2-Phenyl-3-(phenylselanyl)benzofuran elicits acute antidepressant-like action in male Swiss mice mediated by modulation of the dopaminergic system and reveals therapeutic efficacy in both sexes.

RATIONALE: Depression is a psychiatric disorder that constitutes one of the leading causes of disability worldwide. 2-Phenyl-3-(phenylselanyl)benzofuran (SeBZF1) has been studied as a potential antidepressant drug, but its pharmacological action needs more investigation. OBJECTIVES AND METHODS: Our aim was to extend information about the antidepressant-like action of SeBZF1 using the mouse tail suspension test (TST). Initial experiments investigated the mechanisms involved in the acute antidepressant-like action of SeBZF1 in male Swiss mice. For this purpose, males received noradrenergic or dopaminergic receptor antagonists before acute SeBZF1 administration (50 mg/kg, per oral). In parallel, effects of combined treatment with SeBZF1 and bupropion at sub-effective doses (1 and 3 mg/kg, respectively) were tested. The next experiments were designed to determine the acute effects of SeBZF1 in females through a dose-response curve (5-50 mg/kg). Lastly, the efficacy of a 7-day repeated treatment with SeBZF1 (1 and 5 mg/kg) in mice of both sexes and its safety were evaluated. TST and the open-field test (OFT) were employed in all behavioral experiments. RESULTS: Pre-administration of dopaminergic antagonists (SCH23390, a selective D1R antagonist; sulpiride, a selective D2/D3R antagonist; and haloperidol, a non-selective antagonist), but not of adrenergic α1, α2, and ß-R antagonists, blocked the acute antidepressant-like effects of SeBZF1 in males. Co-administration of sub-effective doses of SeBZF1 and bupropion reduced the depressive phenotype. In addition, acute treatment with SeBZF1 at 50 mg/kg produced a reduction of female immobility. Finally, repeated treatment with SeBZF1 (1 and 5 mg/kg) was effective in causing antidepressant-like effects in both sexes. Locomotor activity, plasma transaminases, and urea levels remained unaltered after SeBZF1 exposure. CONCLUSION: Our findings provide evidence of the involvement of the dopaminergic system in the acutely antidepressant-like action of SeBZF1 in male mice and reveal the compound efficacy when acute or repeatedly administered in both sexes.

Insights into serotonergic and antioxidant mechanisms involved in antidepressant-like action of 2-phenyl-3-(phenylselanyl)benzofuran in mice.

Monoaminergic and oxidative dysfunctions have been reported to play a role in depression. The present study investigated the antioxidant potential as well as the antidepressant-like action of 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1) in male Swiss mice. Time and dose-response curves were analyzed with the forced swim (FST) and tail suspension (TST) tests, in which SeBZF1 elicited antidepressant-like effects. Serotonergic mechanisms were investigated in the TST. The pre-administration of WAY100635 (selective 5-HT1A receptor antagonist, 0.1 mg/kg, subcutaneous route), ketanserin (5-HT2A/2C receptor antagonist, 1 mg/kg, intraperitoneal route, i.p.), and chlorophenylalaninemethyl ester (p-CPA) (selective tryptophan hydroxylase inhibitor, 100 mg/kg, i.p., for 4 days), but not of ondansetron (selective 5-HT3 receptor antagonist, 1 mg/kg, i.p.), abolished the antidepressant-like action of SeBZF1 (50 mg/kg, intragastric route, i.g.). Co-administration of sub-effective doses of SeBZF1 (1 mg/kg, i.g.) and fluoxetine (5 mg/kg, i.p., selective serotonin reuptake inhibitor) was effective in producing anti-immobility effects in the TST, revealing a synergistic effect. Besides, p-CPA induced hippocampal oxidative stress, characterized by a reduction of total thiols and lipoperoxidation, which was reversed by SeBZF1 (50 mg/kg). The in vitro screening of the antioxidant action of SeBZF1 in brain tissue reinforced these results. Lastly, SeBZF1 did not cause systemic toxicity at a high dose (300 mg/kg). In summary, the present study demonstrated that SeBZF1 exerted antidepressant-like action in male mice which appears to be mediated by the serotonergic system. Moreover, SeBZF1 elicited in vitro antioxidant action in brain tissue, attenuated the hippocampal oxidative damage induced by 5-HT depletion in mice and showed no toxic signs.