Abstract
Objective Central inflammation is generally accepted to be involved in the pathology of depression. We investigated whether liquiritin exerts antidepressant effects by inhibiting central NLRP3 inflammasomes. Results The behavioral despair model and chronic unpredictable mild stress (CUMS) model in mice were established to evaluate the antidepressant action of liquiritin. In the despair model study, liquiritin (40 mg/kg) administration reduced immobility time in tail suspension test (TST) and forced swimming test (FST) without affecting locomotion activity. In CUMS model study, liquiritin (40 mg/kg, once daily for 4 weeks) significantly increased sucrose consumption and body weight of CUMS mice. The behavioral experiment results showed that liquiritin reduced the immobile time of CUMS mice in TST and FST, respectively, and increased the time spent and open arm entries in the elevated plus-maze (EPM) test. Further, the hippocampal superoxide dismutase (SOD) activity was increased in liquiritin-treated group, while malonaldehyde (MDA) decreased. Additionally, the hippocampal cytokines interleukin-18 (IL-18) and interleukin-1 beta (IL-1β) contents were reduced in the liquiritin-treated group. Further, liquiritin downregulated the expression of NLRP3 in the hippocampus of CUMS mice rather than TLR4. Besides, NLRP3 inflammasome-associated proteins caspase-1 and ASC were also downregulated. However, liquiritin did not alter the thermal stability of NLRP3 in the cellular thermal shift assay (CETSA), suggesting that its inhibition of NLPR3 was not by direct targeting of NLRP3 protein. Conclusions Liquiritin attenuates depression-like behavior of CUMS mice and inhibited cytokines levels triggered by NLRP3 inflammasome, suggesting the antidepressant action is, at least partially, associated with antioxidant stress and inhibition of NLRP3 inflammasome activation.
Highlights
Accumulating evidence suggests that mitigation of neuroinflammation could be a potential therapeutic approach for depression [1]
We mainly found that chronic administration of liquiritin improved depression-like behavior of chronic unpredictable mild stress (CUMS) mice and inhibited inflammasome activation and downstream inflammatory cytokines levels in the hippocampus
As the thermal stability of NLRP3 protein was not altered by liquiritin, liquiritin might inhibit NLRP3 inflammasome activation by acting indirectly through a potential target
Summary
Accumulating evidence suggests that mitigation of neuroinflammation could be a potential therapeutic approach for depression [1]. Clinical studies have shown that inflammatory cytokines in the central nervous system are significantly elevated, such as IL-1β and IL-6, in patients with depression. Recent studies consider that inhibition of NLRP3 inflammasome activation may be a promising strategy for the therapy of depression [2]. E neuroprotective activity of liquiritin has attracted considerable attention. Studies have shown that liquiritin could resist the death of cortical neurons induced by glutamate and promote the axon growth of PC12 cells triggered by nerve growth factor [6, 7]. An early study reported that liquiritin showed antidepressant effect via enhancement of 5-hydroxytryptamine and norepinephrine levels in the hippocampus, hypothalamus, and cortex [8].
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