Dulaglutide impedes depressive-like behavior persuaded by chronic social defeat stress model in male C57BL/6 mice: Implications on GLP-1R and cAMP/PKA signaling pathway in the hippocampus

Aim: There is a well-founded relation between bullying and depression, which may eventually lead to suicidal behavior. Repurposing of antidiabetic drugs for the treatment of depression started to glow, which open new horizons to introduce the antidiabetic medications as new treatment picks in depression. Dulaglutide has been approved as remedy of type 2 diabetes mellitus (T2DM). Consequently, our scope of work is to investigate the ability of dulaglutide to indulgence depression via deeply reconnoitering the Glucagon-like peptide-1 receptor and cAMP/PKA Signaling Pathway.Materials and methods: Eighty mice were divided into two groups; one with and the other without the induction of chronic social defeat stress (CSDS). Each group was subdivided into two subsets; the first one was treated with saline for 42 days, while the other was treated with saline for 20 days, then with dulaglutide (0.6 mg/kg/week) for four weeks.Key findings: CSDS group showed a lessening in the social interaction ratio and sucrose consumption. They spent less exploration time in the open arms, and more time in the closed arms in elevated plus maze test as compared to controls. Furthermore, the CSDS group had a higher expression of NOD- like receptor protein-3 which explained the elevation in inflammatory biomarkers (IL-1 beta, IL-18, IL-6 and TNF-alpha) along with diminution in GLP1R, cAMP/PKA levels. Treatment with dulaglutide markedly reversed the above-mentioned parameters via bolstering the GLP-1R/cAMP/PKA pathway.Significance: NLRP3 inflammasome activation expedites depression. Dulaglutide activates the GLP-1R/cAMP/ PKA pathway, hence offering a novel therapeutic intervention to hinder depression.