YL-0919, a dual 5-HT1A partial agonist and SSRI, produces antidepressant- and anxiolytic-like effects in rats subjected to chronic unpredictable stress.

YL-0919 has been identified as a novel dual 5-HT1A partial agonist and serotonin reuptake inhibitor. In the current study, we demonstrated that YL-0919 produced prominent antidepressant-like and anxiolytic-like effects in a chronic unpredictable stress (CUS) rat model. Male SD rats were exposed to CUS for 5 weeks; YL-0919 (1.25 and 2.5 mg/kg) or a positive control fluoxetine (Flx, 10 mg/kg) was orally administered daily. YL-0919 or Flx treatment significantly increased the sucrose preference rate, the locomotor activity in an open field test (OFT), the latency to feed in a novelty-suppressed feeding test (NSFT), and both the percentage of time spent in the open arms and the number of entries into the open arms in an elevated plus-maze test. YL-0919 or Flx treatment significantly suppressed the serum levels of ACTH and corticosterone in CUS-exposed rats. Additionally, YL-0919 or Flx treatment significantly enhanced the levels of cAMP, the expression of phosphorylated cAMP response element-binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) in the hippocampus of CUS-exposed rats. Similar to Flx, YL-0919 treatment significantly enhanced the dendritic complexity, and increased the number of dendritic nodes as well as the spine length and number of branch nodes in the hippocampal pyramidal neurons of CUS-exposed rats. Overall, our results reveal that YL-0919 suppresses the HPA axis and exerts antidepressant-like and anxiolytic-like effects in CUS-exposed rats, which are associated with the enhanced cAMP signaling and hippocampal dendritic complexity.

Neurochemical and behavioural effects of hypidone hydrochloride (YL-0919): a novel combined selective 5-HT reuptake inhibitor and partial 5-HT1A agonist.

BACKGROUND AND PURPOSE: Our previous studies revealed that hypidone hydrochloride (YL-0919), which acts as a selective 5-HT (serotonin) reuptake inhibitor (SSRI) and displays partial 5-HT1A receptor agonist properties, exerts a significant antidepressant effect in various animal models. The aim of present research was to further investigate the pharmacology of YL-0919. EXPERIMENTAL APPROACH: We first investigated the target profile of YL-0919 using [35 S]-GTPγS binding and microdialysis. To determine whether the 5-HT or noradrenergic systems are involved in the antidepressant-like effect of YL-0919, the 5-hydroxytryptophan (5-HTP)-induced head-twitch test and antagonism with a high dose of apomorphine were performed. Using the learned helplessness paradigm, the novelty suppressed feeding test, the Vogel-type conflict and elevated plus-maze test, we further verified the antidepressant-like and anxiolytic-like effects of YL-0919. The effects of YL-0919 on hippocampal long-term potentiation (LTP) and sexual behaviour were also evaluated. KEY RESULTS: Data from the present study demonstrated that YL-0919 displays partial 5-HT1A receptor agonist properties, producing a greater impact on extracellular 5-HT levels than a conventional SSRI (fluoxetine), as well as significant antidepressant and anxiolytic effects. Furthermore, YL-0919 treatment rapidly influenced the synaptic plasticity (enhancing LTP) of rats. Finally, at doses close to those producing antidepressant-like effects, YL-0919 did not result in a marked inhibition of sexual function. CONCLUSIONS AND IMPLICATIONS: These data suggest that YL-0919 is probably a fast-onset potent antidepressant with few side effects.

Antidepressant-like effects of albiflorin extracted from Radix paeoniae Alba.

ETHNOPHARMACOLOGY RELEVANCE: Albiflorin, a monoterpene glycoside, is a main component of Radix paeoniae Alba, which could be a Chinese herbal medicine used in the treatment of psychiatric disorders. However, the exact role of albiflorin in depression is poorly understood. AIM OF THE STUDY: The current study aimed to evaluate the antidepressant effect of albiflorin in mice and rats, and the possible mechanism was also determined. MATERIALS AND METHODS: The antidepressant-like effects of albiflorin was determined by using animal models of depression including forced swim and tail suspension tests in mice and chronic unpredictable stress (CUS) in rats. The acting mechanism was explored by determining the effect of albiflorin on the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus by western blot and the levels of monoamine in the hippocampus by HPLC. RESULTS: Our results showed that 7 days treatment with albiflorin significantly decreased immobility time in the forced swimming test (FST) and the tail suspension test (TST) at doses of 3.5, 7.0 and 14.0mg/kg without alter the locomotor activity in mice. Moreover, western blot analysis showed that albiflorin could increase the expression of BDNF in the hippocampus. We further exposed rats to a chronic unpredictable stress (CUS) protocol for a period of 35d to induce depressive-like behaviors. We found that chronic treatment with albiflorin, at doses of 7.0 and 14.0mg (i.g., once daily for 35d), restored the sucrose preference in CUS rats. In the open-field test, albiflorin significantly increased the number of crossings and rearings in the CUS rats at three doses. Moreover, chronic treatment with albiflorin up-regulated the hippocampal BDNF expression levels and the hippocampal 5-HT, 5-HIAA, and NA levels. CONCLUSION: Albiflorin produced significant antidepressant-like effects, which were closely related to the hippocampal 5-HT/NE increase and BDNF expression. Our data indicated that albiflorin could be a potential anti-depressant drug.

Detection of Echinoderm Microtubule Associated Protein Like 4-Anaplastic Lymphoma Kinase Fusion Genes in Non-small Cell Lung Cancer Clinical Samples by a Real-time Quantitative Reverse Transcription Polymerase Chain Reaction Method.

Objective To establish a real-time quantitative reverse transcription polymerase chain reaction assay (qRT-PCR) for the rapid, sensitive, and specific detection of echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) fusion genes in non-small cell lung cancer. Methods The specific primers for the four variants of EML4-ALK fusion genes (V1, V2, V3a, and V3b) and Taqman fluorescence probes for the detection of the target sequences were carefully designed by the Primer Premier 5.0 software. Then, using pseudovirus containing EML4-ALK fusion genes variants (V1, V2, V3a, and V3b) as the study objects, we further analyzed the lower limit, sensitivity, and specificity of this method. Finally, 50 clinical samples, including 3 ALK-fluorescence in situ hybridization (FISH) positive specimens, were collected and used to detect EML4-ALK fusion genes using this method. Results The lower limit of this method for the detection of EML4-ALK fusion genes was 10 copies/µl if no interference of background RNA existed. Regarding the method's sensitivity, the detection resolution was as high as 1% and 0.5% in the background of 500 and 5000 copies/µl wild-type ALK gene, respectively. Regarding the method's specificity, no non-specific amplification was found when it was used to detect EML4-ALK fusion genes in leukocyte and plasma RNA samples from healthy volunteers. Among the 50 clinical samples, 47 ALK-FISH negative samples were also negative. Among 3 ALK-FISH positive samples, 2 cases were detected positive using this method, but another was not detected because of the failure of RNA extraction. Conclusion The proposed qRT-PCR assay for the detection of EML4-ALK fusion genes is rapid, simple, sensitive, and specific, which is deserved to be validated and widely used in clinical settings.