title: Melatonin Stimulates the SIRT1/Nrf2 Signaling Pathway Counteracting Lipopolysaccharide (LPS)-Induced Oxidative Stress to Rescue Postnatal Rat Brain.
abstract: OBJECTIVE
  Lipopolysaccharide (LPS) induces oxidative stress and neuroinflammation both in vivo and in vitro. Here, we provided the first detailed description of the mechanism of melatonin neuroprotection against LPS-induced oxidative stress, acute neuroinflammation, and neurodegeneration in the hippocampal dentate gyrus (DG) region of the postnatal day 7 (PND7) rat brain.
  
  
  METHODS
  The neuroprotective effects of melatonin against LPS-induced neurotoxicity were analyzed using multiple research techniques, including Western blotting, immunofluorescence, and enzyme-linked immunosorbent assays (ELISAs) in PND7 rat brain homogenates and BV2 cell lysates in vitro. We also used EX527 to inhibit silent information regulator transcript-1 (SIRT1).
  
  
  RESULTS
  A single intraperitoneal (i.p) injection of LPS to PND7 rats significantly induced glial cell activation, acute neuroinflammation, reactive oxygen species (ROS) production and apoptotic neurodegeneration in hippocampal DG region after 4 h. However, the coadministration of melatonin significantly inhibited both LPS-induced acute neuroinflammation and apoptotic neurodegeneration and improved synaptic dysfunction in the hippocampal DG region of PND7 rats. Most importantly, melatonin stimulated the SIRT1/Nrf2 (nuclear factor-erythroid 2-related factor 2) signaling pathway to reduce LPS-induced ROS generation. The beneficial effects of melatonin were further confirmed in LPS-stimulated BV2 microglia cell lines in vitro using EX527 as an inhibitor of SIRT1. LPS-induced oxidative stress, Nrf2 inhibition, and neuroinflammation are SIRT1-dependent in BV2 microglia cell lines.
  
  
  CONCLUSIONS
  These results demonstrated that melatonin treatment rescued the hippocampal DG region of PND7 rat brains against LPS-induced oxidative stress damage, acute neuroinflammation, and apoptotic neurodegeneration via SIRT1/Nrf2 signaling pathway activation.
authors.affiliation: Department of Biology and Applied Life Science, College of Natural Sciences, Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: Shahid Ali
authors.initials: SA
authors.lastname: Shah
authors.affiliation: Department of Biology and Applied Life Science, College of Natural Sciences, Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: Mehtab
authors.initials: M
authors.lastname: Khan
authors.affiliation: Department of Biology and Applied Life Science, College of Natural Sciences, Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: Myeung-Hoon
authors.initials: MH
authors.lastname: Jo
authors.affiliation: Department of Biology and Applied Life Science, College of Natural Sciences, Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: Min Gi
authors.initials: MG
authors.lastname: Jo
authors.affiliation: Department of Biology and Applied Life Science, College of Natural Sciences, Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: Faiz Ul
authors.initials: FU
authors.lastname: Amin
authors.affiliation: Department of Biology and Applied Life Science, College of Natural Sciences, Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: Myeong Ok
authors.initials: MO
authors.lastname: Kim
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology; D003848:Deoxyguanine Nucleotides / Q000378:metabolism; D005452:Fluoresceins / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009457:Neuroglia; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D000975:Antioxidants; D002227:Carbazoles; D003848:Deoxyguanine Nucleotides; D005452:Fluoresceins; D005904:Glial Fibrillary Acidic Protein; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; C435731:fluoro jade; C078206:8-oxodeoxyguanosine triphosphate; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D008550:Melatonin
keywords: Lipopolysaccharide; Melatonin; Neuroinflammation; Nuclear factor-erythroid 2-related factor 2; Reactive oxygen species; Silent information regulator transcript-1