Protective effects of phosphodiesterase-5 inhibitor (Tadalafil) in stress-induced anxiety, depression and gastric ulceration in rats

Objectives: Prolonged stress is known to precipitate neuropsychiatric and gastrointestinal disorders through disruption of the hypothalamic-pituitary-adrenal (HPA) axis, activation of neuroinflammatory pathways and oxidative damage to the gastric mucosa. Phosphodiesterase-5 (PDE5) inhibitors, including tadalafil, facilitate cyclic guanosine monophosphate-dependent vasodilation, enhance neuroplastic mechanisms and exert anti-inflammatory effects. The role of PDE5 inhibitors in stress modulation and gastric ulceration is not well understood. Therefore, the present study assessed the potential anxiolytic, antidepressant-like effect and gastroprotective actions of tadalafil in restraint stress (RS)-induced changes. Materials and Methods: Forty-eight adult Wistar rats (either sex) were randomised into eight groups ( n = 6): normal control, -stress (RS, 4 h daily × 7 days), RS + diazepam (2 mg/kg, i.p.), RS + imipramine (30 mg/kg, p.o.), RS + ranitidine (150 mg/kg, p.o.) and RS + tadalafil (2, 5 or 10 mg/kg, p.o.). Behaviour was assessed using the Elevated Plus Maze and Open-Field Test. Gastric ulcer index (UI), serum corticosterone, brain tumour necrosis factor α (TNF-α) and interleukin 1β (IL-1β) were quantified by the enzyme-linked immunosorbent assay technique. Dose–response trends were analysed by linear regression. Results: RS significantly increased anxiety index (0.90 ± 0.02 vs. 0.80 ± 0.01; P < 0.001), reduced locomotor activity (crossings: 16.0 ± 5.9 vs. 43.5 ± 4.4; P < 0.001) and raised UI (7.24 ± 0.38 vs. 2.09 ± 0.25 mm 2 ; P < 0.0001). Tadalafil (10 mg/kg) reversed the anxiety index to values comparable with those of stress (0.90 ± 0.02 vs. 0.74 ± 0.02; P < 0.05) and reduced UI to 2.32 ± 0.21 mm 2 ( P < 0.001), findings comparable with those of diazepam and ranitidine. RS caused an increase in TNF-α (15.27 ± 1.66 pg/mL) and IL-1β (16.09 ± 2.71 pg/mL) ( P < 0.001). Treatment with tadalafil reduced these cytokine levels in a dose-dependent manner (TNF-α = −0.223, IL-1β = −0.376); tadalafil (10 mg/kg) reduced serum corticosterone levels compared with the stress group (10.88 ± 1.76 vs. 16.61 ± 1.09 ng/mL, P < 0.05). Linear regression analysis demonstrated a significant inverse dose–response relationship for both the anxiety index (β = −0.0067, R 2 = 0.576, P = 0.0003) and UI (β = −0.0733, R 2 = 0.408, P = 0.0043). Conclusion: Tadalafil exhibits notable anxiolytic and gastroprotective activity in restraint-stressed rats, highlighting PDE5 inhibition as a potential multi-target therapeutic approach for stress-induced neuropsychiatric and gastrointestinal disorders.