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LncRNA ZFAS1 regulates the hippocampal neurons injury in epilepsy through the miR-15a-5p/OXSR1/NF-κB pathway

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Abstract

Long non-coding RNAs (lncRNAs) have been confirmed to be involved in epilepsy development. It has been reported that lncRNA ZFAS1 plays a vital regulatory role in epilepsy progression. Therefore, the role and molecular mechanism of ZFAS1 in epilepsy progression deserve further investigation. Mice status epilepticus (SE) model was constructed, and hippocampal neurons were isolated from mice hippocampus tissues. The expression of ZFAS1, miR-15a-5p and oxidative stress responsive 1 (OXSR1) were determined by quantitative real-time PCR. ELISA assay was used to detect the concentrations of inflammation factors. Cell viability and apoptosis were examined by MTT assay, EdU staining and flow cytometry. Western blot analysis was conducted to measure protein levels, and the productions of SOD and MDA were measured to assess cell oxidative stress. Dual-luciferase reporter assay and RIP assay were employed to validate the relationship between miR-15a-5p and ZFAS1 or OXSR1. LncRNA ZFAS1 was highly expressed in SE mice and SE-stimulated hippocampal neurons. Silenced ZFAS1 promoted viability, while inhibited inflammation, apoptosis and oxidative stress in SE-induced hippocampal neurons. MiR-15a-5p could be targeted by ZFAS1, and its inhibitor also reversed the suppressive effect of ZFAS1 knockdown on SE-induced hippocampal neurons injury. In addition, OXSR1 was a target of miR-15a-5p, and its silencing also could relieve SE-induced hippocampal neurons injury. OXSR1 overexpression reversed the inhibition effect of miR-15a-5p on SE-induced hippocampal neurons injury. Moreover, ZFAS1 positively regulated OXSR1 expression by sponging miR-15a-5p, thereby activating the NF-κB pathway. LncRNA ZFAS1 might contribute to the progression of epilepsy by regulating the miR-15a-5p/OXSR1/NF-κB pathway.

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Data availability

The analyzed data sets generated during the present study are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. School of Basic Medicine, Jiamusi University, 148-Xuefu Street, Jiamusi, Heilongjiang, 154007, People’s Republic of China

    Zengmian Wang

  2. Department of Respiratory and Critical Care Medicine, Mudanjiang First People’s Hospital, No. 76 Jianwei Road, Aimin District, Mudanjiang, Heilongjiang, China

    Zhimin Na

  3. Department of Internal Medicine, Tangyuan Hospital of Traditional Chinese Medicine, West of Hazhao Road, Tangyuan, Jiamusi, Heilongjiang, China

    Ying Cui

  4. Department of Neurology, The First Affiliated Hospital of Jiamusi University, Xiangyang District, Dexiang Street No.348, Jiamusi, Heilongjiang, 154007, China

    Chunjie Wei

  5. Department of Pathophysiology, School of Basic Medicine, Jiamusi University, 148-Xuefu Street, Jiamusi, Heilongjiang, 154007, People’s Republic of China

    Shuqiu Wang

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  1. Zengmian Wang
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Contributions

Conceptualization and Methodology: Zhimin Na and Ying Cui; Formal analysis and Data curation: Ying Cui, Chunjie Wei and Shuqiu Wang; Validation and Investigation: Zengmian Wang and Zhimin Na; Writing - original draft preparation and Writing - review and editing: Zengmian Wang, Zhimin Na, and Ying Cui; Approval of final manuscript: all authors.

Corresponding author

Correspondence to Shuqiu Wang.

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The present study was approved by the ethical review committee of School of Basic Medicine, Jiamusi University. Written informed consent was obtained from all enrolled patients.

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Highlights

1. Knockdown of ZFAS1 alleviates SE-induced hippocampal neurons injury.

2. ZFAS1 acts as a sponge for miR-15a-5p.

3. MiR-15a-5p targets OXSR1.

4. The ZFAS1/miR-15a-5p/OXSR1 regulates the activity of NF-κB pathway.

Supplementary Information

Supplementary Fig. 1

Anti-miR-miR-15a-5p accelerated SE-stimulated hippocampal neurons injury. Hippocampal neurons from SE mice were transfected with anti-miR-NC or anti-miR-miR-15a-5p. Hippocampal neurons from sham mice were used as control. (A) MiR-15a-5p expression was measured by qRT-PCR. (B) The concentrations of IL-6 and TNF-α were examined by ELISA assay. MTT assay (C) and EdU staining (D) were used to analyze cell viability. (E) Cell apoptosis rate was tested using flow cytometry. (F-G) The productions of SOD and MDA were determined using corresponding Assay Kits. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. (PNG 202 kb)

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Wang, Z., Na, Z., Cui, Y. et al. LncRNA ZFAS1 regulates the hippocampal neurons injury in epilepsy through the miR-15a-5p/OXSR1/NF-κB pathway. Metab Brain Dis 37, 2277–2290 (2022). https://doi.org/10.1007/s11011-022-01013-5

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