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Background P. orientalis has previously demonstrated protective effects against diabetic microvascular complications but its specific role in mitigating neurodegenerative events in diabetic retinopathy remains unknown. This study investigates the neuroprotective effects of Platycladus orientalis ethyl acetate fraction (EAPO) on retinal Müller cells (rMc-1) under different glucose stress. Methods Bioactive compounds in the EAPO were identified using liquid chromatography-mass spectrometry, while its cytotoxicity was assessed in vitro . The expression of gene and protein biomarkers related to neuronal survival like mammalian target of rapamycin (mTOR), mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2), rapid accelerated fibrosarcoma-1 (Raf-1), serine/threonine kinase 1 (AKT1), vascular endothelial growth factor (VEGF), and VEGF receptor 2 (VEGFR2) in EAPO- treated rMc-1 were compared with control group under different glucose concentrations. Results Phytochemical analysis of EAPO revealed the presence of diterpenoids, monoterpene esters, phenolic glycosides, and saturated fatty acids. EAPO demonstrated low cytotoxicity (IC 50 = 0.32 mg/mL) in rMc-1 under high-glucose stress conditions. Mechanistic study showed that EAPO treatment significantly mitigated glucose-induced cytotoxicity and neurodegeneration by downregulating the expression of VEGF, VEGFR2, mTOR, Raf-1, and MEK1/2, while enhancing phosphorylation of AKT1. Co-treatment with AICAR, an activator of AMP- activated protein kinase (AMPK), further amplified the neuroprotective effects of EAPO. In contrast, inhibition of AMPK using compound C exacerbated glucose-induced cytotoxicity and neurodegenerative signaling. The combination of EAPO and AICAR synergistically inhibited VEGF/VEGFR2 signaling and its downstream pathways (mTOR and Raf- 1/MEK1/2) while promoting AKT1-mediated neuronal survival. Conclusion This study provides new mechanistic insight into the neuroprotective effects of P. orientalis on rMc-1 under diabetic stress. EAPO could attenuate high-glucose-induced neuronal toxicity in rMc-1 by modulating the AKT1/mTOR and Raf-1/MEK1/2 pathways through AMPK activation.
Lim et al. (Fri,) studied this question.