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The TGR5 Agonist INT-777 Promotes Peripheral Nerve Regeneration by Activating cAMP-dependent Protein Kinase A in Schwann Cells

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Abstract

Schwann cell (SC) myelination is a pivotal event in the normal physiological functioning of the peripheral nervous system (PNS), where myelination is finely controlled by a series of factors within SCs to ensure timely onset and correct myelin thickness for saltatory conduction. Among these, cyclic AMP (cAMP) is a promising factor for driving myelin gene expression in SCs. It has been shown that TGR5 activation is often associated with increased production of cAMP. Therefore, we speculated that the G-protein-coupled receptor (TGR5) might be involved in the PNS myelination. To test this hypothesis, sciatic nerve crush-injured mice were treated with INT-777, a specific agonist of TGR5, which significantly improved remyelination and functional recovery. Furthermore, rats that underwent sciatic nerve transection were treated with INT-777, which also promoted nerve regeneration and functional recovery. In primary SCs, the stimulatory effect of INT-777 on myelin gene expression was largely counteracted by H89, a potent inhibitor of cAMP-dependent protein kinase A (PKA). Additionally, INT-777 stimulated cell migration was blunted in the presence of H89. Overall, these data indicate that INT-777 is capable of promoting peripheral nerve regeneration and functional recovery after injury, and these benefits are likely due to the activation of the TGR5/cAMP/PKA axis. As such, INT-777, together with other TGR5 agonists, may hold great therapeutic potential for treating peripheral nerve injury.

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Data Availability

All datasets generated and analyzed in this study are included in this published article. Materials are available upon reasonable request.

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Funding

This work was supported by the National Key Research and Development Program of China (2017YFA0701304); the National Natural Science Foundation of China (Nos. 81970747; 32271193); the Science and Technology Project of Nantong (No. JC2021068); and the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions.

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  1. Xiaoyu Liu and Jindong Guan contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neurogeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, 19 Qixiu Road, Nantong, China

    Xiaoyu Liu, Jindong Guan, Zhiguan Wu, Lingchi Xu & Cheng Sun

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  1. Xiaoyu Liu
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  2. Jindong Guan
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Contributions

Conceptualization, C.S.; investigation, X.L., J.G., and Z.W.; formal analysis, X.L. and J.G.; writing (original draft preparation), X.L. and G.L.; writing (review and editing), L.X. and C.S.; supervision, C.S.; project administration, L.X. and C.S.; funding acquisition, X.L., L.X. and C.S.

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Correspondence to Lingchi Xu or Cheng Sun.

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All animal experiments were performed with the approval of the Nantong University Animal Ethics Committee.

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Liu, X., Guan, J., Wu, Z. et al. The TGR5 Agonist INT-777 Promotes Peripheral Nerve Regeneration by Activating cAMP-dependent Protein Kinase A in Schwann Cells. Mol Neurobiol 60, 1901–1913 (2023). https://doi.org/10.1007/s12035-022-03182-x

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