Myricetin mitigates trifloxystrobin neurotoxicity by modulating the integrated stress response pathway and antioxidant defense in sH-SY5Y cells

Trifloxystrobin (TFX) is a strobilurin fungicide that has a lipophilic nature, which allows it to accumulate in the brain. Therefore, it is crucial to investigate effective methods for preventing brain damage caused by TFX. We aimed to assess the protective benefits of myricetin (MYR) against toxicities brought on by TFX. SH-SY5Y cells were exposed to an inhibiting concentration of 50% (IC50) of TFX (100 µM), and the protective effect of MYR was tested at concentrations of 5, 10, 20, and 50 µM. Cell viability, oxidative stress, and integrated stress response (ISR) activation via the DELE1-HRI pathway were used to assess cytotoxicity. Apoptosis was evaluated by measuring phosphatidylserine externalization, cytochrome c release, Bax and caspase 3 activation, and loss of mitochondrial transmembrane potential (Δ<i>Ψm</i>). Results showed that TFX (100 µM) significantly decreased cell viability and increased reactive oxygen species (ROS) generation, malondialdehyde (MDA) production, and superoxide dismutase (SOD)/catalase (CAT) activities. However, pretreatment with 50 µM MYR significantly restored cell viability to nearly 100% compared to control cells. Furthermore, MYR pretreatment inhibited ISR activation by reducing ATF4 and CHOP expression and decreased apoptosis in a dose-dependent manner. These quantitative results point to MYR as a potent natural substance that may protect cells from TFX-induced neurotoxicity.