PMID- 36878280 OWN - NLM STAT- MEDLINE DCOM- 20230331 LR - 20230331 IS - 1879-0631 (Electronic) IS - 0024-3205 (Linking) VI - 320 DP - 2023 May 1 TI - 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. PG - 121546 LID - S0024-3205(23)00180-7 [pii] LID - 10.1016/j.lfs.2023.121546 [doi] AB - 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-1beta, IL-18, IL-6 and TNF-alpha) along with diminution in GLP-1R, 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. CI - Copyright (c) 2023 Elsevier Inc. All rights reserved. FAU - Darwish, Amal B AU - Darwish AB AD - Dar EL-Salam Hospital, Ministry of Health, Cairo, Egypt. FAU - El Sayed, Nesrine S AU - El Sayed NS AD - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. FAU - Salama, Abeer A A AU - Salama AAA AD - Pharmacology Department, National Research Centre, 33 El-Buhouth Street, Dokki, Cairo 12622, Egypt. FAU - Saad, Muhammed A AU - Saad MA AD - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Department of Pharmaceutical Sciences, College of Pharmacy, Gulf Medical University, Ajman 4184, United Arab Emirates. Electronic address: mohammed.abdellatif@pharma.cu.edu.eg. LA - eng PT - Journal Article DEP - 20230304 PL - Netherlands TA - Life Sci JT - Life sciences JID - 0375521 RN - WTT295HSY5 (dulaglutide) RN - 0 (Hypoglycemic Agents) RN - 0 (Glucagon-Like Peptide-1 Receptor) SB - IM MH - Male MH - Mice MH - Animals MH - *Diabetes Mellitus, Type 2/drug therapy MH - Social Defeat MH - Mice, Inbred NOD MH - Mice, Inbred C57BL MH - Signal Transduction MH - Hypoglycemic Agents/pharmacology MH - Hippocampus/metabolism MH - Glucagon-Like Peptide-1 Receptor/metabolism OTO - NOTNLM OT - CSDS OT - Depression OT - Dulaglutide OT - GLP-1R OT - NLRP3 COIS- Declaration of competing interest The authors declare that there are no conflicts of interest. EDAT- 2023/03/07 06:00 MHDA- 2023/03/31 06:42 CRDT- 2023/03/06 19:22 PHST- 2022/12/24 00:00 [received] PHST- 2023/02/26 00:00 [revised] PHST- 2023/02/28 00:00 [accepted] PHST- 2023/03/31 06:42 [medline] PHST- 2023/03/07 06:00 [pubmed] PHST- 2023/03/06 19:22 [entrez] AID - S0024-3205(23)00180-7 [pii] AID - 10.1016/j.lfs.2023.121546 [doi] PST - ppublish SO - Life Sci. 2023 May 1;320:121546. doi: 10.1016/j.lfs.2023.121546. Epub 2023 Mar 4.