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The Unpredictable Chronic Mild Stress Protocol for Inducing Anhedonia in Mice
Published on: October 24, 2018
Nootkatone Improves Chronic Unpredictable Mild Stress-Induced Depressive-Like Behaviors by Repressing
Xin-Hua Zhao1, Na An2, Meng-Huan Xia1
1Basic Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Objective:
To explore the effect of nootkatone (NKT) on chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors and the mechanism underlying NKT improving the depressive-like behaviors.
Methods:
The CUMS-induced depression model was established in mice. Fifty mice were randomized into 5 groups (n=10) in accordance with a random number table: control group, CUMS group, CUMS + NKT (6 mg/kg) group, CUMS + NKT (12 mg/kg) group, and CUMS + ketamine group. From the 22th day, NKT (6 or 12 mg/kg) or ketamine (0.5 mg/kg) was given with intragastric administration every day for 21 days. Behavioral tests including forced swimming test (FST), tail suspension test (TST), sucrose preference test (SPT) and open-field test (OFT) were carried out. The mRNA and protein expressions of interleukin (IL)-1β, IL-18, IL-6, and tumor necrosis factor (TNF)-α in hippocampus were assessed using quantitative realtime polymerase chain reaction (PCR), Western blot analysis, and enzyme linked immunosorbent assay. The nuclear factor-κB (NF-κB)/NOD-like receptor 3 (NLRP3) inflammasome pathway was analyzed using Western blot and immunofluorescence analysis.
Results:
NKT treatment improved CUMS-induced depressive-like behaviors in mice (P<0.05 or P<0.01). NKT significantly decreased the mRNA and protein levels of IL-1β, IL-18, IL-6, and TNF-α in hippocampus of CUMS mice (P<0.05 or P<0.01). Furthermore, NKT repressed CUMS-induced activation of NF-κB signaling and NLRP3 inflammasome (P<0.01). More important, Nigericin, a NLRP3 activator, destroyed the effect of NKT on repressing neuroinflammation and improving depressive-like behaviors (P<0.05 or P<0.01).
Conclusion:
NKT ameliorates the depressive-like symptoms, in part by repressing NF-κB/NLRP3-mediated neuroinflammation.
Insights
Nootkatone (NKT) effectively treats depression-like behaviors in mice by reducing neuroinflammation. This natural compound targets the NF-κB/NLRP3 pathway, offering a potential therapeutic strategy for mood disorders.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Chronic unpredictable mild stress (CUMS) is a common model for inducing depression-like behaviors in rodents.
- Neuroinflammation, characterized by elevated pro-inflammatory cytokines and inflammasome activation, plays a crucial role in the pathophysiology of depression.
- Nootkatone (NKT), a natural compound found in grapefruit, has shown potential therapeutic effects, but its mechanism in depression remains unclear.
Purpose of the Study:
- To investigate the antidepressant-like effects of nootkatone (NKT) in a mouse model of chronic unpredictable mild stress (CUMS).
- To elucidate the underlying molecular mechanisms, focusing on the nuclear factor-κB (NF-κB)/NOD-like receptor 3 (NLRP3) inflammasome pathway and associated neuroinflammation.
Main Methods:
- Establishment of a CUMS-induced depression model in mice, with groups receiving NKT (6 or 12 mg/kg), ketamine, or serving as controls.
- Behavioral assessments including the forced swimming test (FST), tail suspension test (TST), sucrose preference test (SPT), and open-field test (OFT).
- Quantification of pro-inflammatory cytokine (IL-1β, IL-18, IL-6, TNF-α) mRNA and protein levels in the hippocampus via qRT-PCR, Western blot, and ELISA.
- Analysis of NF-κB/NLRP3 inflammasome pathway activation using Western blot and immunofluorescence.
Main Results:
- NKT treatment significantly ameliorated CUMS-induced depressive-like behaviors in mice.
- NKT administration markedly reduced the expression of IL-1β, IL-18, IL-6, and TNF-α in the hippocampus of CUMS mice.
- NKT effectively suppressed the activation of the NF-κB signaling pathway and the NLRP3 inflammasome, which was further confirmed by nigericin challenge experiments.
Conclusions:
- Nootkatone exerts antidepressant-like effects by mitigating CUMS-induced depressive behaviors in mice.
- The therapeutic mechanism of NKT involves the repression of NF-κB/NLRP3-mediated neuroinflammation.
- NKT demonstrates potential as a novel therapeutic agent for depression by targeting neuroinflammatory pathways.
