Methylprednisolone as Adjunct to Endovascular Thrombectomy for Large-Vessel Occlusion Stroke: The MARVEL Randomized Clinical Trial.

Importance: It is uncertain whether intravenous methylprednisolone improves outcomes for patients with acute ischemic stroke due to large-vessel occlusion (LVO) undergoing endovascular thrombectomy. Objective: To assess the efficacy and adverse events of adjunctive intravenous low-dose methylprednisolone to endovascular thrombectomy for acute ischemic stroke secondary to LVO. Design, Setting, and Participants: This investigator-initiated, randomized, double-blind, placebo-controlled trial was implemented at 82 hospitals in China, enrolling 1680 patients with stroke and proximal intracranial LVO presenting within 24 hours of time last known to be well. Recruitment took place between February 9, 2022, and June 30, 2023, with a final follow-up on September 30, 2023. Interventions: Eligible patients were randomly assigned to intravenous methylprednisolone (n = 839) at 2 mg/kg/d or placebo (n = 841) for 3 days adjunctive to endovascular thrombectomy. Main Outcomes and Measures: The primary efficacy outcome was disability level at 90 days as measured by the overall distribution of the modified Rankin Scale scores (range, 0 [no symptoms] to 6 [death]). The primary safety outcomes included mortality at 90 days and the incidence of symptomatic intracranial hemorrhage within 48 hours. Results: Among 1680 patients randomized (median age, 69 years; 727 female [43.3%]), 1673 (99.6%) completed the trial. The median 90-day modified Rankin Scale score was 3 (IQR, 1-5) in the methylprednisolone group vs 3 (IQR, 1-6) in the placebo group (adjusted generalized odds ratio for a lower level of disability, 1.10 [95% CI, 0.96-1.25]; P = .17). In the methylprednisolone group, there was a lower mortality rate (23.2% vs 28.5%; adjusted risk ratio, 0.84 [95% CI, 0.71-0.98]; P = .03) and a lower rate of symptomatic intracranial hemorrhage (8.6% vs 11.7%; adjusted risk ratio, 0.74 [95% CI, 0.55-0.99]; P = .04) compared with placebo. Conclusions and Relevance: Among patients with acute ischemic stroke due to LVO undergoing endovascular thrombectomy, adjunctive methylprednisolone added to endovascular thrombectomy did not significantly improve the degree of overall disability. Trial Registration: ChiCTR.org.cn Identifier: ChiCTR2100051729.

Effect of direct endovascular treatment versus standard bridging therapy in large artery anterior circulation stroke (DEVT): 18-month follow-up of a randomized controlled trial.

BACKGROUND: Two trials in Chinese population showed that endovascular treatment (EVT) alone was noninferior to alteplase follow by EVT at 90 days. However, results of long-term clinical outcomes remain unknown. We reported the results of prespecified 18-month analysis of the DEVT trail. MATERIALS AND METHODS: We assessed clinical outcomes 18 months after patients were randomly assigned to receive EVT alone or bridging therapy for acute ischemic stroke (AIS). The primary outcome was the proportion of functional independence [modified Rankin scale (mRS), 0-2] at 18 months. Secondary outcomes included all-cause mortality and the quality of life at 18 months as measured by means of a health utility index according to the European Quality of Life 5-Dimension 5-level scale (EQ-5D-5L). Kaplan-Meier event curves were used to investigate the risk of mortality in participants with EVT alone or bridging therapy. RESULTS: Among 234 patients (EVT alone, n = 116; bridging therapy, n = 118) in the DEVT trial, only 231 (98.7%) patients were extended follow-up to 18 months. A total of 60 (51.7%) patients in the EVT alone achieved functional independence vs 56 (47.5%) patients in the bridging therapy (difference, 4.3%; 1-sided 97.5% CI, - 8.4% to ∞, P for noninferiority =0.014). No significant between-group difference was detected in EQ-5D-5L score (0.81 vs 0.73; difference, 0; 95% CI, 0 to 0.005). The cumulative mortality was 27.6% in the EVT alone and 28.8% in the bridging therapy. CONCLUSION: At 18 months follow-up, EVT alone was noninferior to bridging therapy regarding favorable functional outcome in patients with AIS. TRIAL REGISTRATION: Trial was registered on Chinese Clinical Trial Registry (ChiCTR-IOR-17013568) on 27/11/2017.

m(6)A methyltransferase METTL3 relieves cognitive impairment of hyperuricemia mice via inactivating MyD88/NF-κB pathway mediated NLRP3-ASC-Caspase1 inflammasome.

BACKGROUND: Recent studies have uncovered that hyperuricemia (HUA) leads to cognitive deficits, which are accompanied by neuronal damage and neuroinflammation. Here, we aim to explore the role of methyltransferase-like 3 (METTL3) in HUA-mediated neuronal apoptosis and microglial inflammation. METHODS: A HUA mouse model was constructed. The spatial memory ability of the mice was assessed by the Morris water maze experiment (MWM), and neuronal apoptosis was analyzed by the TdT-mediated dUTP nick end labeling (TUNEL) assay. Besides, enzyme-linked immunosorbent assay (ELISA) was utilized to measure the contents of inflammatory factors (IL-1ß, IL-6, and TNF-α) and oxidative stress markers (MDA, SOD, and CAT) in the serum of mice. In vitro, the mouse hippocampal neuron (HT22) and microglia (BV2) were treated with uric acid (UA). Flow cytometry was applied to analyze HT22 and BV2 cell apoptosis, and ELISA was conducted to observe neuroinflammation and oxidative stress. In addition, the expression of MyD88, p-NF-κB, NF-κB, NLRP3, ASC and Caspase1 was determined by Western blot. RESULTS: METTL3 and miR-124-3p were down-regulated, while the MyD88-NF-κB pathway was activated in the HUA mouse model. UA treatment induced neuronal apoptosis in HT22 and stimulated microglial activation in BV2. Overexpressing METTL3 alleviated HT22 neuronal apoptosis and resisted the release of inflammatory cytokines and oxidative stress mediators in BV2 cells. METTL3 repressed MyD88-NF-κB and NLRP3-ASC-Caspase1 inflammasome. In addition, METTL3 overexpression enhanced miR-124-3p expression, while METTL3 knockdown aggravated HT22 cell apoptosis and BV2 cell overactivation. CONCLUSION: METTL3 improves neuronal apoptosis and microglial activation in the HUA model by choking the MyD88/NF-κB pathway and up-regulating miR-124-3p.

HECTD3 promotes NLRP3 inflammasome and pyroptosis to exacerbate diabetes-related cognitive impairment by stabilising MALT1 to regulate JNK pathway.

BACKGROUND: HECTD3 (HECT domain E3 ubiquitin protein ligase 3) exerts biological activities in neuroinflammation of distinct diseases, such as autoimmune encephalomyelitis and donations after heart death. However, the effect of HECTD3 on diabetes-associated cognitive decline (DACD) remains unclear. METHODS: Wild-type or HECTD3-knockout rats were administered with streptozotocin to establish diabetic model. Pathological changes in the hippocampus were assessed by NISSL and haematoxylin and eosin staining. Morris water maze test was used to assess cognitive function. Neuronal survival and inflammation were investigated by immunofluorescence staining and ELISA assay. NLRP3 inflammasome and pyroptosis were assessed by western blot, immunofluorescence and flow cytometry assays. RESULTS: HECTD3 was up-regulated in hippocampus of streptozotocin-induced diabetic rats and high glucose-induced PC12 cells. Knockout of HECTD3 increased the number of neurons and improved the learning and memory function. Moreover, knockout of HECTD3 promoted in vivo neuronal survival, and reduced levels of IL-1ß, TNF-α, and IL-6 in the hippocampus. Silencing of HECTD3 increased cell viability, and reduced IL-1ß, TNF-α, and IL-6 in high glucose-induced PC12 cells. Fluorescence intensities of NLRP3, GSDMD-N and caspase-1 were reduced in HECTD3-knockout diabetic rats, and knockdown of HECTD3 down-regulated protein expression of NLRP3, GSDMD-N, caspase-1, IL-1ß, and IL-18 in high glucose-induced PC12 cells to suppress the pyroptosis. HECTD3 promoted the stability of mucosa-associated lymphoid tissue 1 (MALT1) through up-regulation of c-JUN and phospho (p)-JNK in high glucose-induced PC12 cells. Over-expression of MALT1 attenuated neuroprotective effects of HECTD3 silencing on high glucose-induced PC12 cells. CONCLUSION: HECTD3 silencing exerted neuroprotective effect against DACD through MALT1-mediated JNK signalling.HighlightsHECTD3 was up-regulated in hippocampus of streptozotocin-induced diabetic rats and high glucose-induced PC12.Knockout of HECTD3 promoted in vivo neuronal survival, reduced inflammation and pyroptosis, and improved the learning and memory function in diabetic rats.Knockout of HECTD3 suppressed the activation of NLRP3 inflammasome in diabetic rats.Silencing of HECTD3 exerted neuroprotective effects through MALT1-mediated JNK signalling.

Inhibition of microRNA-10b-5p up-regulates HOXD10 to attenuate Alzheimer's disease in rats via the Rho/ROCK signalling pathway.

OBJECTIVE: It is believed that microRNAs (miRNAs) participate in the pathogenesis of Alzheimer's disease (AD), but the specified function of miR-10b-5p in the disease has not been thoroughly understood. Thereafter, this research aimed to assess the function of miR-10b-5p in AD. METHODS: Rat AD models were established by injected with amyloid-ß1-42 (Aß1-42), which were mainly treated with lentivirus-miR-10b-5p inhibitor, or lentivirus-overexpressed homeobox D10 (HOXD10). MiR-10b-5p, HOXD10, RhoA, ROCK1 and ROCK2 expression in rat hippocampal tissues were determined. Afterwards, the behaviour of rats was tested, and neuronal apoptosis, pathological injury, and inflammatory factors and oxidative stress-related factors were all assessed. Finally, the target relation between miR-10b-5p and HOXD10 was detected. RESULTS: MiR-10b-5p was upregulated while HOXD10 was downregulated, and the Rho/ROCK signalling pathway was activated in hippocampal tissues of rats with AD. Inhibition of miR-10b-5p could attenuate the neuronal apoptosis, pathological injury, inflammation reaction, and oxidative stress by elevating HOXD10 and inhibiting the Rho/ROCK signalling pathway in AD rats. Moreover, HOXD10 was targeted by miR-10b-5p. CONCLUSION: Inhibited miR-10b-5p decelerated the development of AD by promoting HOXD10 and inactivating the Rho/ROCK signalling pathway, and our findings may contribute to the exploration of AD treatment.

MiR-370 accelerated cerebral ischemia reperfusion injury via targeting SIRT6 and regulating Nrf2/ARE signal pathway.

Cerebral ischemia reperfusion (CIR) is one of the highly lethal diseases in the world. MicroRNA-370 (miR-370) exerts multiple functions in different diseases. However, further research is needed to investigate the potential role of miR-370 in CIR injury. The in vivo middle cerebral artery occlusion (MCAO) rat model and in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) SH-SY5Y cell model were successfully established to mimic CIR injury. The infarct sizes of brain tissues from rats were evaluated. The relationship between miR-370 and silencing information regulatory protein 6 (SIRT6) was confirmed by luciferase activity assay. The cell viability and apoptosis were determined by CCK-8 assay and terminal-deoxynucleoitidyl transferase mediated nick end labeling staining. In this study, miR-370 was upregulated in brain tissues of MCAO rats and knockdown of miR-370 decreased cerebral infarction volume of MCAO rats and it alleviated CIR injury in vivo. The in vitro experiments indicated that knockdown of miR-370 promoted cell viability and alleviated OGD/R-induced SH-SY5Y cell apoptosis. Additionally, the TargetScan predicted that SIRT6 was a target of miR-370 and confirmed by luciferase activity assay. Moreover, miR-370 inhibited SIRT6 expression and regulated Nrf2/ARE signal pathway, whereas overexpression of SIRT6 partly reversed the effect of miR-370 on OGD/R-induced SH-SY5Y cell injury. Thus, we could conclude that miR-370 accelerated CIR injury via targeting SIRT6 and regulating Nrf2/ARE signal pathway, which might provide novel therapeutic targets for CIR injury treatment.