Petatewalide B alleviates oxygen‑glucose deprivation/reoxygenation‑induced neuronal injury via activation of the AMPK/Nrf2 signaling pathway

Neuronal injury is a common, and critical, occurrence in clinical ischemic strokes, and can cause irreversible brain damage. However, the precise pathological mechanisms underlying this condition and effective treatment remain unclear. Increasing evidence shows that the nuclear factor erythroid 2related factor 2 (Nrf2)/activated protein kinase (AMPK) signaling pathway serves a significant role in neuronal injury and is involved in neuroprotection. The present study demonstrated that petatewalide B, the active constituent of Petasites japonicus, otherwise known as butterbur, can alleviate oxygenglucose deprivation/reoxygenation (OGD/R)induced neuronal death via the adenosine monophosphateAMPK/glycogen synthase kinase (GSK)3/beta/Nrf2/antioxidant response element (ARE) signaling pathways in human neuroblastoma SHSY5Y cells. A neuronal injury model was established by depriving SHSY5Y cells of oxygen and glucose for 8 h, followed by 24 h of reoxygenation (OGD/R). The results indicated that the OGD/R model exhibited reduced cell viability but increased lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) production and apoptosis. These were accompanied by increased levels of cleaved PARP, cleaved caspase9, cleaved caspase3, p53, Bax and p21, as well as decreased Bcl2 levels. Treatment with petatewalide B was able to strengthen cell viability but reduced LDH release, ROS production and the expression levels of apoptosisrelated proteins. Additionally, treatment with petatewalide B activated AMPK in the OGD/Rexposed SHSY5Y cells and upregulated activation of the downstream transcription factor Nrf2, which accompanied heme oxygenase 1 (HO1) and NAD(P)H quinone dehydrogenase 1 (NQO1) expression. Furthermore, silencing AMPK, Nrf2, HO1 and NQO1 expression inhibited petatewalide B's protective effect against apoptosis in the OGD/Rexposed SHSY5Y cells. Therefore, petatewalide B protected human neuroblastoma cells against OGD/Rinduced injury by downregulating apoptosis and oxidative stress via upregulation of the AMPK/Nrf2 signaling pathway, suggesting that petatewalide B may be a prospective protector against neuronal injury, having possible therapeutic and medical implications.