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Salidroside Improves Chronic Stress Induced Depressive Symptoms Through Microglial Activation Suppression.

ABSTRACT: Depression is a severe neurological disorder highly associated with chronic mental stress stimulation, which involves chronic inflammation and microglial activation in the central nervous system (CNS). Salidroside (SLDS) has been reported to exhibit anti-neuroinflammatory and protective properties on neurological diseases. However, the mechanism underlying the effect of SLDS on depressive symptoms has not been well elaborated. In the present study, the effects of SLDS on depressive behaviors and microglia activation in mice CNS were investigated. Behavioral tests, including Forced swimming test (FST), Open field test (OFT) and Morris water maze (MWM) revealed that SLDS treatment attenuated the depressive behaviors in stress mice. SLDS treatment significantly reduced the microglial immunoreactivity for both Iba-1 and CD68, characteristic of deleterious M1 phenotype in hippocampus of stress mice. Additionally, SLDS inhibited microglial activation involving the suppression of ERK1/2, P38 MAPK and p65 NF-κB activation and thus reduced the expression and release of neuroinflammatory cytokines in stress mice as well as in lipopolysaccharide (LPS)-induced primary microglia. Also, SLDS changed microglial morphology, attachment and reduced the phagocytic ability in LPS-induced primary microglia. The results demonstrated that SLDS treatment could improve the depressive symptoms caused by unpredictable chronic stress, indicating a potential therapeutic application of SLDS in depression treatment by interfering microglia-mediated neuroinflammation.

SUBMITTER: Fan Y

PROVIDER: S-EPMC8217647 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

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Salidroside Improves Chronic Stress Induced Depressive Symptoms Through Microglial Activation Suppression.

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