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.
Highlights
Major depressive disorder (MDD) is a severe psychiatric disorder that causes considerable socioeconomic burden worldwide [1]
Melatonin prevented LPS-induced increase in cleaved form of caspase-1 (p20) level (Figures 2A,E). These results indicate that melatonin treatment inhibits NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation in the hippocampus of mice
We showed that melatonin ameliorated LPS-induced behavior abnormalities in a mouse model of acute systemic inflammation and depression, and decreased NLRP3 inflammasome activation in mice hippocampi as evidenced by Quantitative real-time PCR (qPCR), Western blot and immunofluorescence staining
Summary
Major depressive disorder (MDD) is a severe psychiatric disorder that causes considerable socioeconomic burden worldwide [1]. According to WHO reports, more than 350 million people globally are affected by depression [2]. Complete remission with current anti-depressants occur in only 50% of all cases [3], with frequent serious side effects and requiring long-term therapy for best results. There is still need for novel, effective and rapidly acting new antidepressants. MDD is a very complex disease and its pathophysiological mechanisms are not completely understood, different but interconnected processes including dysregulation of neurotransmission and neurotransmitter alterations, inflammation and inflammasome activation, oxidative stress, and mitochondrial dysregulation are implicated [1, 4]. MDD is frequently observed with comorbidities such as age, obesity, systemic inflammation, and infection [5]
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