NLRP1-Mediated Antidepressant Effect of Ketamine in ChronicUnpredictable Mild Stress Model in Rats

Objective@#NOD-like receptor protein 1 (NLRP1) inflammasome complex has been recently associated with chronic unpredictablemild stress (CUMS) model of depression. Our aim was to investigate whether ketamine-induced antidepressant effect is associated withsuppression of NLRP1. @*Methods@#Wistar albino rats were divided into control, CUMS, CUMS+acute ketamine (a single 10 mg/kg dose) and CUMS+chronicketamine (daily 10 mg/kg injections for 3 weeks) groups (n=10 for each group). Sucrose preference test and forced swimming test wereperformed to assess anhedonia and immobility time respectively for the severety of depression symptoms. Brain tissues were dissectedand prefrontal cortex and hippocampus regions were used for real-time polymerase chain reaction (PCR) and immunohistochemicalanalysis. @*Results@#CUMS procedure significantly induced depressive-like symptoms whereas both acute and chronic ketamine treatment amelioratedthem. mRNA expression levels of NLRP1, caspase 1, apoptosis-associated speck-like protein containing a CARD (ASC), NF-κB,endothelial nitric oxide synthase, IL-1β, IL-6, toll-like receptor 4 (TLR-4) and purinergic 2×7 receptor (P2X7R) and numbers of Iba-1+and GFAP+glial cells were reduced by acute and/or chronic ketamine treatment. @*Conclusion@#In the present study for the first time upstream and downstream elements of the NLRP1 inflammasome complex are shownto be suppressed by ketamine thus reinforcing the involvement of NLRP1 in the physiopathology of depression.Psychiatry Investig 2020;17(4):283-291

Antidepressant-like Effects Induced by Chronic Blockade of the Purinergic 2X7 Receptor through Inhibition of Non-like Receptor Protein 1 Inflammasome in Chronic Unpredictable Mild Stress Model of Depression in Rats

OBJECTIVE: Purinergic 2X7 receptor (P2X7R) activation is known to be involved in pathogenesis of depression. Our aims were to investigate P2X7R-activated inflammasome pathways in parallel with induction of depression and to test the antidepressant-like effects of the selective P2X7R antagonist Brilliant Blue G (BBG) in a rat model of chronic unpredictable mild stress (CUMS). METHODS: Male Wistar albino rats were divided into control, CUMS, CUMS+BBG25 (25 mg/kg/day) and CUMS+BBG50 (50 mg/kg/day) groups (n=10 for each group). Various stressors were applied to rats for 6 weeks to establish the CUMS model and daily BBG treatment was started at the end of 3rd week. Sucrose preference test and forced swim test (FST) were performed to assess antidepressant-like effects. Brain samples were obtained for real-time polymerase chain reaction and immunohistochemistry analysis. RESULTS: In FST, duration of immobility was reduced in the CUMS+BBG50 group. Also, BBG treatment significantly enhanced sucrose preference. While NLRP3 gene expression levels were unchanged in rats exposed to the CUMS protocol, expression levels of other inflammasome pathway factors NLRP1, caspase-1, ASC, NF-κB, IL-1β, IL-6 and P2X7R were increased. BBG treatment reduced expression levels of these factors. Likewise, Iba-1 and GFAP immunoreactivities were enhanced by the CUMS protocol and this action was reversed by BBG treatment. CONCLUSION: Chronic administration of BBG in CUMS model results in antidepressant-like activity in a dose dependent manner. Molecular and histological results show that these effects might be at least partially related to the suppression of inflammasome-related neuroinflammatory responses and suggest involvement of NLRP1 in depression.

Chemokine and Chemokine Receptor Polymorphisms in Bipolar Disorder

OBJECTIVE: Bipolar disorder (BD) is a debilitating psychiatric disease with unknown etiology. Recent studies have shown inflammation as a potential contributing factor of BD pathogenesis. However, potential associations between chemokine and chemokine receptor polymorphisms and BD have been fundamentally understudied. To identify participation of chemokines in BD pathogenesis, we examined genetic variants of several chemokine and chemokine receptor genes. METHODS: The study population comprised 200 patients with BD and 195 age- and sex-matched healthy controls. Genotyping of monocyte chemotactic protein 1 (MCP-1) A2518G, CCR2 V64I, CCR5 Δ32, CCR5 A55029G, stromal cell-derived factor 1 (SDF-1) 3'A, and CXCR4 C138T polymorphisms was performed using polymerase chain reaction and restriction enzyme digestion. RESULTS: We found that CCR5-Δ32 II and CXCR4-C138T C+ genotype frequencies contributed to an increased risk for BD. However, no statistical significance could be obtained with these genotypes after Bonferroni correction. A significant asssociation was only found with MCP-1 GG and G+ genotypes, which were markedly more prevalent in patients with BD and these genotypes seemed to significantly increase the risk for BD even after Bonferroni correction. CONCLUSION: Our findings indicate an association between genetic variants of certain chemokine and chemokine receptor (especially MCP-1) genes and BD. The exact mechanisms by which these variants contribute to BD pathogenesis and their clinical implications need to be further investigated.

Switch-associated protein 70 antibodies in multiple sclerosis: possible association with disease progression

This study was conducted to identify a biomarker for multiple sclerosis [MS] that can be used as a predictor of relapse and disability. Sera of 26 consecutive relapsing-remitting MS [RRMS] patients were screened for switch-associated protein 70 [SWAP-70] antibody, which was previously identified by protein macroarray. The serum levels of several cytokines, chemokines and soluble adhesion molecules related to MS attacks were measured by enzyme-linked immunosorbent assay [ELISA]. A possible correlation was sought among levels of SWAP-70 antibody, measured humoral factors and disability scores. ELISA studies showed high-titre SWAP-70 antibodies in 16 [61.5%] RRMS sera obtained during the attack period and 9 [34.6%] sera obtained during remission. There was a significant inverse correlation between SWAP-70 antibody levels and expanded disability status scale scores, CXCL10, soluble VCAM-1, CXCL13 and soluble VLA-4 levels. Our results showed that SWAP-70 antibodies could potentially be utilized as relapse and prognostic biomarkers in MS. Whether or not SWAP-70 antibodies have any effect on disease mechanisms requires further investigation

Increased complement consumption in musk-antibody-positive myasthenia gravis patients

To investigate the activation of different complement pathways in myasthenia gravis [MG] subtypes. Levels of complement breakdown products for different complement pathways were measured using ELISA in sera of acetylcholine receptor antibody [AChR-Ab]-positive [n = 21], muscle-specific receptor tyrosine kinase [MuSK]-Ab-positive [n = 23] and seronegative generalized MG patients [n = 21] and healthy controls [n = 22]. Levels of factor Bb [FBb], the breakdown product of factor B, and C4d, the breakdown product of C4, were measured to evaluate the activity of the alternative and classical complement pathways, respectively. Serum iC3b levels were analyzed to assess total complement activity. The results were expressed as OD values. MuSK-Ab-positive MG patients had a significantly higher mean concentration of serum FBb [0.638] than other MG subtypes [0.446 for AChR-Ab-positive, 0.537 for seronegative MG patients] and healthy controls [0.434] [p = 0.045]. Mean serum iC3b [1.549-1.780] and C4d [0.364-0.395] levels were comparable among the groups. Our results suggest that MuSK-Ab-positive MG patients might have a complement-activating serum factor and the alternative complement pathway might be involved in the pathogenesis of the disease