Effect modification of tumor necrosis factor-α on the kynurenine and serotonin pathways in major depressive disorder on type 2 diabetes mellitus.

Major depressive disorder (MDD) is strongly associated with type 2 diabetes mellitus (T2DM). The kynurenine and serotonin pathways, as well as chronic low-grade inflammation, are being considered potential links between them. MDD associated with T2DM is less responsive to treatment than that without T2DM; however, the underlying mechanism remains unknown. We aimed to investigate the effects of inflammatory cytokines on the kynurenine and serotonin pathways in patients with comorbid MDD and T2DM and those with only MDD. We recruited 13 patients with comorbid MDD and T2DM and 27 patients with only MDD. We measured interleukin-6 and tumor necrosis factor-α (TNF-α) levels as inflammatory cytokines and metabolites of the kynurenine pathway and examined the relationship between the two. TNF-α levels were significantly higher in patients with comorbid MDD and T2DM than in those with only MDD in univariate (p = 0.044) and multivariate (adjusted p = 0.036) analyses. TNF-α showed a statistically significant effect modification (interaction) with quinolinic acid/tryptophan and serotonin in patients from both groups (ß = 1.029, adjusted p < 0.001; ß = - 1.444, adjusted p = 0.047, respectively). Limitations attributed to the study design and number of samples may be present. All patients were Japanese with mild to moderate MDD; therefore, the generalizability of our findings may be limited. MDD with T2DM has more inflammatory depression components and activations of the kynurenine pathway by inflammatory cytokines than MDD without T2DM. Hence, administering antidepressants and anti-inflammatory drugs in combination may be more effective in patients with comorbid MDD and T2DM.

Risk Factors in Japanese Drug Overdose Patients: Identifying Their Associations With Suicide Risk.

Several suicide attempts presented at the emergency department are due to drug overdose associated with psychiatric disorders. We examined and identified the major risk factors among Japanese drug overdose patients and several close associations of suicide risk. We enrolled 101 patients who attempted suicide by drug overdose between January 2015 and April 2018, assessed their background using the SAD PERSONS scale, and performed association rule analysis to characterize the major risk factors and their associations. We identified three main nodes-depressive state, social support lacking, and no spouse-as considerable risk factors. Furthermore, we identified several close associations of suicide risk and their intensity; in cases with previous suicide attempts and ethanol abuse or substance use, a simultaneous social support lacking is likely. These findings align with previous studies that used conventional statistical analysis on suicide and suicide attempt risk and highlight its importance.

Ketamine Induces Lasting Antidepressant Effects by Modulating the NMDAR/CaMKII-Mediated Synaptic Plasticity of the Hippocampal Dentate Gyrus in Depressive Stroke Model.

Background: Ketamine has been shown to possess lasting antidepressant properties. However, studies of the mechanisms involved in its effects on poststroke depression are nonexistent. Methods: To investigate these mechanisms, Sprague-Dawley rats were treated with a single local dose of ketamine after middle cerebral artery occlusion and chronic unpredicted mild stress. The effects on the hippocampal dentate gyrus were analyzed through assessment of the N-methyl-D-aspartate receptor/calcium/calmodulin-dependent protein kinase II (NMDAR/CaMKII) pathway, synaptic plasticity, and behavioral tests. Results: Ketamine administration rapidly exerted significant and lasting improvements of depressive symptoms. The biochemical analysis showed rapid, selective upregulation and downregulation of the NMDAR2-ß and NMDAR2-α subtypes as well as their downstream signaling proteins ß-CaMKII and α-phosphorylation in the dentate gyrus, respectively. Furthermore, the colocalization analysis indicated a significant and selectively increased conjunction of ß-CaMKII and postsynaptic density protein 95 (PSD95) coupled with a notable decrease in NMDAR2-ß association with PSD95 after ketamine treatment. These changes translated into significant and extended synaptic plasticity in the dentate gyrus. Conclusions: These findings not only suggest that ketamine represents a viable candidate for the treatment of poststroke depression but also that ketamine's lasting antidepressant effects might be achieved through modulation of NMDAR/CaMKII-induced synaptic plasticity in key brain regions.

Chronic Unexpected Mild Stress Destroys Synaptic Plasticity of Neurons through a Glutamate Transporter, GLT-1, of Astrocytes in the Ischemic Stroke Rat.

Background and Objective: Chronic unexpected mild stress (CUMS) destroys synaptic plasticity of hippocampal regenerated neurons that may be involved in the occurrence of poststroke depression. Astrocytes uptake glutamate at the synapse and provide metabolic support for neighboring neurons. Currently, we aim to investigate whether CUMS inhibits synaptic formation of regenerated neurons through a glutamate transporter, GLT-1, of astrocytes in the ischemic stroke rats. Method: We exposed the ischemic stroke rats to ceftriaxone, during the CUMS intervention period to determine the effects of GLT-1 on glutamate circulation by immunofluorescence and mass spectrometry and its influences to synaptic plasticity by western blot and transmission electron microscopy. Result: CUMS evidently reduced the level of astroglial GLT-1 in the hippocampus of the ischemic rats (p < 0.05), resulting in smaller amount of glutamate being transported into astrocytes surrounding synapses (p < 0.05), and then expression of synaptophysin was suppressed (p < 0.05) in hippocampal dentate gyrus. The ultrastructures of synapses in dentate gyrus were adversely influenced including decreased proportion of smile synapses, shortened thickness of postsynaptic density, reduced number of vesicles, and widened average distance of the synaptic cleft (all p < 0.05). Moreover, ceftriaxone can promote glutamate circulation and synaptic plasticity (all p < 0.05) by raising astroglial GLT-1 (p < 0.05) and then improve depressive behaviors of the CUMS-induced model rats (p < 0.05). Conclusion: Our study shows that CUMS destroys synaptic plasticity of regenerated neurons in the hippocampus through a glutamate transporter, GLT-1, of astrocytes in the ischemic stroke rats. This may indicate one potential pathogenesis of poststroke depression.

Volumetric assessment of individual thalamic nuclei in patients with drug-naïve, first-episode major depressive disorder.

Introduction: Despite the previous inconsistent findings of structural and functional abnormalities of the thalamus in patients with major depressive disorder (MDD), the disruption of the thalamic nuclei in the pathophysiology of this disorder has not yet been adequately studied. Therefore, we investigated the volumetric changes of thalamic subregions and their nuclei in drug-naïve, first-episode MDD patients. We also investigated the association between HAM-D scores, a clinical scale frequently used to evaluate the severity of depression and thalamic nuclei volumes in MDD patients. Methods: This study included 76 drug-naïve MDD patients and an equal number of healthy subjects. Magnetic resonance imaging (MRI) data were obtained using a 3T MR system and thalamic nuclei volumes were evaluated using FreeSurfer ver.7.11. The volumetric differences were compared by one-way analysis of covariance (ANCOVA) and to ensure that effects were not accounted for by other factors, age, sex, and ETICV variables were included as covariates. Results: We observed significant volume reductions of the left whole thalamus (p < 0.003) and several thalamic nuclei mostly on the left side in the MDD group compared with healthy controls (HCs). Furthermore, we have revealed weak negative correlations between several thalamic nuclei volumes and HAM-D total and subscale scores. Discussion: This is the first research study to investigate alterations of the various thalamic nuclei volumes in MDD patients compared with HCs. Moreover, we first analyzed the association between individual thalamic nuclei volumes and HAM-D subscale scores. Though our study may be restricted at certain levels, especially by the demographic difference between the two groups, they possibly contribute at a preliminary level to understanding the thalamic structural changes at its subregions in patients with drug-naïve, first-episode MDD.

Association between salivary mature brain-derived neurotrophic factor and psychological distress in healthcare workers.

INTRODUCTION: Previous studies have suggested association between brain-derived neurotrophic factor (BDNF) and the stress level of workers. However, no studies have investigated the potential of salivary mature BDNF (mBDNF) level as a noninvasive biomarker for psychological distress. This study aimed to explore the reliability of salivary mBDNF as a biomarker for psychological distress in healthcare workers. Furthermore, we examined the relationship between salivary and plasma mBDNF levels and their correlation with age, sex, body mass index (BMI), and exercise habits. METHODS: Fifty-one healthy healthcare workers (26 men) from the University of Occupational and Environmental Health, Japan, participated in this study. In this cross-sectional study, participants provided demographic information. Psychological distress was assessed using the Kessler 6 (K6). Saliva and blood samples were collected, and mBDNF was measured by ELISA. Spearman's rank correlation coefficient was performed to analyze the relationship between mBDNF (saliva and plasma) and K6. Statistical analyses were conducted using Stata 17.0, and a significance level of p < .05 was applied. RESULTS: The median K6 score was 1 (interquartile range [IQR]: 0-3). The median (IQR) salivary mBDNF was 1.36 (1.12-1.96) pg/mL, whereas the mean (standard deviation) plasma mBDNF was 1261.11 (242.98) pg/mL. No correlation was observed between salivary and plasma mBDNF concentrations or with the K6 score. Additionally, there were no associations between salivary or plasma mBDNF concentrations and age, sex, or exercise habits. Finally, an association between plasma mBDNF concentration and BMI was found only in univariate analysis. CONCLUSION: Our findings indicate that salivary mBDNF can be accurately measured noninvasively in healthcare workers. Within our study sample, salivary mBDNF did not demonstrate any correlation with K6 and plasma mBDNF. Future studies with a larger study sample and a diverse study population consisting of healthy participants and patients with psychiatric disorders are warranted.

Gyrification patterns in first-episode, drug-naïve major depression: Associations with plasma levels of brain-derived neurotrophic factor and psychiatric symptoms.

Background and objectives: Cortical structural changes in major depressive disorder (MDD) are usually studied using a voxel-based morphometry approach to delineate the cortical gray matter volume. Among cortical structures, gyrification patterns are considered a relatively stable indicator. In this study, we investigated differences in gyrification patterns between MDD patients and healthy controls (HCs) and explored the association of gyrification patterns with plasma brain-derived neurotrophic factor (BDNF) levels and depressive symptoms in MDD patients. Methods: We evaluated 79 MDD patients and 94 HCs and assessed depression severity in the patients using the 17-item Hamilton Depression Rating Scale (HAM-D). Blood samples of both groups were collected to measure plasma BDNF levels. Magnetic resonance imaging (MRI) data were obtained using three-dimensional fast-spoiled gradient-recalled acquisition. Differences in plasma BDNF levels between groups were examined using the Mann-Whitney U test. Principal component analysis and orthogonal partial least squares discriminant analysis (OPLS-DA) were conducted to investigate the gyrification patterns which were significantly different between the groups, i.e., those with variable importance in projection (VIP) scores of >1.5 and p-value < 0.05 in multiple regression analyses adjusted for age and sex. Finally, multiple regression analysis was performed on the selected gyrification patterns to examine their association with BDNF levels in the two groups and HAM-D in the patients. Results: There were no significant differences in plasma BDNF levels between the groups. We found that 108 (71.0%) of 152 total local gyrification indices were MDD < HC. We identified 10 disease-differentiating factors based on critical gyrification features (VIP > 1.5 and p-value adjusted for age and sex < 0.05). However, we found no significant correlations between the 10 gyrification patterns and plasma BDNF levels and no interaction with group. Moreover, no significant correlations were observed between the local gyrification indices and HAM-D total scores. Conclusion: These results suggest that abnormal early cortical neurodevelopment may mediate vulnerability to MDD, independent of plasma BDNF levels and depressive symptoms.

Melatonin Ameliorates Lipopolysaccharide-Induced Microglial Inflammation via Triggering SIRT1/HMGB1 Signaling Axis.

Stroke is one of the highest incidence neurological disorder with great morbidity and mortality rate. The secondary neuroinflammation contributed by microglial activation is a consequential response observed in the pathogenesis of stroke. High-mobility group box 1, a non-histone nuclear protein, interacts with immune cells, such as microglia, and leads to a cascade amplification of the secondary neuroinflammatory responses, which are related to neuronal damage later. Melatonin is a neurohormone, well-known as its anti-oxidative and anti-inflammatory effects. However, until now, more findings are required for better understanding about anti-inflammatory effect of melatonin on HMGB1 and HMGB1-triggered pathway in LPS-induced microglial activation. Melatonin effect on the viability of BV2 microglial cells was measured by CCK-8 assay; mRNA levels of HMGB1 and other inflammatory cytokines were determined by quantitative real-time polymerase chain reaction assay or enzyme-linked immunosorbent assays; the protein expression levels of TLR4/MyD88/NF-κB and SIRT1 were detected by Western blot, and HMGB1 translocation and release from BV2 microglial cells were examined by immunofluorescence assay. The results of this study demonstrated that melatonin suppressed LPS-triggered BV2 microglial activation-mediated inflammation by inhibiting high expression and release of HMGB1 and moderating the activation of subsequent TLR4/MyD88/NF-κB signaling pathway, which was activated by SIRT1 elevation. Furthermore, LPS-induced expression of pro-inflammatory cytokines (i.e., TNF-α, IL-6, and IL-1ß) was notably reversed by melatonin pre-treatment. In summary, our findings suggest that melatonin may act as a promising therapeutic agent for reducing post-stroke neuroinflammation by targeting HMGB1 and the subsequent signaling axis.

Alarmin HMGB1 Plays a Detrimental Role in Hippocampal Dysfunction Caused by Hypoxia-Ischemia Insult in Neonatal Mice: Evidence from the Application of the HMGB1 Inhibitor Glycyrrhizin.

Hippocampal dysfunction related to cognitive impairment and emotional disorders in young children and adolescents caused by neonatal hypoxic-ischemic brain injury (HIBI) has attracted increasing attention in recent years. Crosstalk between the nervous and immune systems organized by hypoxia-ischemia (HI) insult may contribute to hippocampal dysfunction after HIBI. Extracellular HMGB1 functions as a damage-associated molecular pattern to instigate and amplify inflammatory responses, but whether this molecule is correlated with hippocampal dysfunction after HIBI is largely unknown. Therefore, this study examined hippocampal function after HMGB1 inhibition in an experimental HIBI model to verify the hypothesis that HMGB1 is a key mediator of hippocampal neuropathology in neonatal HIBI. By administering different doses of the HMGB1-specific inhibitor glycyrrhizin (GLY), we first found that GLY reversed the HI insult-induced loss of neurons and myelin in the hippocampal region and neurobehavioral impairments, partially in a dose-dependent manner, and based on this, we determined the optimal drug concentration to be 50 mg/kg. Subsequent analysis found that this neuroprotective effect was achieved through the inhibition of HMGB1 expression and nucleocytoplasmic translocation, a reduction in the abnormal expression of proteins associated with the downstream signaling pathway of HMGB1, a decrease in the inflammatory response, the suppression of increases in microglia/astrocytes, and the inhibition of hippocampal cell apoptosis. Collectively, our discoveries contribute to the rising appreciation of the role of HMGB1 in the neuropathology of hippocampal dysfunction and related behavioral outcomes following HIBI.

Down-expressed GLT-1 in PSD astrocytes inhibits synaptic formation of NSC-derived neurons in vitro.

Little is known about the effect of astroglial GLT-1 of post-stroke depression (PSD) rat model on the function of neural stem cells (NSCs). This study aimed to investigate whether astroglial GLT-1 of PSD rats affect differentiation of NSCs from neonatal rat hippocampus and synaptic formation of NSC-derived neurons. Astrocytes were isolated from the left hippocampus of normal adult SD rats and PSD rats. A lentiviral vector was used to silence the expression of GLT-1 in astrocytes of PSD rats. NSCs were respectively co-cultured with normal (control), PSD, and GLT-1 silenced astrocytes for 7 days. GLT-1, GFAP, MAP2, Synaptophysin (SYN), glutamate (Glu) and glutamine (Gln) were respectively measured by qRT-PCR, western blot, immunofluorescence and efficient mass spectrometry (MS). PSD astrocytes increased the number of NSC-derived astrocytes, but inhibited the expression of GLT-1 of NSC-derived astrocytes and synapses of NSC-derived neurons. On the basis of the low expression of GLT-1 in PSD astrocytes, we further silenced GLT-1 in PSD astrocytes. Interestingly, GLT-1 silenced PSD astrocytes more obviously inhibited synapses of NSC-derived neurons, but increased the number of NSC-derived neurons and reversed the expression of GLT-1 in NSC-derived astrocytes. At the same time, concentration of glutamate in the medium elevated, and glutamine in the medium gradually reduced. In NSC-derived neurons and astrocytes, glutamate metabolism was also affected by changed GLT-1. Down-expressed GLT-1 in PSD astrocytes stimulated NSCs differentiating into astrocytes, but inhibiting the formation of functional synapses by influencing glutamate metabolism in vitro.