2. Academic Validation
  3. The microRNA-211-5p/P2RX7/ERK/GPX4 axis regulates epilepsy-associated neuronal ferroptosis and oxidative stress

The microRNA-211-5p/P2RX7/ERK/GPX4 axis regulates epilepsy-associated neuronal ferroptosis and oxidative stress

  • J Neuroinflammation. 2024 Jan 8;21(1):13. doi: 10.1186/s12974-023-03009-z.
Xueying Li # 1,  Pusheng Quan # 1 2,  Yao Si # 1,  Fei Liu 1,  Yuwei Fan 1,  Feifan Ding 1,  Lina Sun 1,  Han Liu 1,  Shuo Huang 1,  Linlin Sun # 3,  Fan Yang # 4,  Lifen Yao # 5
Affiliations

Affiliations

  • 1 Department of Neurology, The First Affiliated Hospital, Harbin Medical University, Harbin, 150081, China.
  • 2 Department of Neurology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia, China.
  • 3 Department of Neurology, The First Affiliated Hospital, Harbin Medical University, Harbin, 150081, China. [email protected].
  • 4 Department of Neurology, The First Affiliated Hospital, Harbin Medical University, Harbin, 150081, China. [email protected].
  • 5 Department of Neurology, The First Affiliated Hospital, Harbin Medical University, Harbin, 150081, China. [email protected].
  • # Contributed equally.
PMID: 38191407 DOI: 10.1186/s12974-023-03009-z
Abstract

Ferroptosis is an iron-dependent cell death mechanism involving the accumulation of lipid peroxides. As a critical regulator, Glutathione Peroxidase 4 (GPX4) has been demonstrated to be downregulated in epilepsy. However, the mechanism of Ferroptosis in epilepsy remains unclear. In this study, bioinformatics analysis, analysis of epilepsy patient blood samples and cell and mouse experiments revealed strong associations among epilepsy, Ferroptosis, microRNA-211-5p and purinergic receptor P2X 7 (P2RX7). P2RX7 is a nonselective ligand-gated homotrimeric cation channel, and its activation mainly increases neuronal activity during epileptic seizures. In our study, the upregulation of P2RX7 in epilepsy was attributed to the downregulation of MicroRNA (miR)-211-5p. Furthermore, P2RX7 has been found to regulate GPX4/HO-1 by alleviating lipid peroxidation induced by suppression of the MAPK/ERK signaling pathway in murine models. The dynamic decrease in miR-211-5p expression induces hypersynchronization and both nonconvulsive and convulsive seizures, and forebrain miR-211-5p suppression exacerbates long-lasting pentylenetetrazole-induced seizures. Additionally, in this study, induction of miR-211-5p expression or genetic-silencing of P2RX7 significantly reduced the seizure score and duration in murine models through the abovementioned pathways. These results suggest that the miR-211-5p/P2RX7 axis is a novel target for suppressing both Ferroptosis and epilepsy.

Keywords

Bioinformatics technology; Epilepsy; Ferroptosis; MAPK signaling pathways; P2RX7; microRNA-211-5p.

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