Melatonin Attenuates LPS-Induced Acute Depressive-Like Behaviors and Microglial NLRP3 Inflammasome Activation Through the SIRT1/Nrf2 Pathway

Abstract

Inflammation is a crucial component of various stress-induced responses that contributes to the pathogenesis of major depressive disorder (MDD). Depressive-like behavior (DLB) is characterized by decreased mobility and depressive behavior that occurs in systemic infection induced by Lipopolysaccharide (LPS) in experimental animals and is considered as a model of exacerbation of MDD. We assessed the effects of melatonin on behavioral changes and inflammatory cytokine expression in hippocampus of mice in LPS-induced DLB, as well as its effects on NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation, oxidative stress and pyroptotic cell death in murine microglia in vitro . Intraperitoneal 5 mg/kg dose of LPS was used to mimic depressive-like behaviors and melatonin was given at a dose of 500 mg/kg for 4 times with 6 h intervals, starting at 2 h before LPS administration. Behavioral assessment was carried out at 24 h post-LPS injection by tail suspension and forced swimming tests. Additionally, hippocampal cytokine and NLRP3 protein levels were estimated. Melatonin increased mobility time of LPS-induced DLB mice and suppressed NLRP3 expression and interleukin-1β (IL-1β) cleavage in the hippocampus. Immunofluorescence staining of hippocampal tissue showed that NLRP3 is mainly expressed in ionized calcium-binding adapter molecule 1 (Iba1) -positive microglia. Our results show that melatonin prevents LPS and Adenosine triphosphate (ATP) induced NLRP3 inflammasome activation in murine microglia in vitro , evidenced by inhibition of NLRP3 expression, Apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, caspase-1 cleavage and interleukin-1β (IL-1β) maturation and secretion. Additionally, melatonin inhibits pyroptosis, production of mitochondrial and cytosolic reactive oxygen species (ROS) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. The beneficial effects of melatonin on NLRP3 inflammasome activation were associated with nuclear factor erythroid 2–related factor 2 (Nrf2) and Silent information regulator 2 homolog 1 (SIRT1) activation, which were reversed by Nrf2 siRNA and SIRT1 inhibitor treatment.

Melatonin attenuates AFB1-induced cardiotoxicity via the NLRP3 signalling pathway

“…Melatonin's ability to suppress NLRP3 inflammasome activation and decrease IL-1β hypersecretion, due to its various antioxidant actions, has been fully documented in an LPS/ATP-induced murine microglia model. 33 In the present study, the addition of melatonin was shown to significantly attenuate ROS generation induced by high-dose AFB1. Notably, treatment with melatonin efficiently downregulated the degree of cardiac injury and serum LDH levels in high-dose AFB1-exposed rats.…”

α-Cyperone Confers Antidepressant-Like Effects in Mice via Neuroplasticity Enhancement by SIRT3/ROS Mediated NLRP3 Inflammasome Deactivation

“…Compared with wild-type mice, NLRP3 gene knockout mice didn’t exhibit depression-like behaviors in SPT or TST after 4 weeks of CUMS exposure; meanwhile, NLRP3 gene knockout prevented the promotion of IL-1β in serum and hippocampi of CUMS mice ( Su et al, 2017 ). Melatonin, a hormone produced from L-tryptophan mainly in the pineal gland, significantly reversed the depression-like behaviors induced by LPS, which was tightly linked with NLRP3 inflammasome inhibition generated decrease in GSDMD cleavage and pyroptotic cell death ( Arioz et al, 2019 ). In this study, Cy effectively decreased the expression of NLRP3 inflammasome complex and cleaved IL-1β, IL-18, and GSDMD in mice received CUMS modeling, suggesting that Cy-related improvements in depressive behaviors and neuroplasticity defects were partially resulted from the suppression of NLRP3 inflammasome.…”

Can melatonin reduce the severity of COVID-19 pandemic?

“…On the model of bacterial pneumonia, LPS-induced ALI mouse model, it was shown that melatonin successfully inhibits pneumonia through interfering with NLRP3 inflammasome, protecting macrophages from pyroptosis [40]. Other publications also demonstrate that melatonin may be an effective inhibitor of pyroptosis and pathologies associated with it [41][42][43][44][45][46].…”