• Rui Wei, Lin Zhang, Wei Hu, Jie Wu, and Wei Zhang.
• Department of Emergency Medicine, The First Affiliated Hospital of Kunming Medical University, No. 295 Xichang Road, Wu Hua District, Kunming 650032, Yunnan Province, China.
• Exp. Neurol. 2019 Apr 1; 314: 100-110.

AbstractEmerging evidence has suggested a significant role of long non-coding RNAs (lncRNAs) in ischemic stroke by acting as competing endogenous RNAs (ceRNAs) for microRNAs (miRNAs) to regulate certain RNA transcripts. AK038897 is an lncRNA that was reported to be upregulated in rat brains in response to transient focal ischemia. We aimed to investigate the possible regulatory role of AK038897 in ischemic stroke. We detected increased AK038897 and decreased miR-26a-5p levels in mouse brains following middle cerebral artery occlusion/reperfusion (MCAO/R) and in neuro-2A (N2a) neuroblastoma cells following oxygen-glucose deprivation and reoxygenation (OGD/R). With bioinformatics, we identified shared putative miR-26a-5p binding sites in AK038897 as well as in the 3'-UTR of death-associated protein kinase 1 (DAPK1), which is a central mediator of ischemic neuronal death. MiR-26a-5p overexpression attenuated OGD/R-induced N2a cell apoptosis. The luciferase reporter assay results confirmed that miR-26a-5p directly targets DAPK1. Further studies showed that AK038897 directly binds to miR-26a-5p and functions as a ceRNA for miR-26a-5p to regulate DAPK1. As a result, AK038897 overexpression antagonized while AK038897 knockdown enhanced the inhibitory effects of miR-26a-5p on DAPK1 expression and OGD/R-induced N2a cell apoptosis. Further, AK038897 knockdown protected against MCAO/R-induced brain injury and neurological deficits in vivo. In summary, we identified a AK038897/miR-26a-5p/DAPK1 signaling cascade as a key mechanism controlling cerebral ischemia/reperfusion injury. Pharmaceutical intervention of this cascade may provide novel therapy for ischemic insults.Copyright © 2019 Elsevier Inc. All rights reserved.

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