Lomitapide ameliorates middle cerebral artery occlusion‐induced cerebral ischemia/reperfusion injury by promoting neuronal autophagy and inhibiting microglial migration. (2nd September 2022)

• Record Type: Journal Article
• Authors: Zheng, Yangmin; Hu, Yue; Han, Ziping; Yan, Feng; Zhang, Sijia; Yang, Zhenhong; Zhao, Fangfang; Li, Lingzhi; Fan, Junfen; Wang, Rongliang; Luo, Yumin
• Is Part Of: CNS neuroscience & therapeutics. Volume 28:Number 12(2022)
• Page Start: 2183
• Page End: 2194
• Publication Date: 2022-09-02
• Subjects: autophagy flux -- drug repurposing -- ischemic stroke -- lomitapide -- microglia migration; Neuropharmacology -- Periodicals; Central nervous system -- Diseases -- Effect of drugs on -- Periodicals; 612.8
• DOI: 10.1111/cns.13961
• Languages: English
• ISSNs: 1755-5930

Abstract

Abstract: 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 : Lomitapide ameliorates cerebral ischemia/reperfusion injury via promoting neuron autophagy and inhibiting microglia migration and can be repositioned as a potential therapeutic drug for stroke treatment.