Chronic blockade of the purinergic 2X7 receptor produces antidepressant-like effects through inhibition of NLRP1 inflammasome in chronic unpredictable mild stress model of depression in rats
Feyza Aricioglu 1, Ceren Sahin Ozkartal 1, Tugce Bastaskin 1, Erdem Tuzun 2*, Cansu Kandemir 3, Serap Sirvanci 3, Cem İsmail Küçükali 2, Tijen Utkan 4
1Marmara University School of Pharmacy, Department of Pharmacology and Psychopharmacology Research Unit, Istanbul, Turkey, 2Istanbul University Aziz Sancar Institute of Experimental Medical Research, Neuroscience Department, Istanbul, Turkey, 3Marmara University School of Medicine, Department of Histology and Embryology, Istanbul, Turkey, 4Kocaeli University School of Medicine, Department of Pharmacology, Kocaeli, Turkey
Received: June 6, 2018; Revised: July 11, 2018; Accepted: July 23, 2018; Published online: July 23, 2018.
© The Korean College of Neuropsychopharmacology. All rights reserved.

Abstract
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 PCR 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-1ß, 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.
Keywords: depression, Brilliant Blue G, purinergic, P2X7, CUMS

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