3′,4′,7-Trihydroxyflavone prevents apoptotic cell death in neuronal cells from hydrogen peroxide-induced oxidative stress

In this study, we investigated the mechanisms of 3′,4′,7-trihydroxyflavone (THF) protection of neuronal cells from neuronal cell death induced by the oxidative stress-related neurotoxin hydrogen peroxide (H₂O₂). Pretreatment with THF significantly elevated cell viability, reduced H₂O₂-induced lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) production, glutathione (GSH) content, superoxide dismutase (SOD) activity, catalase (CAT) activity, and mitochondria membrane potential (MMP) loss. Western blot data demonstrated that THF inhibited the H₂O₂-induced up- or down-regulation of cleaved caspase-3, cleaved caspase-9, cleaved poly-ADP-ribose polymerase (PARP), Bax, Bcl-2, and Bcl-xL, and attenuated the H₂O₂-induced release of cytochrome c from the mitochondria to the cytosol. In addition, pretreatment with THF attenuated H₂O₂-induced rapid and significant phosphorylation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinases (PI3K)/Akt. THF also inhibited nuclear factor-κB (NF-κB) translocation to the nucleus induced by H₂O₂, down-stream of H₂O₂-induced phosphorylation of MAPKs and PI3K/Akt. These data provide the first evidence that THF protects neuronal cells against H₂O₂-induced oxidative stress, possibly through ROS reduction, mitochondria protection, and NF-κB modulation via MAPKs and PI3K/Akt pathways. The neuroprotective effects of THF make it a promising candidate as a therapeutic agent for neurodegenerative diseases.