Potential antidepressant properties of aminophylline in male mice exposed to chronic restraint stress

BACKGROUND: Aminophylline, a bronchodilator used for treating airway obstruction, has been predicted through in silico models to exert antidepressant effects. However, there are still no studies that have validated these claims in a biological system. In this paper, we evaluated the antidepressant effects of aminophylline in mice subjected to chronic restraint stress (CRS). METHODS: CRS was conducted for a duration of 15 days, with 4-hour daily stress exposure. Aminophylline (5 mg/kg, 10 mg/kg, and 20 mg/kg) and fluoxetine (10 mg/kg, positive control) were administered daily via intraperitoneal injection. Behavioral assessments, including the tail suspension test (TST), forced swimming test (FST), and sucrose splash test (SST), were conducted on days 0, 5, 10, and 15. Molecular docking and pathway analyses were performed to provide insight into its possible mechanism of action. RESULTS: CRS exposure successfully induced depressive-like behavior, characterized by prolonged immobility in the TST and FST and diminished grooming activity in the SST. Administration of aminophylline attenuated these behavioral deficits, reducing immobility time and increasing grooming time in a dose-dependent manner. Molecular docking analysis demonstrated favorable binding of aminophylline to phosphodiesterase 3, phosphodiesterase 4, and the serotonin transporter, targets associated with antidepressant activity. Pathway analysis revealed upregulation of PPAR signaling, calcium signaling, and the synaptic vesicle cycle, while downregulating the glutamatergic synapse pathway. CONCLUSION: The study provides the first evidence of the antidepressant activity of aminophylline in a validated model of depression, prompting further clinical investigation into its therapeutic potential. Moreover, molecular and biochemical analyses are warranted to validate its precise mechanism of action.