Empagliflozin mitigates depression-like behavior in diabetic mice via putative CRF₁ receptor modulation: behavioral,...

Diabetes is one of the main cause and major risk factor for the development of neurodegenerative and neuropsychiatric disorders, including depression, with rising prevalence and increasing co-morbidities worldwide. However, the relationship between diabetes and depression in animal models has not been thoroughly investigated. The present study aimed to investigate the antidepressant potential of empagliflozin (EMPA) in diabetic mice subjected to a chronic unpredictable mild stress (CUMS) model, focusing on its interaction with the corticotropin-releasing factor 1 receptor (CRF₁). Initially, diabetes was induced in animals by injection of streptozotocin (STZ) at low dose (35 mg/kg, i.p.), followed by CUMS to provoke depression-like state (1-20 days). EMPA at doses of 5 and 10 mg/kg was administered orally as the test compound, while metformin (MET; 200 mg/kg) and clomipramine (CLMP, 10 mg/kg) alone and in combination (MET + CLMP) were used as standard treatments. All treatments were given once daily for 14 consecutive days (21-35 days). Behavioral assessments were carried out from days 36 to 41, using several paradigms like splash tests, sucrose preference test, open field test, tail suspension test, and forced swim test, respectively. EMPA, particularly at 10 mg/kg, significantly improved behavioral outcomes, indicated by increased distance traveled, higher open-arm entries, reduced immobility time, and shorter grooming latency. Biochemically, EMPA restored antioxidant levels (glutathione and catalase), reduced lipid peroxidation in the brain, and decreased blood corticosterone (CORT) levels. In silico molecular docking and MD-simulation analysis revealed strong binding affinity and interactions between EMPA and CRF₁. This proposes that the potential of EMPA to regulate CUMS-induced aggravated depression in diabetic animals may be mediated through CRF₁ modulation. These results suggested that EMPA has potential as a therapeutic agent for depression, especially in diabetic conditions linked to oxidative stress, likely through the CRF₁-receptor.