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Melatonin, a hormone produced by the pineal gland, exerts neuroprotective effects against brain damage. However, the effect of melatonin on diabetes\u2010induced brain injury has not been elucidated. This study was to evaluate the role of melatonin against neuronal death in DM and to elucidate the underlying mechanisms. Herein, we found that melatonin administration significantly alleviated the neuronal death in both streptozotocin (STZ)\u2010induced diabetic mice and high glucose (HG)\u2010treated neuronal cells. Melatonin inhibited neuronal pyroptosis and excessive autophagy, as evidenced by decreased levels of NLRP3, cleaved caspase\u20101, GSDMD\u2010N, IL\u20101\u03b2, LC3, Beclin1, and ATG12 both in vivo and in vitro. MicroRNA\u2010214\u20103p (miR\u2010214\u20103p) was decreased in DM mice and HG\u2010treated cells, and such a downregulation was corrected by melatonin, which was accompanied by repression of caspase\u20101 and ATG12. Furthermore, downregulation of miR\u2010214\u20103p abrogated the anti\u2010pyroptotic and anti\u2010autophagic actions of melatonin in vitro. Our results indicate that melatonin exhibits a neuroprotective effect by inhibiting neuronal pyroptosis and excessive autophagy through modulating the miR\u2010214\u20103p\/caspase\u20101 and miR\u2010214\u20103p\/ATG12 axes, respectively, and it might be a potential agent for the treatment of brain damage in the setting of DM.<\/jats:p>","DOI":"10.1096\/fj.202001328r","type":"journal-article","created":{"date-parts":[[2020,9,21]],"date-time":"2020-09-21T03:17:56Z","timestamp":1600658276000},"page":"14042-14054","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Melatonin exerts neuroprotective effects by inhibiting neuronal pyroptosis and autophagy in STZ\u2010induced diabetic mice"],"prefix":"10.1096","volume":"34","author":[{"given":"Hui","family":"Che","sequence":"first","affiliation":[{"name":"Department of Endocrinology The Second Affiliated Hospital of Harbin Medical University Harbin 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