Open AccessLomitapide ameliorates middle cerebral artery occlusion‐induced cerebral ischemia/reperfusion injury by promoting neuronal autophagy and inhibiting microglial migration
Author(s) -
Zheng Yangmin,
Hu Yue,
Han Ziping,
Yan Feng,
Zhang Sijia,
Yang Zhenhong,
Zhao Fangfang,
Li Lingzhi,
Fan Junfen,
Wang Rongliang,
Luo Yumin
Publication year - 2022
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.13961
Subject(s) - neuroprotection , medicine , ischemia , stroke (engine) , microglia , pharmacology , autophagy , reperfusion injury , anesthesia , apoptosis , inflammation , biology , biochemistry , mechanical engineering , engineering
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.