2-Phenyl-3-(Phenylselanyl)Benzofuran As a Promising Antidepressant Candidate: Mechanistic Insights Into Nitrergic Modulation and Subchronic Efficacy and Safety Profiling
Abstract
The compound 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1), a selenium-containing molecule based on a benzofuran scaffold, has shown antidepressant-like effects. This study investigated the involvement of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway, the efficacy of subchronic treatment in male Swiss mice, and computational analyses. Acute SeBZF1 administration (50 mg/kg, i.g.) showed antidepressant-like effects in the tail suspension test (TST). These effects were reversed by pretreatment with L-arginine (a NO precursor, 750 mg/kg, intraperitoneal, i.p.) or sildenafil (a phosphodiesterase-5 inhibitor, 5 mg/kg, i.p.), suggesting NO-cGMP pathway involvement. A subeffective dose of SeBZF1 (1 mg/kg, i.g.) elicited synergistic antidepressant-like effects when combined with N(ω)-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase (NOS) inhibitor, 10 mg/kg, i.p.) or 7-nitroindazole (a specific neuronal NOS inhibitor, 30 mg/kg, i.p.). Furthermore, methylene blue (an inhibitor of NOS and soluble guanylate cyclase (sGC), 10 mg/kg, i.p.) and 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, a sGC inhibitor, 30 pmol/site, intracerebroventricular), both soluble guanylate cyclase (sGC) inhibitors, enhanced the subeffective SeBZF1 dose. Subchronic SeBZF1 treatment (1 mg/kg, i.g., for 35 days) significantly produced antidepressant-like action without causing weight loss or organ damage. Biochemical analysis revealed reduced nitrate/nitrite levels in the…
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