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HDAC3 is an essential negative regulator of neuronal plasticity and memory formation. Although a chemical inhibitor has been invented, little is known about its endogenous modulators. We explored whether miR-494 affects HDAC3-mediated neuronal injury following acute ischemic stroke. A substantial increase in plasma miR-494 was detected in AIS patients and was positively associated with the mRS at one year after symptom onset. The miR-494 levels were transiently increased in the infarcted brain tissue of mice. In contrast, miR-494 levels were reduced in neurons but increased in the medium after OGD. Intracerebroventricular injection of miR-494 agomir reduced neuronal apoptosis and infarct volume at the acute stage of MCAO, promoted axonal plasticity and long-term outcomes at the recovery stage, suppressed neuronal ataxin-3 and HDAC3 expression and increased acetyl-H3K9 levels in the ipsilateral hemisphere. In vitro studies confirmed that miR-494 posttranslationally inhibited HDAC3 in neurons and prevented OGD-induced neuronal axonal injury. The HDAC3 inhibitor increased acetyl-H3K9 levels and reversed miR-494 antagomir-aggravated acute cerebral ischemic injury, as well as brain atrophy and long-term functional recovery. These results suggest that miR-494 may serve as a predictive biomarker of functional outcomes in AIS patients and a potential therapeutic target for the treatment of ischemic stroke. [ABSTRACT FROM AUTHOR]

Aims: Stroke has a high incidence and is a disabling condition that can lead to severe cognitive, motor, and sensory dysfunction. In this study, we employed a drug repurposing strategy to investigate the neuroprotective effect of lomitapide on focal ischemic brain injury and explore its potential mechanism of action. Methods: Experimental cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in adult male C57BL/6 mice and simulated by oxygen–glucose deprivation in N2a‐BV2 cells in co‐cultivation. Results: Lomitapide significantly increased the survival rate, reduced the neuronal tissue loss, and improved the neurological function after MCAO. Furthermore, lomitapide could increase the expression of LC3‐II, reduce the expression of P62 and LAMP2, promote autophagic flux, and inhibit apoptosis by increasing and inhibiting the expression of the apoptosis‐associated proteins Bcl‐2 and Bax, respectively. In addition, lomitapide inhibited the migration of pro‐inflammatory microglia. Conclusion: Lomitapide is a lipid‐lowering drug, and this is the first study to explore its protective effect on ischemic nerve injury in vitro and in vivo. Our results suggest that lomitapide can be repositioned as a potential therapeutic drug for the treatment of stroke. [ABSTRACT FROM AUTHOR]

Background and objective: Stroke is a major contributor to the global burden of disease. Although numerous modifiable risk factors (RF) for stroke have been identified, some remain unexplained. Increasing studies have investigated stroke risk in arthritis, but their results are inconsistent. We aimed to synthesize, quantify, and compare the risk of stroke for the major types of arthritis in cohort studies by using a systematic review and meta-analysis approach. Methods: We searched Chinese and English databases to identify relevant studies from inception to April 30, 2020. Only studies adjusting at least for age and sex were included. We calculated pooled effect estimates for relative risk (RR) and 95% confidence interval (CI) and identified potential sources of heterogeneity and publication bias. Results: A total of 1,348 articles were retrieved, and after an preliminary screening of titles and abstracts, 69 were reviewed for full text, and finally, 32 met the criteria for meta-analysis. Stroke risk in arthritis was significantly increased in studies adjusting for age and sex (RR = 1.36, 95% CI: 1.27–1.46) and for at least one traditional risk factor (RR = 1.40, 95% CI: 1.28–1.54). The results of studies stratified by stroke subtype were consistent with the main finding (ischemic stroke: RR = 1.53, 95% CI: 1.32–1.78; hemorrhagic stroke: RR = 1.45, 95% CI: 1.15–1.84). In subgroup analysis by arthritis type, stroke risk was significantly increased in rheumatoid arthritis (RR = 1.38, 95% CI: 1.29–1.48), ankylosing spondylitis (RR = 1.49, 95% CI: 1.25–1.77), psoriatic arthritis (RR = 1.33, 95% CI: 1.22–1.45), and gout (RR = 1.40, 95% CI: 1.13–1.73) but not osteoarthritis (RR = 1.03, 95% CI: 0.91–1.16). Age and sex subgroup analyses indicated that stroke risk was similar by sex (women: RR = 1.47, 95% CI: 1.31–1.66; men: RR = 1.44, 95% CI: 1.28–1.61); risk was higher with younger age (<45 years) (RR = 1.46, 95% CI: 1.17–1.82) than older age (≥65 years) (RR = 1.17, 95% CI: 1.08–1.26). Conclusions: Stroke risk was increased in multiple arthritis and similar between ischemic and hemorrhagic stroke. Young patients with arthritis had the highest risk. [ABSTRACT FROM AUTHOR]

Global DNA and histone methylation patterns in astrocytes following ischemia are influenced by age; however, it is unknown whether aberrant methylation can induce reactive astrogliosis after ischemic stroke in elderly rodents. Here we showed that phosphorylated signal transducer and activator of transcription 3 (STAT3) level increased along with that of the astrogliosis marker glial fibrillary acidic protein (GFAP) on days 1, 3, and 14 post‐reperfusion in 9‐month‐old male mice with middle cerebral artery occlusion (MCAO). Methylation of the STAT3 binding site in the GFAP gene promoter was increased in these mice on days 3 and 14 postreperfusion. The repressive modification histone 3 lysine 27 trimethylation (H3K27me3) was decreased, whereas the permissive modification histone 3 lysine 4 trimethylation was increased in GFAP‐positive cells in the ipsilateral cortex. Furthermore, DNA methyltransferase 1 (DNMT1) expression in astrocytes was upregulated in the ischemic brain. In primary astrocyte cultures, the microRNA miR‐424 was found to target nuclear factor IA (NFIA); miR‐424 agomir increased DNMT1 and H3K27me3 levels in U87 cells subjected to oxygen and glucose deprivation and induced cell cycle arrest in primary astrocytes while suppressing reactive astrocytosis, thereby preserving the structure of neurons and their axons in MCAO mice. These results demonstrate that miR‐424 prevents astrogliosis following cerebral ischemia/reperfusion in elderly mice by enhancing H3K27me3 via NFIA/DNMT1 signaling. [ABSTRACT FROM AUTHOR]