Melatonin Alleviates Radiculopathy Against Apoptosis and NLRP3 Inflammasomes Via the Parkin-Mediated Mitophagy Pathway.

Abstract

STUDY DESIGN\nAnimal experimental study with intervention.\n\n\nOBJECTIVE\nTo investigate the effect of melatonin on rat radiculopathy model and dorsal root ganglion (DRG) cells, and to elucidate the underlying mechanism.\n\n\nSUMMARY OF BACKGROUND DATA\nMelatonin has a well-documented efficacy in intervertebral disc degeneration (IVDD) and low back pain. IVDD can also lead to other complications such as disc herniation which will cause radiculopathy. Herniated nucleus pulposus (NP) induced apoptosis and NLR pyrin domain containing 3 (NLRP3) activation in DRG. However, the effect and underlying mechanism of melatonin on radiculopathy and DRG cells are still unclear.\n\n\nMETHODS\nRat radiculopathy model was induced by implanting NP tissue from the tail disc of the same rat into the left L4/5 inter-laminar space near the left DRG. Melatonin was injected intraperitoneally in the treated group to test its function. Apoptosis was determined by Tunnel staining and flow cytometry. NLRP3 inflammasome activation was determined by levels of NLRP3, ASC, GSMDM-N, IL-1β, and Caspase-1. Mitophagy was determined by levels of Parkin, Beclin-1, p62, and LCB-II. Mitophagy was blocked by treatment with Parkin-si or cyclosporine A (CsA).\n\n\nRESULTS\nNLRP3 was significantly upregulated in DRG of rat radiculopathy model; moreover, melatonin markedly decreased pain behavior in rat radiculopathy model. Furthermore, melatonin treatment decreases the incidence of apoptosis in DRG cells. Melatonin also promotes mitophagy and inhibits NLRP3 inflammasomes in DRG cells. In addition, mitophagy was blocked by treatment with Parkin-si and CsA. Both Parkin-si and CsA attenuated melatonin s inhibitory effect on apoptosis and the NLRP3 inflammasome, indicating that the beneficial effects of melatonin in DRG cells are mediated through the Parkin-mediated mitophagy.\n\n\nCONCLUSION\nMelatonin alleviates radiculopathy against apoptosis and NLRP3 inflammasomes by promoting Parkin-mediated mitophagy, which may help us provide a potential target for the treatment of radiculopathy.Level of Evidence: N/A.