The Faster-onset Antidepressant-like Behaviors And Their Associated Mechanisms Of Hypidone Hydrochloride(YL-0919)

The current clinical first-line antidepressants?such as Selective Serotonin Reuptake Inhibitors,SSRIs?often have delayed onset?4-6 weeks?,low efficiency?50-70%?,many adverse reactions including sexual dysfunction and even severe cognitive impairment.Hypidone hydrochloride?Designation NO.YL-0919?is an internationally patented antidepressant candidate?china,America,Japan,Europe and so on?with totally novel structure developed by our institute.YL-0919 has been got the national approval of I-III clinical trials for 1.1 class new drug and it also has been entered into a phase?clinical trial in China.Previous studies have revealed that YL-0919 is a potent triple SSRI,5-HT_1A receptor partial agonist and 5-HT₆ receptor full agonist,producing significant antidepressant-like,anxiolytic-like effects without sexual dysfunction in several kinds of animals'models and clear memory-enhancing effects on normal mice.More interestingly,we also found that rats treatment with YL-0919?for 7days?by gavage rapidly enhance the long-term potentiation?LTP?in the hippocampus while treatment with fluoxetine?FLX?need 3 weeks to exert this effect.Further study has showed that a single dose of YL-0919?2.5 mg/kg,i.p.?can rapidly stimulate pyramidal neurons in medial prefrontal cortex?mPFC?after 1 hour,but fluoxetine?FLX?does not have this effect.These studies imply that,Yl-0919 may have the faster-onset antidepressant-like effects.Objective:To study the rapid-onset antidepressant-like effect and their possible related mechanisms of hypidone hydrochloride?YL-0919?.Methods:To explore the onset-time course of actions on depressive and cognition-impairment behaviors of YL-0919 in the depressive models of rodent animals induced by exposure to the high-frequency electromagnetic radiation and the chronic unpredictablestress?CUS?procedure,sucrosepreferencetest?SPT?,novelty-suppressed feeding?NSF?test and novel object recognition test?NOR?were used in the section of behavioral tests.Further studies were to detect the rapid improvement of YL-0919 on chronic stress-induced hyperactivity in the hypothalamic-pituitary-adrenal?HPA?axis using corticosterone and adrenocorticotropin?ACTH?ELISA kits.At the onset-time of antidepressant-like effects,western blot was used to detect the expressions of synaptic related proteins?postsynaptic density protein95,PSD-95;Synapsin1;glutamate receptor1,GluR1?,brain-derived neurotrophic factor?BDNF?,the phosphorylated cAMP response element-binding protein?pCREB?and phosphorylated mammalian target of rapamycin?pmTOR?in prefrontal cortex?PFC?of CUS rats.Meanwhile,the dendritic complexity,including the number of dendritic branches and the length of dendrites of pyramidal neurons in PFC area was observed after the brain tissue of rats was stained by Golgi staining.At the level of ex vivo cells,the primary cultured neurons in PFC were used to detect the expression the serotonin transporter?Sert?and 5-HT₆ protein genes with real-time qPCR while the expression of5-HT_1A receptor was detected by western blot and immunofluorescence staining.Furthermore,the fluorescent staining of MAP-2 antibody and AAV-eGFP transfection were used to detect the effects on dendritic branches and dendritic spine density of primary cultured neurons incubated with YL-0919 for 24 h and 48 h.Results:?1?In the depressive model of mice induced by high-frequency electromagnetic radiation:Exposure to the high-frequency electromagnetic radiation?3GHz,SAR 4 w/kg?4 h/d for 7 days resulted in depression and anxiety-like behaviors in mice with cognitive injury.Prophylactic administration of YL-0919?2.5 mg/kg,i.g.,once daily?significantly improved emotional and cognitive-like behavioral damage in mice caused by electromagnetic radiation and the positive cellls labeled with5-bromo-2'-deoxyuridine?Brdu?in dentate gyrus of the hippocampal were observed obviously increased after the rats exposed to the high-frequency electromagnetic radiation with YL-0919 treatment.Further study showed that depression-like behaviors in mice were rapidly reversed by treatment with YL-0919?2.5 mg/kg,once daily?for 3days,showing on the sucrose preference increased.?2?In the CUS model of rats:YL-0919?1.25 mg/kg,2.5 mg/kg,i.g.,once daily?administrated exerted faster antidepressant-like behaviors?increased the sucrose preference with 4 days treatment in SPT and shorten the latency to feed with 6 days treatment in NSF test?and rapidly reversed the learning-memory impairment induced by CUS procedure?increased the discrimination index with treatment for 8 days in NOR test?while it needed almost 3weeks for the clinical first-line drug FLX?10 mg/kg,i.g.,once daily?to exerted antidepressant actions?20 days,increased the sucrose preference;22 days,shorten the latency to feed?without any improvement in the cognitive behavioral impairments?treatment or 21 days?.?3?YL-0919?1.25mg/kg,2.5mg/kg,i.g.?treatment for 7 days significantly reversed the hyper-function of HPA axis in CUS rats with the decrease of the expression levels of corticosterone and ACTH in the serum.?4?At the overall level:YL-0919?1.25 mg/kg,2.5 mg/kg,i.g.?significantly reversed the decrease of BDNF-mTOR signaling in the PFC region caused by CUS paradigm,which were expressed in PSD-95,Synapsin1,GluR1,BDNF,pCREB and pmTOR/mTOR protein.In addition,the number and length of dendritic branches of pyramidal neurons were observed significantly increased in the PFC region with administration of YL-0919 for 5days.?5?At the level of ex vivo cells:the Sert and 5-HT₆ protein genes respectively had moderate and high abundance expression in primary cultured PFC neurons.Meanwhile,5-HT_1A receptor also expressed in primary prefrontal cortical neurons.The primary cultured PFC pyramidal neurons incubation with YL-0919?3?M/L?for 48 h significantly increased the number of dendritic branches,dendritic length and dendrite spines,but the pyramidal neurons with FLX?1?M/L?treatment did not exert these effects.Conclusion:Compared to FLX,one of the clinical first-line antidepressants?SSRIs?,hypidone hydrochloride?YL-0919?has faster onset-time on the antidepressive-like behaviors and the function of improving learning and memory.Besides that,the treatment of YL-0919 also increase the synaptic complexity of pyramidal neurons in the PFC of rats.The increase of synaptic-associated proteins mediated by the BDNF-mTOR signaling maybe the important mechanism of faster-onset of YL-0919.