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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 Purpose: T helper cell 1 (Th1)-skewed neurotoxicity contributes to the poor outcome of stroke in rodents. Here, we have elucidated the mechanism of the Th1/Th2 shift in acute ischaemic stroke (AIS) patients at hyperacute phase and have looked for a miRNA-based therapeutic target.Experimental Approach: MiR-494 levels in blood from AIS patients and controls were measured by real-time PCR. C57BL/6J mice were subjected to transient middle cerebral artery occlusion, and cortical neurons were subjected to oxygen-glucose deprivation. Luciferase reporter system, chromatin immunoprecipitation sequencing (ChIP-Seq), and ChIP-PCR were used to uncover possible mechanisms.Key Results: In lymphocytes from AIS patients, there was a Th1/Th2 shift and histone deacetylase 2 (HDAC2) was markedly down-regulated. ChIP-seq showed that HDAC2 binding sites were enriched in regulation of Th1 cytokine production, and ChIP-PCR confirmed that HDAC2 binding was changed at the intron of STAT4 and the promoter of T-box transcription factor 21 (T-bet) in lymphocytes from AIS patients. MiR-494 was the most significantly increased miRNA in lymphocytes from AIS patients, and miR-494-3p directly targeted HDAC2. A strong association existed between miR-494 and Th1 cytokines, and neurological deficit as measured by the National Institute of Health Stroke Scale (NIHSS) in AIS patients. In vitro and in vivo experiments showed that antagomir-494 reduced Th1 shift-mediated neuronal and sensorimotor functional damage in the mouse model of ischaemic stroke, via the HDAC2-STAT4 pathway.Conclusion and Implications: We demonstrated that miR-494 inhibition prevented Th1-skewed neurotoxicity through regulation of the HDAC2-STAT4 cascade. [ABSTRACT FROM AUTHOR]