Apigenin Regulating PI3K/AKT Pathway to Improve Depressive Behavior in Epileptic Rats.

Introduction: Depression is a common comorbidity in epilepsy, significantly impacting patients' quality of life. The hippocampus, linked to depression and neurodegeneration, is vulnerable in epilepsy. Epileptogenesis involves inflammation, oxidative stress, and neuronal damage, with the PI3K/AKT pathway playing a key role. Apigenin (API), a flavonoid in fruits and vegetables, shows neuroprotective, anti-inflammatory, and anti-apoptotic effects. This study investigates API's mechanisms in a LiCl-pilocarpine epileptic rat model, focusing on hippocampal neurogenesis and PI3K/AKT signaling as potential therapeutic targets.

Methods: We studied the effects of API and valproate (VPA) on depressive behavior and astrocytes in Lithium chloride (LiCl)-pilocarpine-induced epileptic rats. Additionally, we predicted the potential molecular targets of API for treating epilepsy using network pharmacology. Finally, we conducted in vivo experiments to validate the predicted mechanism.

Results: In the API and VPA groups, there was a reduction in seizure frequency and seizure severity compared with the control group. The model group showed more depressive behavior than the control (CON) group, and these behaviors improved significantly after VPA and API treatment. HE staining showed that both API and VPA treatment improved LiCl-pilocarpine-induced nuclear contraction and cell swelling. Nissl staining demonstrated that Nissl vesicles in the CA3 region of the hippocampus were decreased in the model group, but the neurons were larger, more abundant, and more neatly arranged after API and VPA treatment. In the model group, the p-PI3K/PI3K and p-AKT/AKT protein ratios and PI3K, AKT mRNA expression were reduced, while brain-derived neurotrophic factor (BDNF) and glial fibrillary acidic protein (GFAP) were markedly increased. API and VPA treatment effectively reversed these changes.

Discussion: API reduces seizures and depressive behaviors in LiCl-pilocarpine-induced epileptic rats, comparable to VPA API mitigates hippocampal neuronal damage, preserves Nissl bodies, and suppresses astrocyte activation via the PI3K/AKT pathway, suggesting neuroprotective and anti-inflammatory effects. While API shows promise as an antiepileptic and antidepressant agent, further studies are needed to confirm its direct modulation of PI3K/AKT and efficacy in other epilepsy models.

Conclusion: Our study suggests that API improves depression in rats and has anti-epilepsy activity, which may be involved in activating the PI3K/AKT pathway to protect astrocytes.