Melatonin Stimulates the SIRT1/Nrf2 Signaling Pathway Counteracting Lipopolysaccharide (LPS)‐Induced Oxidative Stress to Rescue Postnatal Rat Brain

Summary Aims 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 ( PND 7) 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 ( ELISA s) in PND 7 rat brain homogenates and BV 2 cell lysates in vitro . We also used EX 527 to inhibit silent information regulator transcript‐1 ( SIRT 1). 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 SIRT 1/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 EX 527 as an inhibitor of SIRT1. LPS ‐induced oxidative stress, Nrf2 inhibition, and neuroinflammation are SIRT 1‐dependent in BV 2 microglia cell lines. Conclusion These results demonstrated that melatonin treatment rescued the hippocampal DG region of PND 7 rat brains against LPS ‐induced oxidative stress damage, acute neuroinflammation, and apoptotic neurodegeneration via SIRT 1/Nrf2 signaling pathway activation.