Liu, Jiahao, Li, Jiawei, Fu, Ruting, Fang, Liya, Liu, Yuanyuan, Liu, Ruici, Kong, Deming, Jiang, Zhimei, Liu, Lei, Wang, Luchuan, Gong, Chao, Zeng, Pei, Fu, Youdi, Zhu, Xinru, Guo, JIn and Zhou, Shaobo ORCID: https://orcid.org/0000-0001-5214-2973 (2026) Vitamin D3 prevents epileptic seizures by modulating the Ras signalling pathway via Gnb1 and Casr in acute epilepsy mouse models. Epilepsy Research:107820. ISSN 0920-1211 (Print), 1872-6844 (Online) (doi:10.1016/j.eplepsyres.2026.107820)

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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.

Item Type:	Article
Uncontrolled Keywords:	Vitamin D3, Calcium-sensing receptor, Guanine nucleotide-binding protein subunit beta-1, Ras signalling pathway, epilepsy, neuroprotection
Subjects:	Q Science > Q Science (General) R Medicine > R Medicine (General)
Faculty / School / Research Centre / Research Group:	Faculty of Engineering & Science Faculty of Engineering & Science > School of Science (SCI)
Last Modified:	18 May 2026 09:50
URI:	https://gala.gre.ac.uk/id/eprint/53473

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