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Pinocembrin-7-Methylether Protects SH-SY5Y Cells Against 6-Hydroxydopamine-Induced Neurotoxicity via Modulating Nrf2 Induction Through AKT and ERK Pathways

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Abstract

The present study aimed to evaluate the neuroprotective effects and underlying mechanisms of pinocembrin-7-methylether (PME), a natural bioflavonoid, in 6-hydroxydopamine (6-OHDA)-induced models of Parkinson’s disease in vivo and in vitro. First, we found that PME decreased apoptosis in 6-OHDA-intoxicated SH-SY5Y cells. PME also blocked several 6-OHDA-induced mitochondrial apoptotic cascades, including loss of mitochondrial membrane potential, caspase 3 and PARP activation, and a decrease in the Bcl-2/Bax ratio. Also, PME suppressed 6-OHDA-induced oxidative stress while increasing antioxidant enzymatic activity. Further investigations indicated that PME significantly enhanced nuclear accumulation of Nrf2, improved ARE promoter activity, and upregulated HO-1 and NQO1 expression levels. In addition, siRNA-mediated Nrf2 knockdown abolished PME-induced anti-oxidative and anti-apoptotic effects. Interestingly, we found that PME promoted phosphorylation of AKT and ERK, whereas pharmacological inhibition of AKT or ERK pathways diminished PME-induced Nrf2 activation and protective actions. Moreover, PME attenuated 6-OHDA-induced loss of dopaminergic neurons and ameliorated locomotor deficiency in zebrafish, supporting the neuroprotective actions of PME in vivo. In summary, we found that PME conferred neuroprotection against 6-OHDA-induced neurotoxicity in PD models in vivo and in vitro. Taken together, our findings suggest that activation of Nrf2/ARE/HO-1 signaling cascades contributes to PME-induced anti-oxidative and neuroprotective actions, which are at least partially mediated by AKT and ERK pathways.

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Funding

This research was funded by grants from the Guangdong Basic and Applied Basic Research Foundation (2020A1515110899); Educational Commission of Guangdong Province, China (2019KQNCX118); Medical Scientific Research Foundation of Guangdong Province, China (A2020396) and College Student Laboratory Opening Project of Guangzhou Medical University, China (01-408-2102053).

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  1. Zhi-Cong Zou, Ji-Jun Fu, and Yuan-Ye Dang are equally contributed to this work.

Authors and Affiliations

  1. Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China

    Zhi-Cong Zou, Ji-Jun Fu, Yuan-Ye Dang, Qian Zhang & Chu-Wen Li

  2. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China

    Xiu-Fen Wang, Han-Bin Chen, Simon Ming-Yuen Lee & Chu-Wen Li

  3. College of Food Science and Technology, Guangdong Ocean University, Zhanjiang, 524088, China

    Xue-Jing Jia

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  1. Zhi-Cong Zou
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Correspondence to Simon Ming-Yuen Lee or Chu-Wen Li.

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Zou, ZC., Fu, JJ., Dang, YY. et al. Pinocembrin-7-Methylether Protects SH-SY5Y Cells Against 6-Hydroxydopamine-Induced Neurotoxicity via Modulating Nrf2 Induction Through AKT and ERK Pathways. Neurotox Res 39, 1323–1337 (2021). https://doi.org/10.1007/s12640-021-00376-4

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