Melatonin Stimulates the <scp>SIRT</scp>1/Nrf2 Signaling Pathway Counteracting Lipopolysaccharide (<scp>LPS</scp>)‐Induced Oxidative Stress to Rescue Postnatal Rat Brain

<jats:title>Summary</jats:title><jats:sec><jats:title>Aims</jats:title><jats:p>Lipopolysaccharide (<jats:styled-content style="fixed-case">LPS</jats:styled-content>) induces oxidative stress and neuroinflammation both <jats:italic>in vivo</jats:italic> and <jats:italic>in vitro</jats:italic>. Here, we provided the first detailed description of the mechanism of melatonin neuroprotection against <jats:styled-content style="fixed-case">LPS</jats:styled-content>‐induced oxidative stress, acute neuroinflammation, and neurodegeneration in the hippocampal dentate gyrus (DG) region of the postnatal day 7 (<jats:styled-content style="fixed-case">PND</jats:styled-content>7) rat brain.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>The neuroprotective effects of melatonin against <jats:styled-content style="fixed-case">LPS</jats:styled-content>‐induced neurotoxicity were analyzed using multiple research techniques, including Western blotting, immunofluorescence, and enzyme‐linked immunosorbent assays (<jats:styled-content style="fixed-case">ELISA</jats:styled-content>s) in <jats:styled-content style="fixed-case">PND</jats:styled-content>7 rat brain homogenates and <jats:styled-content style="fixed-case">BV</jats:styled-content>2 cell lysates <jats:italic>in vitro</jats:italic>. We also used <jats:styled-content style="fixed-case">EX</jats:styled-content>527 to inhibit silent information regulator transcript‐1 (<jats:styled-content style="fixed-case">SIRT</jats:styled-content>1).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>A single intraperitoneal (i.p) injection of <jats:styled-content style="fixed-case">LPS</jats:styled-content> to PND7 rats significantly induced glial cell activation, acute neuroinflammation, reactive oxygen species (<jats:styled-content style="fixed-case">ROS</jats:styled-content>) production and apoptotic neurodegeneration in hippocampal <jats:styled-content style="fixed-case">DG</jats:styled-content> region after 4 h. However, the coadministration of melatonin significantly inhibited both <jats:styled-content style="fixed-case">LPS</jats:styled-content>‐induced acute neuroinflammation and apoptotic neurodegeneration and improved synaptic dysfunction in the hippocampal <jats:styled-content style="fixed-case">DG</jats:styled-content> region of PND7 rats. Most importantly, melatonin stimulated the <jats:styled-content style="fixed-case">SIRT</jats:styled-content>1/Nrf2 (nuclear factor‐erythroid 2‐related factor 2) signaling pathway to reduce <jats:styled-content style="fixed-case">LPS</jats:styled-content>‐induced <jats:styled-content style="fixed-case">ROS</jats:styled-content> generation. The beneficial effects of melatonin were further confirmed in <jats:styled-content style="fixed-case">LPS</jats:styled-content>‐stimulated BV2 microglia cell lines <jats:italic>in vitro</jats:italic> using <jats:styled-content style="fixed-case">EX</jats:styled-content>527 as an inhibitor of SIRT1. <jats:styled-content style="fixed-case">LPS</jats:styled-content>‐induced oxidative stress, Nrf2 inhibition, and neuroinflammation are <jats:styled-content style="fixed-case">SIRT</jats:styled-content>1‐dependent in <jats:styled-content style="fixed-case">BV</jats:styled-content>2 microglia cell lines.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>These results demonstrated that melatonin treatment rescued the hippocampal <jats:styled-content style="fixed-case">DG</jats:styled-content> region of <jats:styled-content style="fixed-case">PND</jats:styled-content>7 rat brains against <jats:styled-content style="fixed-case">LPS</jats:styled-content>‐induced oxidative stress damage, acute neuroinflammation, and apoptotic neurodegeneration via <jats:styled-content style="fixed-case">SIRT</jats:styled-content>1/Nrf2 signaling pathway activation.</jats:p></jats:sec>