{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T16:15:48Z","timestamp":1790266548285,"version":"4.1.0"},"reference-count":36,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2018,4,27]],"date-time":"2018-04-27T00:00:00Z","timestamp":1524787200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81603336"],"award-info":[{"award-number":["81603336"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2018,7]]},"abstract":"Summary<\/jats:title>Aims<\/jats:title>Depression is currently the most common mood disorder. Regulation of intracellular cyclic adenosine monophosphate (cAMP<\/jats:styled-content>) and\/or cyclic guanosine monophosphate (cGMP<\/jats:styled-content>) signaling by phosphodiesterase (PDE<\/jats:styled-content>) inhibition has been paid much attention for treatment of depression. This study aimed to investigate the neuroprotective effects of Hcyb1, a novel PDE<\/jats:styled-content>2 inhibitor, in HT<\/jats:styled-content>\u201022 cells and antidepressant\u2010like effects in mouse models of depression.<\/jats:p><\/jats:sec>Methods<\/jats:title>Hcyb1 was synthesized and its selectivity upon PDE<\/jats:styled-content>2 was tested. Moreover, HT<\/jats:styled-content>\u201022 hippocampal cells were used to determine the effects of Hcyb1 on cell viability, cyclic nucleotide levels, and the downstream molecules related to cAMP<\/jats:styled-content>\/cGMP<\/jats:styled-content> signaling by neurochemical, enzyme\u2010linked immunosorbent, and immunoblot assays in vitro. The antidepressant\u2010like effects of Hcyb1 were also determined in the forced swimming and tail suspension tests in mice.<\/jats:p><\/jats:sec>Results<\/jats:title>Hcyb1 had a highly selective inhibition of PDE<\/jats:styled-content>2A (IC<\/jats:styled-content>50<\/jats:sub>\u00a0=\u00a00.57\u00a0\u00b1\u00a00.03\u00a0\u03bcmol\/L) and over 250\u2010fold selectivity against other recombinant PDE<\/jats:styled-content> family members. Hcyb1 at concentrations of 10\u221210<\/jats:sup> and 10\u22129<\/jats:sup>\u00a0mol\/L significantly increased cell viability after treatment for 24\u00a0hours. At concentrations of 10\u22129<\/jats:sup>~10\u22127<\/jats:sup>\u00a0mol\/L, Hcyb1 also increased cGMP<\/jats:styled-content> levels by 1.7~2.3 folds after 10\u2010minute treatment. Furthermore, Hcyb1 at the concentrations of 10\u22129<\/jats:sup>\u00a0mol\/L increased both cGMP<\/jats:styled-content> and cAMP<\/jats:styled-content> levels 24\u00a0hours after treatment. The levels of phosphorylation of CREB<\/jats:styled-content> and BDNF<\/jats:styled-content> were also increased by Hcyb1 treatment in HT<\/jats:styled-content>\u201022 cells for 24\u00a0hours. Finally, in the in vivo tests, Hcyb1 (0.5, 1, and 2\u00a0mg\/kg, i.g.) decreased the immobility time in both forced swimming and tail suspension tests, without altering locomotor activity.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>These results suggest that the novel PDE<\/jats:styled-content>2 inhibitor Hcyb1 produced neuroprotective and antidepressant\u2010like effects most likely mediated by cAMP<\/jats:styled-content>\/cGMP<\/jats:styled-content>\u2010CREB<\/jats:styled-content>\u2010BDNF<\/jats:styled-content> signaling.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.12863","type":"journal-article","created":{"date-parts":[[2018,4,28]],"date-time":"2018-04-28T05:00:56Z","timestamp":1524891656000},"page":"652-660","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["The neuroprotective and antidepressant\u2010like effects of Hcyb1, a novel selective PDE2 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