Background: Schizophrenia is a serious psychiatric disorder that significantly affects the quality of life of patients. The objective of this study is to discover a novel antipsychotic candidate with highly antagonistic activity against both serotonin and dopamine receptors, demonstrating robust efficacy in animal models of positive, negative, and cognitive symptoms of schizophrenia.Methods: In the present study, we examined the activity of antipsychotic drug (NH300094) on 5-HT2A, 5-HT2C, 5-HT1A, 5-HT1B, 5-HT7, H1, M1, Alpha1A, D2L, D2S, Alpha2A, D3 receptor functional assay in vitro. In addition, multiple animal models, including dizocilpine (MK-801) induced hyper-locomotion; APO induced climbing; Conditioned Avoidance Response (CAR); DOI-Induced Head Twitch; Forced swimming test; Scopolamine induced cognitive impairment model, were used to verify the antipsychotic activity of NH300094 in preclinical.Results: In vitro functional assays have indicated that NH300094 is a potent antagonist of 5-HT receptors and dopamine receptors, with higher relative antagonistic activity against 5-HT2A receptor (5-HT2A IC50 = 0.47 nM) than dopamine receptors (D2L IC50 = 1.04 nM; D2S IC50 = 11.71 nM; D3 IC50 = 31.55 nM). Preclinical in vivo pharmacological study results showed that NH300094 was effective in multiple models, which is more extensive than the clinic drug Risperidone. Furthermore, the safety window for extrapyramidal side effects of NH300094 is significantly wider than that of Risperidone (For NH300094, mice catalepsy model ED50/ Mice MK-801 model ED50 = 104.6-fold; for Risperidone, mice catalepsy model ED50/ Mice MK-801 model ED50 = 12.9-fold), which suggests a potentially better clinical safety profile for NH300094.Conclusion: NH300094 is a novel potent serotonin and dopamine receptors modulator, which has good safety profile and therapeutic potential for the treatment of schizophrenia with cognition disorders.
Xuejun Yuan,Wenjie Chen,Rui Li,Huijun Guo,Chunyang Wang
Deoxynivalenol (DON) is one of the most prevalent mycotoxins and can induce weight loss and vomiting in animals. This study aimed to elucidate the molecular mechanisms underlying DON-induced anorexia in rabbits through the microbial-gut-brain axis. A total of forty rabbits were randomly divided into a DON group and a control group, receiving 1.5 mg/kg.BW of DON and an equivalent volume of saline daily via intragastric administration, respectively. The pre-treatment period lasted for 7 days, followed by a formal experimental period of 24 days. The findings revealed that DON exposure significantly reduced daily food intake and weight gain, leading to intestinal apoptosis and barrier injuries. 16S rRNA sequencing data indicated that DON exposure decreased the diversity and richness of cecal microflora, suppressed probiotic populations, and disrupted host lipid metabolism. RNA-Seq and iTRAQ data were used to cross-analyze the shared differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) in the hypothalamus and jejunum, along with their shared enrichment pathways, indicating that TNF-α, NF-κB, and NPY may play pivotal roles in DON-induced anorexia. qRT-PCR and Western blotting results confirmed significant increases in mRNA and protein expression levels of TNF-α, NF-κB and 5-HT2A in both the hypothalamus and jejunum. In conclusion, DON ingestion in rabbits can disrupt the intestinal barrier, up-regulate the expression of IFN-γ, TNF-α, NF-κB, and 5-HT2A in the intestine, and trigger an immuno-inflammatory response in the hypothalamus via the microbial-gut-brain axis, ultimately resulting in appetite suppression and weight loss.
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