Melatonin promotes Schwann cell proliferation and migration via the shh signalling pathway after peripheral nerve injury

Abstract

Peripheral nerve injury (PNI) is a common and incurable disease in the clinic, but the effects of available treatments are still not satisfactory. Therefore, it is necessary to explore new treatment methods. To explore the effect and mechanism of melatonin in peripheral nerve regeneration, we administered melatonin to mice with PNI by intraperitoneal injection. We applied microarray analysis to detect differentially expressed genes of mice with sciatic nerve injury after melatonin application. Then, we conducted gene ontology and protein–protein interactions to screen out the key genes related to peripheral nerve regeneration. Cell biology and molecular biology experiments were performed in Schwann cells in vitro to verify the key genes identified by microarray analysis. Our results showed that a total of 598 differentially expressed genes were detected after melatonin subcutaneously injecting into mice with sciatic nerve injury. Bioinformatics analysis showed that Shh may be the key gene for the promotion of peripheral nerve regeneration by melatonin. In vitro, the proliferation and migration abilities of schwann cells in the melatonin group were significantly higher than those of Schwann cells in the control group; while after treating with both melatonin and luzindole (a Shh signalling pathway inhibitor), the proliferation and migration abilities of Schwann cells decreased compared with the melatonin group. Our study suggests that melatonin might improve the proliferation and migration of Schwann cells via the Shh signalling pathway after PNI, thus promoting peripheral nerve regeneration. Our study provides a new approach and target for the clinical treatment of PNI.

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“…Accumulating evidence reveals that melatonin can inhibit PC12 cell growth (28)(29)(30). The GO pathway analysis results highlight the link between Schwann cells and melatonin, which may align with the findings that melatonin can promote Schwann cell proliferations (31)(32)(33). The SNAP-25 gene has been associated with distinct brain diseases, including attention deficit hyperactivity disorder (ADHD), schizophrenia and bipolar disorder-which is possibly due to its encoded protein is involved in synaptic functions.…”

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“…reported that MLT could promote axonal extension via MT1 receptors for peripheral nerve regeneration [ 23 ]. In addition, MLT could activate the Wnt/β-catenin signaling pathway to promote SC migration and reduce SC apoptosis [ 24 ]. In this study, addition of MLT in the composite scaffold improved the hydrophilicity and biocompatibility of electrospun scaffolds for cell attachment and proliferation, and improved ATP synthesis for energy supply by increasing the mitochondrial potential in vitro.…”

“…[ 23 ] found that MLT could promote peripheral nerve axon regeneration via MT1 receptors [ 24 ]. MLT promoted SC migration by activating Wnt/β-catenin signaling pathway, and thus it reduced the apoptosis of SCs [ 24 ]. In addition, Qian et al.…”

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“…Of note, also topically applied melatonin has been found to support regeneration, yet not at the same level of magnitude as to when the hormone had been administered systemically ( Tuna Edizer et al, 2019 ). It is noteworthy in this context that subcutaneous melatonin injection has been found to significantly improve Schwann cell proliferation and migration as well ( Pan et al, 2021 ). Similar histomorphological findings were obtained when applying melatonin to injured nerves in other studies, but the electrophysiological parameters contradicted the data of Edizer and colleagues.…”