Panax notoginseng Flower Extract Attenuates Pentylenetetrazole-Induced Epilepsy by Restoring Glutamate Homeostasis

<b>Objectives:</b> One-third of patients experience inadequate seizure control with antiseizure medications. Therefore, safer and more effective therapeutic strategies remain urgently needed. Research evidence indicates that <i>Panax notoginseng</i> flower may exhibit potential antiepileptic properties. The study aimed to investigate the neuroprotective and antiepileptic effects of <i>Panax notoginseng</i> flower (PNF) extract in a chronic pentylenetetrazole (PTZ)-kindled mouse model and explore its potential mechanisms, focusing on glutamate homeostasis. <b>Methods:</b> Chronic epilepsy was induced in ICR mice via repeated subconvulsive PTZ intraperitoneal injections. Following successful kindling, mice were orally treated with PNF (1.5 g/kg or 3 g/kg) for 30 days. Seizure behaviors were scored using Racines scale. Neuronal survival, systemic and cerebral cytokines, hippocampal glutamate levels (in vivo microdialysis with LC-MS/MS analysis), glutamate homeostasis related proteins glutamate transporter-2 (GLT-1), glutamate-aspartate transporter-1 (GLAST), and glutamine synthetase (GS) were investigated. <b>Results:</b> PNF treatment significantly reduced seizure severity and restored neuronal nuclei (NeuN+) cell neurons in the cortex and hippocampal CA1 region of PTZ kindled mice. PNF attenuated systemic and neuroinflammation by lowering interleukin-1ß (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-a (TNF-α) levels and increasing interleukin-10 (IL-10) in serum and brain of PTZ mice. PNF reduced hippocampal glutamate accumulation and upregulated GLT-1, GLAST, and GS expression, which were altered by PTZ stimulation. <b>Conclusions:</b> The PNF extract exhibits significant neuroprotective and antiepileptic effects in PTZ-kindled mice, likely through restoring glutamate homeostasis, and suppressing inflammation. These findings, with further clinical development, support the therapeutic potential of PNF as a complementary approach for epilepsy management.