Vitamin D3 prevents epileptic seizures by modulating the ras signalling pathway via Gnb1 and Casr in acute epilepsy mouse models

  • Epilepsy Res. 2026 May 14:225:107820. doi: 10.1016/j.eplepsyres.2026.107820.
Jiahao Liu  1 ,  Jiawei Li  2 ,  Ruting Fu  2 ,  Liya Fang  2 ,  Yuanyuan Liu  2 ,  Ruici Liu  3 ,  Deming Kong  2 ,  Zhimei Jiang  4 ,  Lei Liu  4 ,  Luchuan Wang  5 ,  Chao Gong  2 ,  Pei Zeng  6 ,  Youdi Fu  2 ,  Xinru Zhu  2 ,  Jin Guo  7 ,  Shaobo Zhou  8
Affiliations
  • 1. Key laboratory of Microecology-immune Regulatory Network and Related Diseases School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang Province 154000, PR China.
  • 2. Heilongjiang Provincial Key Laboratory of Child Neurorehabilitation, School of Rehabilitation Medicine, Jiamusi University, Jiamusi, Heilongjiang Province 154007, PR China.
  • 3. School of Health Medicine, Jingzhou University, Jingzhou, Hubei Province 434020, PR China.
  • 4. Jiamusi University, Jiamusi, Heilongjiang Province 154007, PR China.
  • 5. The First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang Province 154007, PR China.
  • 6. The Third Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang Province 154007, PR China.
  • 7. Key laboratory of Microecology-immune Regulatory Network and Related Diseases School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang Province 154000, PR China; The Third Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang Province 154007, PR China. Electronic address: [email protected].
  • 8. Faculty of Engineering and Science, University of Greenwich, Medway Campus Central Avenue, ChathamMaritime Kent, England ME4 4TB, UK. Electronic address: [email protected].
PMID: 42150281 DOI: 10.1016/j.eplepsyres.2026.107820
Abstract

Objective: This study aimed to investigate the neuroprotective effects of vitamin D3 (cholecalciferol, hereinafter referred to as VitD) in acute epilepsy mouse models by examining its modulation of the calcium-sensing receptor (CaSR), the Ras signalling pathway, and the potential mediator role of guanine nucleotide-binding protein subunit beta-1 (Gnb1).

Methods: Acute epilepsy was induced in 135 C57BL/6 J mice via intraperitoneal injection(i.p.) of pentylenetetrazole (PTZ) or kainic acid (KA). Mice were randomly assigned to receive VitD pretreatment, valproate (VPA) emergency treatment, or a combination of VitD and Salirasib, a Ras pathway inhibitor. Seizure behaviours and electroencephalography (EEG) were recorded to confirm successful model establishment and to assess the efficacy of interventions. Hippocampal tissue was analysed for histopathological changes, as well as protein and mRNA expression levels of CaSR, Gnb1, and Ras pathway-related molecules (Kras, Raf-1, MEK, ERK) using western blot (WB) and quantitative real-time polymerase chain reaction (qRT-PCR).

Results: Both PTZ and KA models showed successful seizure induction with associated hippocampal neuronal damage. CaSR and Gnb1 expression were upregulated in both models, more prominently in the KA group, while Ras pathway activity was suppressed. VitD pretreatment reduced seizure frequency, delayed seizure onset, and alleviated neuronal damage-particularly in the PTZ model. VitD downregulated CaSR, upregulated Gnb1, and partially restored Ras pathway activity. Co-treatment with Salirasib enhanced neuroprotection and reduced Gnb1 expression. VPA similarly increased Gnb1 expression and suppressed Ras pathway activity.

Conclusion: VitD exerts neuroprotective effects in acute epilepsy, potentially through regulation of CaSR and the Ras signalling pathway. In this context, Gnb1 likely acting as a downstream potential mediator linking CaSR activation to Ras signalling. These findings highlight VitD's potential as a neuroprotective agent in epilepsy and provide new insights into the molecular mechanisms underlying its action.

Keywords
Calcium-sensing receptor; Epilepsy; Guanine nucleotide-binding protein subunit beta-1; Neuroprotection; Ras signalling pathway; Vitamin D(3).
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