Preventive effects of vitamin D on epileptic seizures and its regulation of PTEN and autophagy in acute epilepsy mouse models

Objective Epilepsy treatments often lead to vitamin D (VitD) deficiency. Although vitamin D₃ (VitD3) has been shown to reduce epileptic symptoms by 43%, its preventive effects remain unclear. This study investigated the potential of VitD pretreatment in two common acute epilepsy mouse models and explored its effects on seizure severity, latency, and molecular mechanisms involving calcium-sensing receptor (CaSR), phosphatase and tensin homolog (PTEN), and autophagy.Methods Mice were randomly divided into nine groups (n = 15). VitD or vehicle was administered 40 min before pentylenetetrazole (PTZ) or kainic acid (KA) given intraperitoneal injection (i.p). Seizure behavior and electroencephalograms (EEGs) were recorded for 60 min. After 24 h, hippocampal tissues were analyzed histologically and assessed for expression of autophagy-related proteins, CaSR, and PTEN.Results Both PTZ and KA induced acute seizures (Racine Grade IV+), with corresponding high-amplitude EEG spikes, neuronal damage, and mossy fiber sprouting. CaSR and autophagy markers were upregulated, while PTEN was downregulated, especially in the KA group. VitD pretreatment reduced seizure frequency, prolonged latency, alleviated hippocampal damage, downregulated CaSR and autophagy markers, and upregulated PTEN. These effects were milder than those of valproate. Combined VitD and Oroxin B treatment further improved outcomes.Conclusions (1) PTZ-induced seizures increased CaSR and decreased PTEN, triggering autophagy and worsening symptoms. (2) KA-induced epilepsy caused more severe damage with stronger autophagy activation. (3) VitD pretreatment mitigated seizures by modulating CaSR, PTEN, and autophagy, showing greater efficacy in the PTZ model.