Melatonin-mediated Calcineurin Inactivation Attenuates Prion Protein-induced Nf-Kb- Driven Pro-Inflammation Response

Abstract Background: Prion diseases are a group of prevalent and rapidly progressive neurodegenerative disorders that lead to chronic inflammation and neuronal cell death. Calcineurin and autophagy mediate prion-induced neurodegeneration, suggesting that inhibition of calcineurin and autophagy could be a target for therapy. Melatonin has been reported to exert neuroprotective effects against calcium-dependent neuronal cell death.Methods: Real-time quantitative PCR was used to detect mRNA levels of proinflammatory cytokines. Western blot was used to analysis p-nfkb, p-bcl10, calcineurin, prpc and autophagy flux pathway. Immunocytochemistry was used to analysis p-nfkb and calcineurin. Ca2+ levels were measured by fluo-4 using confocal microscope. Calcineurin activity was used to detect with calcineurin cellular activity assay kit. Transmission electron microscopy (TEM) was used to detect autophagy flux.Results: In the present study, we investigated whether melatonin attenuates prion peptide-mediated neuroinflammation and reduces calcineurin. We found that melatonin treatment inhibits prion protein-induced apoptosis. Melatonin inhibited calcium up-regulation and protected the cells against prion peptide‑induced neuron cell death by calcineurin inactivation. Furthermore, melatonin increased p62 protein levels and decrease LC3-II protein levels indicating autophagic flux inhibition and melatonin inhibited prion protein-induced neurotoxicity through autophagy flux inhibition.Conclusions: Taken together, our results illuminate that melatonin attenuated prion protein-induced neurinflammation through calcineurin inactivation and autophagic flux reduction, and also suggest that melatonin may provide effective strategy for therapy against neurodegenerative diseases, including prion diseases.