The neuroprotective and antidepressant‐like effects of Hcyb1, a novel selective PDE2 inhibitor

Abstract

These results suggest that the novel PDE2 inhibitor Hcyb1 produced neuroprotective and antidepressant-like effects most likely mediated by cAMP/cGMP-CREB-BDNF signaling.

GW117: A novel serotonin (5‐HT2C) receptor antagonist and melatonin (MT1/MT2) receptor agonist with potential antidepressant‐like activity in rodents

“…The first‐line medications for MDD selective 5‐hydroxytryptamine reuptake inhibitors (SSRIs) that block the 5‐hydroxytryptamine transporter protein are also widely used psychiatric drugs for many other psychiatric disorders currently, including anxiety disorders, panic disorders, and bipolar disorder. Despite widespread use of these drugs, there are challenges in terms of their efficacy and side effects, 3 which cognitive dysfunction, sexual dysfunction, sleep disorders, and weight gain and it often require 6–8 weeks to achieve effectiveness 4,5 . Growing evidence suggests that several side effects of SSRIs, especially anhedonia, apathy, and extrapyramidal motor symptoms, affect the behavioral and emotional efficacy of SSRIs 6‐11 .…”

“…Of particular importance, however, is the fact that currently more than 30% of depressed patients do not respond to first‐line treatment, 3 whereas lower doses of ketamine confer a rapid antidepressant effect in these patients 13,14 . But its application is limited because of its psychotropic and addictive properties 15 .…”

“…values of the percent of the respective basal binding obtained from 3 experiments performed in duplicate had no effect on the number of crossings (one-way ANOVA, F [3, 44] = 0.04090, p = 0.9888) and rearings in the spontaneous activity test (one-way ANOVA, F [7, 92] = 0.5962, p = 0.7575). In rats, GW117(5, 10, 20, or 40 mg/kg) given by gavage also had no effect on the number of crossings (one-way ANOVA, F[3,35] = 0.1522, p = 0.9276) and rearings (one-way ANOVA, F[7, 76] = 0.3042, p = 0.9499).…”

“…12 Agomelatine, which play the role of "synergism" as a MT 1 /MT 2 receptor agonist and 5-HT 2C receptor antagonist, alleviated depressive symptoms in both rodents and patients, while also showing anxiolytic effects, sleep-promoting, and anti-circadian desynchronization effects. 12 Of particular importance, however, is the fact that currently more than 30% of depressed patients do not respond to firstline treatment, 3 whereas lower doses of ketamine confer a rapid antidepressant effect in these patients. 13,14 But its application is limited because of its psychotropic and addictive properties.…”

Emerging and evolving concepts in the pathobiology and treatment of psychosis

“…Given emerging recognition that the psychopathologies of psychotic illness and major depressive disorder are not mutually exclusive but, rather, can and often do co‐occur in the same individual, it is timely to reconsider also the action of antidepressant drugs. Liu and colleagues investigate the effects of Hcyb1, a novel inhibitor of phosphodiesterase2A (PDE2A), in 2 contexts: as a putative antidepressant agent and as a neuroprotective agent in terms of increasing cell viability/promoting neuronal proliferation. They report Hcyb1 to exert both antidepressant‐like effects in behavioral models and neuroprotective effects in cell lines that are likely mediated by cAMP/cGMP‐CREB‐BDNF signaling, disruption of which has been implicated both in depression and psychosis and in antidepressant and antipsychotic drug action …”