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

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.
Animals ; Brain ; Depression ; Gene Expression ; Humans ; Immunohistochemistry ; Inflammasomes ; Interleukin-6 ; Male ; Models, Animal ; Rats ; Real-Time Polymerase Chain Reaction ; Receptors, Purinergic P2 ; Receptors, Purinergic P2X7 ; Sucrose