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The Neurotrophic Effects and Mechanism of Action for FK1706 in Neurorrhaphy Rat Models and SH-SY5Y Cells

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Abstract

FK1706 is a novel non-immunosuppressive immunophilin ligand with neurotrophic activity and exerts its neurotrophic effect through NGF. The present study aimed to elaborate on the neurotrophic activity and the mechanism of action of FK1706 in end-to-side neurorrhaphy rats and SH-SY5Y cells. In the regenerating nerves of neurorrhaphy rats, FK1706 increased the thickness of myelin sheath and the level of nerve regeneration-related proteins. The mechanism of action of FK1706 on neurite regrowth was elucidated in vitro by incubating SH-SY5Y cells in different conditions (Control, NGF, FK1706, NGF + FK1706, NGF + FK1706 + geldanamycin). Under the conditions where NGF was used, the phosphorylation level of major proteins (Raf-1 and ERK) in the Ras/Raf/MAPK/ERK signaling pathway related to SH-SY5Y cell proliferation was significantly enhanced following the application of FK1706. The number of viable cells, cell viability and neurite length of SH-SY5Y cells was maximal when NGF and FK1706 were used simultaneously. The binding level of HSP90 and Raf-1 in FK1706 group was the highest. These results indicated that FK1706 could significantly promote nerve regeneration after neurorrhaphy. The putative mechanism of action stated that FK1706 could promote the binding of HSP90 and Raf-1, make Raf-1 continue to be activated, thereby affecting key proteins in the Ras/Raf/MAPK/ERK signaling pathway related to the neurotrophic effects of NGF to promote the proliferation and neurite regrowth of nerve cells.

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Data Availability

The datasets generated during and analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We are grateful to be supported by the members of pediatric surgical pelvic floor functional reconstruction team led by professor Jianguo Wen, the First Affiliated Hospital of Zhengzhou University; Team No. SZSM201612013.

Funding

This study was funded by the National Natural Science Foundation of China [Grant Numbers 81400689, 81670689].

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Authors and Affiliations

  1. Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, China

    Wansheng Gao, Han Yang, Le Xu, Wenbo Huang & Yanfeng Yang

  2. Children Hospital of Shenzhen, Shenzhen, 518000, Guangdong Province, China

    Wansheng Gao

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Contributions

WG is the group director and main designer of this research project who planed and supervised the research and played a substantial role in editing the manuscript. HY prepared all the data in suitable format for manuscript and wrote the preliminary manuscript. LX cultured the SH-SY5Y cells and performed the molecular assessment in the research. WH performed the surgical procedures in rats and finished the morphological study in the molecular assessment. YY helped finished the molecular assessment, performed the Co-IP and analyzed the quantitative results. All authors have read and approved the final manuscript.

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Correspondence to Wansheng Gao.

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The authors have no relevant financial or non-financial interests to disclose.

Ethical Approval

This study was performed in line with the principles of the Declaration of Helsinki. This study was approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University (Ethical Approval Number: 2014-1282).

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Gao, W., Yang, H., Xu, L. et al. The Neurotrophic Effects and Mechanism of Action for FK1706 in Neurorrhaphy Rat Models and SH-SY5Y Cells. Neurochem Res 46, 2897–2908 (2021). https://doi.org/10.1007/s11064-021-03391-1

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  • DOI: https://doi.org/10.1007/s11064-021-03391-1

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