Assessment of the 3-substituted thietane-1,1-dioxide derivative antidepressant effect using rat model of depression induced by reserpine

Introduction: 3-ethoxythietane-1,1-dioxide (3ETD) is a novel molecule that has demonstrated significant antidepressant properties when administered intraperitoneally (i.p.) to mice once or repeatedly. The aim of the study was to evaluate the antidepressant effect of 3ETD in a model of depressive-like state in rats induced by seven-fold administration of reserpine. Materials and Methods: We conducted two sets of experiments in white outbred male rats. In Experiment 1, reserpine(0.5 mg/kg) was administered intraperitoneally daily from Day 0 to Day +6; 3ETD (2 mg/kg) and the reference drug amitriptyline (10 mg/kg) were administered i.p. daily from Day 0 to Day +11. The sucrose intake and preference (Days 0, +6, +12), the coat state (Days 0, +6, +12), the behavior of the rats in the forced swimming test (FST, +12 day), the open field test (OF, Day +13) and the elevated plus maze test (EPM, Day +13), as well as the body weight (daily) were assessed. On Day +13, the animals were sacrificed and the weight coefficients of their internal organs (liver, spleen, thymus, adrenal glands) were measured and serum chemistry was performed. Brain-derived neurotrophic factor (BDNF) level in the hippocampus was quantified by enzyme-linked immunosorbent assay (ELISA). In Experiment 2, reserpine, amitriptyline, and 3 ETD were administered similarly to Experiment 1, and on Day +13, rats were euthanized and brain samples were collected for immunohistochemical determination of glial fibrillary acidic protein (GFAP) and anti-apoptotic B-cell lymphoma-2 protein (Bcl-2) in the hippocampus. Results and Discussion: Seven-fold administration of reserpine significantly increased immobility time (IT) in FST, caused anhedonia and coat state deterioration, decreased motor activity in OF and EPM, decreased body weight, increased the adrenal glands and spleen weight coefficients, increased GFAP level and decreased Bcl-2 level in the hippocampus. 3ETD (2 mg/kg) significantly reduced IT FST by 39%, increased sucrose preference to the level of the control group and sucrose consumption by 137%, eliminated self-care deficit, prevented weight loss in rats by the end of the experiment (Experiment 1); significantly reduced GFAP level (CA1-CA4, dentate gyrus) and increased Bcl-2 level (CA1, dentate gyrus) in the hippocampus compared with the reserpine group (Experiment 2). Conclusion: 3ETD eliminated depressive-like symptoms in rats induced by seven-fold administration of reserpine.