While glutamate, a key neurotransmitter in the central nervous system, is fundamental to neuronal viability and normal brain function, its excessive accumulation leads to oxidative stress, contributing to neuronal damage and neurodegenerative diseases. In this study, we investigated the effect of β-lapachone (β-Lap), a naturally occurring naphthoquinone, on glutamate-induced injury in HT22 cells and explored the underlying mechanism involved. Our results show that β-Lap significantly improved cell viability in a dose-dependent manner. Additionally, β-Lap exhibited a significant antioxidant activity, reducing intracellular reactive oxygen species levels and restoring glutathione levels. The antioxidant capacity of β-Lap was further demonstrated through 2,2-Diphenyl-1-picrylhydrazyl (DPPH) and 2,2’-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) radical scavenging assays. Western blot analysis revealed that β-Lap upregulated brain-derived neurotrophic factor (BDNF) and promoted the phos-phorylation of tropomyosin receptor kinase B (TrkB), extracellular signal-regulated kinase (ERK), and cAMP response element-binding protein (CREB), which were downregulated by glutamate. Furthermore, β-Lap enhanced the cellular antioxidant mole-cules, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). In conclusion, β-Lap can protect HT22 cells against glutamate-induced injury by activating the BDNF/TrkB/ERK/CREB and ERK/Nrf2/HO-1 signaling pathways, suggesting its therapeutic potential for neurodegenerative diseases.
