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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 SeBZF\n                    <jats:bold>1<\/jats:bold>\n                    administration (50\u00a0mg\/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\u00a0mg\/kg, intraperitoneal, i.p.) or sildenafil (a phosphodiesterase-5 inhibitor, 5\u00a0mg\/kg, i.p.), suggesting NO-cGMP pathway involvement. A subeffective dose of SeBZF\n                    <jats:bold>1<\/jats:bold>\n                    (1\u00a0mg\/kg, i.g.) elicited synergistic antidepressant-like effects when combined with N(\u03c9)-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase (NOS) inhibitor, 10\u00a0mg\/kg, i.p.) or 7-nitroindazole (a specific neuronal NOS inhibitor, 30\u00a0mg\/kg, i.p.). Furthermore, methylene blue (an inhibitor of NOS and soluble guanylate cyclase (sGC), 10\u00a0mg\/kg, i.p.) and 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, a sGC inhibitor, 30\u00a0pmol\/site, intracerebroventricular), both soluble guanylate cyclase (sGC) inhibitors, enhanced the subeffective SeBZF\n                    <jats:bold>1<\/jats:bold>\n                    dose. Subchronic SeBZF\n                    <jats:bold>1<\/jats:bold>\n                    treatment (1\u00a0mg\/kg, i.g., for 35\u00a0days) significantly produced antidepressant-like action without causing weight loss or organ damage. Biochemical analysis revealed reduced nitrate\/nitrite levels in the prefrontal cortex and hippocampus, indicating modulation of NO signaling. Molecular docking suggested interactions between SeBZF\n                    <jats:bold>1<\/jats:bold>\n                    and NOS isoforms, while pharmacokinetic analysis suggested brain penetration and absence of overt toxicity. The present study concludes that SeBZF\n                    <jats:bold>1<\/jats:bold>\n                    exhibits antidepressant-like effects through the NO\u2013cGMP pathway, is effective at low subchronic doses, and displays favorable pharmacokinetic and safety profiles, supporting its potential as a novel antidepressant candidate.\n                  <\/jats:p>","DOI":"10.1007\/s12035-026-06058-6","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T06:58:46Z","timestamp":1784185126000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["2-Phenyl-3-(Phenylselanyl)Benzofuran As a Promising Antidepressant Candidate: Mechanistic Insights Into Nitrergic Modulation and Subchronic Efficacy and Safety Profiling"],"prefix":"10.1007","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9151-4637","authenticated-orcid":false,"given":"Ta\u00eds da Silva Teixeira","family":"Rech","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2358-6695","authenticated-orcid":false,"given":"Ediandra Tissot","family":"Castro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5656-3134","authenticated-orcid":false,"given":"Mariana Parron","family":"Paim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7375-5434","authenticated-orcid":false,"given":"Dianer Nornberg","family":"Strelow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4157-3481","authenticated-orcid":false,"given":"Jos\u00e9 Sebasti\u00e3o Santos","family":"Neto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1411-2658","authenticated-orcid":false,"given":"Gustavo Bierhals","family":"Bl\u00f6dorn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1074-0294","authenticated-orcid":false,"given":"Diego","family":"Alves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1832-982X","authenticated-orcid":false,"given":"Suzan Gon\u00e7alves","family":"Rosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0814-0203","authenticated-orcid":false,"given":"C\u00e9sar Augusto","family":"Br\u00fcning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9509-4446","authenticated-orcid":false,"given":"Cristiani Folharini","family":"Bortolatto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"6058_CR1","doi-asserted-by":"publisher","first-page":"ITC65","DOI":"10.7326\/AITC202105180","volume":"174","author":"RM McCarron","year":"2021","unstructured":"McCarron RM, Shapiro B, Rawles J, Luo J (2021) Depression. 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