Butylphthalide may inhibit blood-brain barrier disruption through complement-related pathways to alleviate cognitive impairment in epileptic mice

Background: Temporal lobe epilepsy is often accompanied by comorbid symptoms such as anxiety, depression, and cognitive dysfunction. Research indicates a close relationship between blood-brain barrier (BBB) impairment and these symptoms. DL-3n-butylphthalide (NBP) has been reported to protect the BBB, but the molecular mechanisms by which NBP protects the BBB in epilepsy models remain unclear. This study investigated the protective effects of NBP on the BBB in epileptic mice to alleviate the comorbid symptoms associated with epilepsy. Methods: We utilized Mendelian randomization to explore the association between VEGFA and epilepsy. In the animal experiments, adult male C57BL/6 mice were used to establish a KA-induced epilepsy model, receiving daily intraperitoneal injections of NBP for 30 days. After this period, behavioral experiments and Western blot analyses were conducted to assess whether the comorbid symptoms of epilepsy and BBB disruption were alleviated. Subsequently, RNA sequencing was performed to analyze potential signaling pathways involved in the pharmacological effects of NBP. Results: Elevated circulating levels of VEGFA may be a risk factor for the onset of epilepsy. Animal experiments demonstrated that NBP treatment improved BBB disruption in KA-induced epileptic mice and alleviated depressive and anxious behaviors, as well as cognitive impairments. RNA sequencing results suggest that the pharmacological effects of NBP may be mediated through the inhibition of complement and coagulation cascades. Conclusion: NBP can protect the integrity of the BBB in KA-induced epileptic mice, inhibiting depression, anxiety behaviors, and cognitive dysfunction. This pharmacological effect may be associated with pathways involving complement and coagulation cascades.