A Novel Gastrodin Derivative with Neuroprotection Promotes NGF-Mimic Activity by Targeting INSR and ACTN4 to Activate PI3K/Akt Signaling Pathway in PC12 Cells
Gastrodin (gas) has been shown to promote neuroprotection and reverse Alzheimer’s disease (AD) pathology. However, its high effective dose limits its potential in treating AD. In this study, a bioassay system using PC12 cells and the nerve growth factor (NGF)-mimic effect was employed to investigate...
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MDPI AG
2025-03-01
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| Series: | Antioxidants |
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| author | Jiayuan Zeng Jianxia Mo Makoto Muroi Hiroyuki Osada Lan Xiang Jianhua Qi |
| author_facet | Jiayuan Zeng Jianxia Mo Makoto Muroi Hiroyuki Osada Lan Xiang Jianhua Qi |
| author_sort | Jiayuan Zeng |
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| description | Gastrodin (gas) has been shown to promote neuroprotection and reverse Alzheimer’s disease (AD) pathology. However, its high effective dose limits its potential in treating AD. In this study, a bioassay system using PC12 cells and the nerve growth factor (NGF)-mimic effect was employed to investigate the structure–activity relationship of gas derivatives. Among the synthesized compounds, GAD037 demonstrated the highest NGF-mimic activity, surpassing gas. Additionally, GAD037 exhibited significant neuroprotective effects, reducing reactive oxygen species (ROS) and malondialdehyde (MDA) levels, thereby improving the survival of PC12 cells under oxidative stress. It also protected cells from A<i>β</i>-induced toxicity. Target protein identification and mechanistic studies revealed that insulin receptor (INSR) and alpha-actinin-4 (ACTN4) are potential targets of GAD037, confirmed through specific inhibitors, small interfering RNA (siRNA) analysis, a cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS). Moreover, the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) and rat sarcoma (Ras)/protooncogene serine–threonine protein kinase (Raf)/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways were found to be involved in the NGF-mimic activity of GAD037. In conclusion, GAD037 exhibits superior NGF-mimic and neuroprotective activities compared to gas, suggesting its potential as a lead compound for anti-AD applications. |
| format | Article |
| id | doaj-art-98fa2b3be7a6449597531f43c705e052 |
| institution | OA Journals |
| issn | 2076-3921 |
| language | English |
| publishDate | 2025-03-01 |
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| spelling | doaj-art-98fa2b3be7a6449597531f43c705e0522025-08-20T02:11:21ZengMDPI AGAntioxidants2076-39212025-03-0114334410.3390/antiox14030344A Novel Gastrodin Derivative with Neuroprotection Promotes NGF-Mimic Activity by Targeting INSR and ACTN4 to Activate PI3K/Akt Signaling Pathway in PC12 CellsJiayuan Zeng0Jianxia Mo1Makoto Muroi2Hiroyuki Osada3Lan Xiang4Jianhua Qi5College of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road 866, Hangzhou 310058, ChinaCollege of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road 866, Hangzhou 310058, ChinaChemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Wako 351-0198, Saitama, JapanChemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Wako 351-0198, Saitama, JapanCollege of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road 866, Hangzhou 310058, ChinaCollege of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road 866, Hangzhou 310058, ChinaGastrodin (gas) has been shown to promote neuroprotection and reverse Alzheimer’s disease (AD) pathology. However, its high effective dose limits its potential in treating AD. In this study, a bioassay system using PC12 cells and the nerve growth factor (NGF)-mimic effect was employed to investigate the structure–activity relationship of gas derivatives. Among the synthesized compounds, GAD037 demonstrated the highest NGF-mimic activity, surpassing gas. Additionally, GAD037 exhibited significant neuroprotective effects, reducing reactive oxygen species (ROS) and malondialdehyde (MDA) levels, thereby improving the survival of PC12 cells under oxidative stress. It also protected cells from A<i>β</i>-induced toxicity. Target protein identification and mechanistic studies revealed that insulin receptor (INSR) and alpha-actinin-4 (ACTN4) are potential targets of GAD037, confirmed through specific inhibitors, small interfering RNA (siRNA) analysis, a cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS). Moreover, the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) and rat sarcoma (Ras)/protooncogene serine–threonine protein kinase (Raf)/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways were found to be involved in the NGF-mimic activity of GAD037. In conclusion, GAD037 exhibits superior NGF-mimic and neuroprotective activities compared to gas, suggesting its potential as a lead compound for anti-AD applications.https://www.mdpi.com/2076-3921/14/3/344gastrodin derivativesnerve growth factorneuroprotectioninsulin receptoralpha-actinin-4 |
| spellingShingle | Jiayuan Zeng Jianxia Mo Makoto Muroi Hiroyuki Osada Lan Xiang Jianhua Qi A Novel Gastrodin Derivative with Neuroprotection Promotes NGF-Mimic Activity by Targeting INSR and ACTN4 to Activate PI3K/Akt Signaling Pathway in PC12 Cells Antioxidants gastrodin derivatives nerve growth factor neuroprotection insulin receptor alpha-actinin-4 |
| title | A Novel Gastrodin Derivative with Neuroprotection Promotes NGF-Mimic Activity by Targeting INSR and ACTN4 to Activate PI3K/Akt Signaling Pathway in PC12 Cells |
| title_full | A Novel Gastrodin Derivative with Neuroprotection Promotes NGF-Mimic Activity by Targeting INSR and ACTN4 to Activate PI3K/Akt Signaling Pathway in PC12 Cells |
| title_fullStr | A Novel Gastrodin Derivative with Neuroprotection Promotes NGF-Mimic Activity by Targeting INSR and ACTN4 to Activate PI3K/Akt Signaling Pathway in PC12 Cells |
| title_full_unstemmed | A Novel Gastrodin Derivative with Neuroprotection Promotes NGF-Mimic Activity by Targeting INSR and ACTN4 to Activate PI3K/Akt Signaling Pathway in PC12 Cells |
| title_short | A Novel Gastrodin Derivative with Neuroprotection Promotes NGF-Mimic Activity by Targeting INSR and ACTN4 to Activate PI3K/Akt Signaling Pathway in PC12 Cells |
| title_sort | novel gastrodin derivative with neuroprotection promotes ngf mimic activity by targeting insr and actn4 to activate pi3k akt signaling pathway in pc12 cells |
| topic | gastrodin derivatives nerve growth factor neuroprotection insulin receptor alpha-actinin-4 |
| url | https://www.mdpi.com/2076-3921/14/3/344 |
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