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Gigantol, A Biphenyl Phenolic Compound of Medicinal Orchids, against Amyloid β Aggravation of SH-SY5Y Neuroblastoma Cell Injury Induced by Advanced Glycation End Products

Mei Chou Lai, Wayne Young Liu, Shorong-Shii Liou, I-Min Liu

Background: Advanced Glycation End products (AGEs) has been identified as a significant source of neurotoxicity in Alzheimer's Disease (AD). There is growing evidence confirming that many medicinal plants and natural compounds can potentially lessen the progression of neurodegenerative disorders or avert the onset of neurodegeneration, thus attracting much attention. Gigantol, a biphenyl phenolic compound isolated from orchids of the genus Dendrobium, has been reported to halt high glucose-induced renal dysfunction. Based on these data, gigantol has been proposed as a preventive treatment against cells from hyperglycemia or glycation-associated damages; however, there is no comprehensible evidence. AGEs induced damage in SH-SY5Y neuroblastoma cells was used to clarify the beneficial effects of gigantol on AD.

Methods and findings: Before stimulation with AGEs, SH-SY5Y cells were pretreated with gigantol. Gigantol (25 μmol/L) increased the cell viability reduced by AGEs (50 μg/mL); it also attenuated AGEs-induced reactive oxygen species generation and ameliorated downregulation of superoxide dismutase, glutathione peroxidase, and catalase. We found that AGEs increased Amyloid-Beta (Aβ) secretion in parallel with Amyloid Precursor Protein (APP) upregulation was reversed by gigantol. Gigantol did not affect β-site APP-cleaving enzyme 1 expression but induced insulin-degrading enzyme and neprilysin expression, which promoted degradation of Aβ. Gigantol also decreased the AGEs-induced protein levels of Endoplasmic Reticulum (ER) stress-associated molecules, including 78-kDa glucoseregulated protein and C/EBP homologous protein, and lowered phosphorylation of protein kinase R-like endoplasmic reticulum kinase and activating transcription factor 4. The neuro apoptosis effects caused by AGEs, such as upregulation of Bax, active caspase 12, cleaved caspase 3, and downregulation of Bcl-2, were alleviated by gigantol.

Conclusion: Gigantol could counteract AGEs related adverse effects by modulating Aβ degradation and inhibiting ER stress-associated apoptosis. Gigantol could be a potential therapeutic compound to halt or cure AD.