinant human brain natriuretic peptide (rhBNP) has been reported to alleviate sepsis-induced cognitive dysfunction and brain I/R injury. However, the function and molecular mechanisms of rhBNP in ischemic brain injury have not been clarified. For establishment of an animal model of ischemic brain injury, C57BL/6 mice were treated with middle cerebral artery occlusion (MCAO) surgery for 1 h and reperfusion for 24 h. After subcutaneous injection of rhBNP into model mice, neurologic deficits were assessed by evaluating behavior of mice according to Longa scoring system, and TTC staining was utilized to determine the brain infarct size of mice. The levels of oxidative stress markers, superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and malondialdehyde (MDA), were detected in hippocampal tissues of mice by corresponding kits. Cell apoptosis in hippocampus tissues was examined by TUNEL staining. Protein levels of antioxidant enzymes (HO-1 and NQO1) in cerebral cortex, apoptotic markers (Bax, Bcl-2, and cleaved caspase), and PI3K/AKT pathway-associated factors in hippocampus were tested by western blot analysis. The results revealed that injection of rhBNP decreased neurologic deficit scores, the percent of brain water content, and infarct volume. Additionally, rhBNP downregulated MDA level, upregulated the levels of SOD, CAT, and GSH in hippocampus of mice, and increased protein levels of HO-1 and NQO1 in the cortex. Cell apoptosis in hippocampus tissues of model mice was inhibited by rhBNP which was shown as the reduced TUNEL-positive cells, the decreased Bax, cleaved caspase-3, and cleaved caspase-9 protein levels, and the enhanced Bcl-2 protein level. In addition, rhBNP treatment activated the PI3K/AKT signaling pathway and upregulated the protein levels of HO-1 and NRF2. Overall, rhBNP activates the PI3K/AKT/HO-1/NRF2 pathway to attenuate ischemic brain injury in mice after MCAO by suppression of cell apoptosis and oxidative stress.

Effect of Admission Hyperglycemia on Safety and Efficacy of Intravenous Alteplase Before Thrombectomy in Ischemic Stroke: Post-hoc Analysis of the DIRECT-MT trial.

Hyperglycemia is associated with decreased recanalization probability and increased risk of hemorrhagic complications for stroke patients treated with intravenous alteplase. However, whether hyperglycemia modifies alteplase treatment effect on clinical outcome in patients with large vessel occlusion stroke undergoing endovascular thrombectomy is uncertain. We conducted this study to determine a possible interaction effect between admission hyperglycemia and intravenous alteplase prior to thrombectomy in patients with large vessel occlusion stroke. In this post-hoc analysis of a randomized trial (DIRECT-MT) comparing intravenous alteplase before endovascular treatment vs. endovascular treatment only, 649 with available baseline glucose measurements were included. The treatment-by-admission hyperglycemia (defined as plasma glucose levels ≥ 7.8 mmol/L [140 mg/dL]) interaction was assessed using logistic regression models. As a result, among 649 patients included, 224 (34.5%) were hyperglycemic at admission. There was evidence of alteplase treatment effect modification by hyperglycemia (Pinteraction = 0.025). In patients without hyperglycemia, combination therapy was associated with better outcomes compared to mechanical thrombectomy alone (adjusted common odd ratio [acOR] 1.46, 95% CI [1.04-2.07]), but not in hyperglycemic patients (acOR 0.74, 95% CI [0.46-1.20]). Combination therapy led to an absolute increase of 6% excellent outcome (mRS 0-1) in non-hyperglycemic patients (aOR 1.71, 95% CI [1.05-2.79]), but resulted in a 12.3% absolute decrease (aOR 0.42 [95% CI, 0.19-0.95] in hyperglycemic patients (Pinteraction = 0.003). In conclusion, for large vessel occlusion patients directly presenting to a thrombectomy-capable hospital, hyperglycemia modified combination treatment effect on clinical outcome. Combination therapy was beneficial in patients without hyperglycemia, while thrombectomy alone may be preferred in hyperglycemic patients. Further studies are needed to confirm this result.Trial Registration Information: clinicaltrials.gov Identifier: NCT03469206.

Utility of Thromboelastography to Identify Hypercoagulability in Lung Cancer Related Ischemic Stroke Patients.

Lung cancer related hypercoagulability could increase the risk of ischemic stroke. Routine coagulation tests may have limited capacity in evaluating hypercoagulability. The aim of this study was to investigate the ability of thromboelastography (TEG) in the identification of hypercoagulability in patients with lung cancer and cryptogenic ischemic stroke (LCIS). Between January 2016 and December 2018, whole citrated blood from LCIS patients (n = 35) and age- and gender-matched lung cancer patients and healthy volunteers were used for TEG and routine coagulation tests. The coagulation indicator and clinical data were compared among the 3 groups. There were 27/35 (77.14%) on TEG and 18/35 (51.43%) on routine coagulation tests of LCIS patients who had evidence of hypercoagulability. The detection rate of hypercoagulability by TEG in LCIS patients was higher than routine coagulation tests (P = 0.018). Comparing with lung cancer patients and healthy controls, LCIS patients have a significantly higher maximum amplitude (MA), fibrinogen, and D-dimer. Multivariate analysis showed that D-dimer and MA were significantly associated with ischemic stroke in lung cancer patients. ROC curve showed that the area under the curve of TEG (0.790 ± 0.048, 95% CI: 0.697-0.864) was significantly higher than routine coagulation tests (0.673 ± 0.059, 95% CI: 0.572-0.763) (P = 0.04) in identifying hypercoagulability in LCIS patients. Therefore, TEG could identify hypercoagulability in LCIS patients and healthy controls. Identification of hypercoagulability in lung cancer patients by TEG may be helpful to prevent the occurrence of LCIS.