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

作者：Shah, Shahid Ali; Khan, Mehtab; Jo, Myeung-Hoon; Jo, Min Gi; Amin, Faiz Ul; Kim, Myeong Ok^*

来源：CNS Neuroscience & Therapeutics, 2017, 23(1): 33-44.

DOI：10.1111/cns.12588

• Lipopolysaccharide
• Melatonin
• Neuroinflammation
• Nuclear factor-erythroid 2-related factor 2
• Reactive oxygen species
• Silent information regulator transcript-1

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 (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. Conclusion: 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.

• 出版日期2017-1