Biochanin A prevents neurodegeneration and oxidative stress in a kainic acid model of epilepsy by activating the PI3K/Akt/Nrf2 signaling pathway

Epilepsy is a serious neurodegenerative disorder, which affects approximately 50 million people worldwide. Growing evidence indicates that oxidative stress caused by an excessive production of free radicals is considered one of the etiologies of epilepsy. Several studies have demonstrated that neurotoxicity-induced oxidative stress leads to neuronal cell death and seizure severity. In this study, we investigated the possible effects of biochanin A (BA), a natural isoflavone containing antioxidant and neuroprotective activities, in a mouse model of epilepsy, induced by an intraperitoneal injection of kainic acid (KA). The administration of KA produced severe seizure activity, and a decrease in memory function. Histological studies following KA injection revealed significant neurodegeneration, astrocyte dysfunction, and microglia activation in CA1, CA3, and hilus of the hippocampus. Moreover, KA administration exhibited an increase in caspase-3, a decrease in antioxidative enzyme levels, and downregulation of the PI3K/Akt/Nrf2 signaling pathway. Conversely, BA treatment significantly increased seizure threshold and memory function. In addition, BA treatment reduced neuronal death, restored astrocyte function, and suppressed microglia activation in CA1, CA3, and hilus. The BA-mediated neuroprotection was accompanied by the significant upregulation of a crucial cellular pathway particularly related to the antioxidant defense system and cell survival, the PI3K/Akt/Nrf2 signaling pathway, thereby increasing antioxidant enzyme levels (GSH, SOD, CAT) and reducing neuronal death. Taken together, our results suggest that BA possesses a neuroprotective effect through bolstering antioxidant defense mechanisms and activating neuronal survival. Thus, BA could be a possible pharmacological agent for the amelioration of epilepsy or other neurodegenerative diseases where oxidative stress is a key factor.