miR-214 Alleviates Ischemic Stroke-Induced Neuronal Death by Targeting DAPK1 in Mice

Yan Shi; Tian Tian; Er-Li Cai; Can Yang; Xin Yang

doi:10.3389/fnins.2021.649982

miR-214 Alleviates Ischemic Stroke-Induced Neuronal Death by Targeting DAPK1 in Mice

Front Neurosci. 2021 Mar 26:15:649982. doi: 10.3389/fnins.2021.649982. eCollection 2021.

Authors

Yan Shi¹, Tian Tian^{2

3}, Er-Li Cai⁴, Can Yang⁵, Xin Yang^{2

3}

Affiliations

¹ Faculty of Laboratory Medicine, School of Medicine, Hunan Normal University, Changsha, China.
² The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
³ Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Guangdong Key Lab of Brain Connectomics, Shenzhen, China.
⁴ Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan, China.
⁵ Department of Emergency Surgery, Hubei Provincial Hospital of Integrated Chinese and Western Medicine, Wuhan, China.

Abstract

Background: Ischemic stroke induces neuronal cell death and causes brain dysfunction. Preventing neuronal cell death after stroke is key to protecting the brain from stroke damage. Nevertheless, preventative measures and treatment strategies for stroke damage are scarce. Emerging evidence suggests that microRNAs (miRNAs) play critical roles in the pathogenesis of central nervous system (CNS) disorders and may serve as potential therapeutic targets.

Methods: A photochemically induced thrombosis (PIT) mouse model was used as an ischemic stroke model. qRT-PCR was employed to assess changes in miRNAs in ischemic lesions of PIT-stroke mice and primary cultured neurons subjected to oxygen-glucose deprivation (OGD). 2,3,5-triphenyltetrazolium chloride (TTC) staining was performed to evaluate brain infarction tissues in vivo. TUNEL staining was employed to assess neuronal death in vitro. Neurological scores and motor coordination were investigated to evaluate stroke damage, including neurological deficits and motor function.

Results: In vivo and in vitro results demonstrated that levels of miR-124 were significantly decreased following stroke, whereas changes in death-associated protein kinase 1 (DAPK1) levels exhibited the converse pattern. DAPK1 was identified as a direct target of miR-124. N-methyl-D-aspartate (NMDA) and OGD-induced neuronal death was rescued by miR-124 overexpression. Upregulation of miR-124 levels significantly improved PIT-stroke damage, including the overall neurological function in mice.

Conclusion: We demonstrate the involvement of the miR-124/DAPK1 pathway in ischemic neuronal death. Our results highlight the therapeutic potential of targeting this pathway for ischemic stroke.

Keywords: DAPK1; cell death; miR-124; neuron; stroke.