There is growing evidence that neuroinflammation is closely linked to depression. Honokiol, a biologically active substance extracted from Magnolia officinalis, which is widely used in traditional Chinese medicine, has been shown to exert significant anti-inflammatory effects and improve depression-like behavior caused by inflammation. However, the specific mechanism of action of this activity is still unclear. In this study, the lipopolysaccharide (LPS) mouse model was used to study the effect of honokiol on depression-like behavior induced by LPS in mice and its potential mechanism. A single administration of LPS (1 mg/kg, intraperitoneal injection) increased the immobility time in the forced swimming test (FST) and tail suspension test (TST), without affecting autonomous activity. Pretreatment with honokiol (10 mg/kg, oral administration) for 11 consecutive days significantly improved the immobility time of depressed mice in the FST and TST experiments. Moreover, honokiol ameliorated LPS-induced NF-κB activation in the hippocampus and significantly reduced the levels of the pro-inflammatory cytokines; tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and interferon γ (IFN-γ). In addition, honokiol inhibited LPS-induced indoleamine 2,3-dioxygenase (IDO) activation and quinolinic acid (a toxic product) increase and reduced the level of free calcium in brain tissue, thereby inhibiting calcium overload. In summary, our results indicate that the anti-depressant-like effects of honokiol are mediated by its anti-inflammatory effects. Honokiol may inhibit the LPS-induced neuroinflammatory response through the NF-κB signaling pathway, reducing the levels of related pro-inflammatory cytokines, and furthermore, this may affect tryptophan metabolism and increase neuroprotective metabolites.

Background: There is growing evidence to suggest that ginsenoside Rd (GRd) has a therapeutic effect on depression, but the specific mechanisms behind its activity require further study. Objective: This study is designed to investigate the antidepressant-like effect and underlying mechanisms of GRd. Methods: In this study, the behavioral despair mouse model of depression and chronic unpredictable mild stress (CUMS) rat model of depression were established to explore the effects of GRd on depression-like behavior and its underlying mechanisms. Behavioral tests were used to evaluate the replication of animal models and depression-like behaviors. The hypoxia-inducible factor-1α (HIF-1α) blocker 2-methoxyestradiol (2-ME) was injected to determine the role of HIF-1α in the antidepressant-like effect of GRd. In addition, molecular biology techniques were used to determine the mRNA and protein expression of HIF-1ɑ signaling pathway and synaptic plasticity-related regulators, that is synapsin 1 (SYN 1) and postsynaptic density protein 95 (PSD 95). In silico binding interaction studies of GRd with focused target proteins were performed using molecular docking to predict the affinity and optimal binding mode between ligands and receptors. Results: Our data show that GRd significantly reversed depression-like behavior and promoted mRNA and protein expression of HIF-1ɑ signaling pathway and synaptic plasticity-related regulators. However, the antidepressant-like effect of GRd disappeared upon inhibition of HIF-1α expression following administration of 2-ME. Furthermore, molecular docking results showed that GRd possessed significant binding affinity for HIF-1α, VEGF, and VEGFR-2. Conclusion: Our results show that GRd exhibits significant antidepressant-like effect and that HIF-1α signaling pathway is a promising target for the treatment of depression.

The habenula has been implicated in the pathogenesis of pain and analgesia, while evidence concerning its function in chronic low back pain (cLBP) is sparse. This study aims to investigate the resting‐state functional connectivity (rsFC) and effective connectivity of the habenula in 52 patients with cLBP and 52 healthy controls (HCs) and assess the feasibility of distinguishing cLBP from HCs based on connectivity by machine learning methods. Our results indicated significantly enhanced rsFC of the habenula‐left superior frontal cortex (SFC), habenula‐right thalamus, and habenula‐bilateral insular pathways as well as decreased rsFC of the habenula‐pons pathway in cLBP patients compared to HCs. Dynamic causal modelling revealed significantly enhanced effective connectivity from the right thalamus to right habenula in cLBP patients compared with HCs. RsFC of the habenula‐SFC was positively correlated with pain intensities and Hamilton Depression scores in the cLBP group. RsFC of the habenula‐right insula was negatively correlated with pain duration in the cLBP group. Additionally, the combination of the rsFC of the habenula‐SFC, habenula‐thalamus, and habenula‐pons pathways could reliably distinguish cLBP patients from HCs with an accuracy of 75.9% by support vector machine, which was validated in an independent cohort (N = 68, accuracy = 68.8%, p = .001). Linear regression and random forest could also distinguish cLBP and HCs in the independent cohort (accuracy = 73.9 and 55.9%, respectively). Overall, these findings provide evidence that cLBP may be associated with abnormal rsFC and effective connectivity of the habenula, and highlight the promise of machine learning in chronic pain discrimination.

Previous studies have suggested abnormal morphology and function of the thalamus and cortex in KOA. However, it is not known whether the thalamocortical network is differentially affected in this disorder. In this study, we examined functional and effective connectivity between thalamus and the major divisions of the cortex in 27 healthy controls and 27 KOA participants using functional magnetic resonance imaging. We also explored the topological features of the whole brain based on graph theory analysis. The results suggested that patients with KOA had significantly reduced resting-state functional connectivity (rsFC) of the thalamo-sensorimotor pathway, enhanced rsFC of the thalamo-medial/lateral frontal cortex (mFC/LFC), parietal, lateral temporal and occipital pathways, decreased effective connectivity of the left sensorimotor-to-thalamus pathway and enhanced effective connectivity of the right thalamus-to-sensorimotor pathway as compared with of healthy controls. The functional connectivity of the thalamo-sensorimotor and thalamo-mFC pathways was enhanced when performing multi-source interference task. Moreover, patients with KOA showed changed nodal properties associated with thalamo-cortical circuits including the medial and dorsal superior/middle frontal gyrus, inferior parietal gyrus, left thalamus, etc. as compared with healthy controls. Correlation analysis suggested significant negative correlation between thalamo-mFC’s rsFC and pain intensity, between thalamo-sensorimotor task-related connectivity and disease duration/depression scores, as well as positive correlation between right frontal nodal properties and pain intensity in KOA. Taken together, these findings establish abnormal and differential alterations of the thalamocortical network associated with pain characteristics in KOA, which extends our understanding of its’ role in the pathophysiology of KOA.