Ginsenoside Rh2 inhibits CBP/p300-mediated FOXO3a acetylation and epilepsy-induced oxidative damage via the FOXO3a-KEAP1-NRF2 pathway

Epilepsy is a chronic disease that affects a wide range of people. Furthermore, a third of patients suffering from epileptic seizures do not respond to antiepileptic drugs. In recent years, increasing attention has focused on the role of oxidative stress in acquired epilepsy, and adjuvant antiepileptic drugs to reduce oxidative stress may be a new therapeutic strategy. In this study ginsenoside Rh2 was resistant to oxidative stress induced by epileptic activity in vivo and in vitro. Using online databases, we identified forkhead box O3a (FOXO3a) overexpression in epilepsy tissue and validated this in vitro, in vivo, and in clinical tissues of patients with epilepsy. An in vitro epilepsy model revealed that the overexpression of FOXO3a led to more severe oxidative stress, while the knockdown of FOXO3a had a protective effect on SH-SY5Y cells. Moreover, our results showed that the positive effect of FOXO3a on oxidative stress was caused by the transcriptional activation of Kelch-like ECH-associated protein 1 (KEAP1), a negative regulator of nuclear factor erythroid 2-related factor 2 (NRF2). We also found that ginsenoside Rh2 can directly inhibit the activation of FOXO3a by selectively blocking CREB-binding protein (CBP)/p300-mediated FOXO3a acetylation and play a role in regulating the KEAP1-NRF2 pathway to resist oxidative stress.

Automated summary

Epilepsy is a chronic disease that affects a wide range of people, and one-third of patients do not respond to antiepileptic drugs. Oxidative stress has been recognized as playing a role in acquired epilepsy, and targeting oxidative stress with adjuvant antiepileptic drugs may be a new therapeutic strategy. This study reveals the resistance of ginsenoside Rh2 to oxidative stress induced by epileptic activity and identifies the overexpression of FOXO3a in epilepsy tissue, which leads to more severe oxidative stress. In addition, the study uncovers the involvement of the KEAP1-NRF2 pathway in regulating oxidative stress and demonstrates the ability of ginsenoside Rh2 to inhibit the activation of FOXO3a, thus providing potential targets for the development of new treatments for epilepsy.