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KMID : 1034820190150020145
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Molecular & Cellular Toxicology
2019 Volume.15 No. 2 p.145 ~ p.152
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Inhibition of oxaliplatin-induced neurotoxicity by silymarin through increased expression of brain-derived neurotrophic factor and inhibition of p38-MAPK
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Choi Ji-Young
Yi Hyeon-Gyu
Park Chang-Shin
Shin Dong-Wun
Kang Ju-Hee
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Abstract
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Backgrounds: Oxaliplatin is a chemotherapeutic agent that induces neuropathy through unknown mechanisms and therefore, its pharmacological performance is limited. Silymarin, a well-known hepatoprotective natural flavonoid mixture, has neuroprotective effects against certain neurodegenerative or neurotoxic stimuli.
Methods: We tested whether silymarin protects against oxaliplatin-induced neurotoxicity by using a neuronal cell culture system. Using differentiated SH-SY5Y cells, effects of silymarin on the oxaliplatin-mediated cytotoxicity for cell viability, oxidative stress and BDNF expression.
Results: Treatment of neuronal cells with oxaliplatin decreased cell viability, which was accompanied by increase in levels of the apoptotic marker cleaved poly-(ADP-ribose) polymerase (PARP) and malondialdehyde (MDA), a marker of lipid peroxidation. We found that oxaliplatin-induced cell death was partially mediated by p38-MAPK activation, which was significantly inhibited by silymarin. Silymarin slightly but not significantly inhibited oxaliplatin-induced oxidative stress. It also upregulated brain-derived neurotrophic factor (BDNF) expression and increased calcium-calmodulin kinase II and CREB activities. The observation of cell morphology revealed that silymarin induced dendritic outgrowth, which was validated by the increased expression of β-III tubulin protein. Furthermore, we observed that oxaliplatin-induced loss of dendritic outgrowth and BDNF downregulation were partially blocked by silymarin.
Conclusion: Our results suggested that oxaliplatin-induced neuropathy may be caused by combined mechanisms of increased oxidative stress, p38 MAPK-mediated apoptosis, and reduction of BDNF expression. All these changes were significantly inhibited by silymarin.
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KEYWORD
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Silymarin, Oxaliplatin, Neuropathy, Brain-derived neurotrophic factor, P38 mitogen-activated protein kinase
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