MOLECULES
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2022
·Vol. 27
·期 8
·2550
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IF 4.927
Lingzhi Liang,Xia Ren,Junyi Xu,Yurong Ma,Yunlin Xue,Tao Zhuang,Guisen Zhang
Olanzapine is a commonly used drug in the treatment of schizophrenia, but its clinical application has been restricted by metabolic-related side effects. In order to mitigate the weight gain side effects caused by olanzapine, other drugs with different targets were selected for combined use and evaluated in animal models of schizophrenia. SEP-363856 is a novel psychotropic agent which is under phase III clinical trials for schizophrenia treatment. The aim of the research was to evaluate whether co-administration of olanzapine and SEP-363856 exerts synergistic anti-schizophrenic effects in the apomorphine (APO)-induced climbing test, the MK-801-induced hyperactivity test, and the Morris water maze test, and therefore reduces the weight gain side effects induced by olanzapine. Through isobolographic analysis, the results showed a synergistic interaction in the climbing test; the experimental ED30(3 mg/kg) was significantly smaller (p< 0.05) than the theoretical ED30(5 mg/kg). Additionally, such potentiating effects appeared additive in the MK-801 challenge experiment. Co-treatment with an effective dose of olanzapine and a low dose of SEP-363856 reversed MK-801-induced cognitive impairment symptoms in mice. Moreover, combination treatment with olanzapine and SEP-363856 controls sustained weight gain in mice with chronic exposure to olanzapine. These results support further clinical trials to test the effectiveness of co-treatment of olanzapine and SEP-363856 for controlling symptoms and weight gain in patients with schizophrenia during antipsychotic treatments.Keywords:olanzapine;SEP-363856;schizophrenia;synergistic;side effects
研究领域:
神经科学
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药理学
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精神病学
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DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
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2024
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IF 6.7
Biao Zhang,Jun Cao,Si-Jie Liao,Peng-Cheng Zhou,Yu-Ting Shen,Wei Yu,Wei Li,Ai-Guo Shen
At present, there is a lack of sufficiently specific laboratory diagnostic indicators for schizophrenia. Serum homocysteine (Hcy) levels have been found to be related to schizophrenia. Cysteine (Cys) is a demethylation product in the metabolism of Hcy, and they always coexist with highly similar structures in vivo. There are few reports on the use of Cys as a diagnostic biomarker for schizophrenia in collaboration with Hcy, mainly because the rapid, economical, accurate, and high-throughput simultaneous detection of Cys and Hcy in serum is highly challenging. Herein, a click reaction-based surface-enhanced Raman spectroscopy (SERS) sensor was developed for simultaneous and selective detection of Cys and Hcy. Through the efficient and specific CBT-Cys click reaction between the probe containing cyan benzothiazole and Cys/Hcy, the tiny methylene difference between the molecular structures of Cys and Hcy was converted into the difference between the ring skeletons of the corresponding products that could be identified by plasmonic silver nanoparticle enhanced molecular fingerprint spectroscopy to realize discriminative detection. Furthermore, the SERS sensor was successfully applied to the detection in related patient serum samples, and it was found that the combined analysis of Cys and Hcy can improve the diagnostic accuracy of schizophrenia compared to a single indicator.
研究领域:
医学诊断
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分析化学
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生物医学工程
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DOI
PubMed
高影响因子
American Journal of Translational Research
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2021
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IF 4.06
Shaochang Wu,Guidong Zhu,Dajin Zhou,Hongtao Xu,Longyou Zhao
Objective: This study was designed to demonstrate the accuracy of ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) in detecting serum concentration of anti-schizophrenic drugs in patients with mental illness. Methods: The study participants were 186 schizophrenia patients treated in our hospital. Serum concentrations of anti-schizophrenic drugs in Chinese patients with mental illness were evaluated according to the reference intervals of drug therapy recommended in the guidelines. Results: Five drugs, namely Aripiprazole (ARI), Amisulpride (AMI), Olanzapine (OLA), Paliperidone (PAL) and Ziprasidone (ZIP) all showed good linearity within the linear range. The within-day precision of the above five drugs was all between 1.3%-8.9% and the inter-day precision was between 1.8%-7.6%, with within-day and inter-day relative standard deviations (RSDs) less than 15.00% and accuracy ranging from 87.00% to 106.73%. However, AMI had a mean blood concentration of 436.31±241.05 ng/mL (median concentration: 379.34 ng/mL), which was significantly higher than the reference range (100-320 ng/mL) recommended in the guidelines. Good recovery rates (86.21%-99.77%) were obtained after the samples were stored at room temperature for 24 h, at 4°C for 48h and at -20°C for half a year. Conclusions: Given that UPLC-MS/MS renders more accurate results in detecting the concentration of psychotropic drugs, it can be applied clinically to detect the concentration of therapeutic drugs in patients with mental illness.
研究领域:
临床医学
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药理学
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DOI
PubMed
高影响因子
Scientific Reports
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2025
·Vol. 15
·期 1
·1-15
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IF 3.9
Huang Zhengyuan,Ren Zhongyu,Wang Sanwang,Xiao Ling,Ling Yipeng,Xie Yinping,Wang Gaohua,Zhou Benhong
Cognitive impairment in schizophrenia occurs in the early stages of the disease and is closely associated with prognosis. Alleviation of cognitive impairment in schizophrenia faces major challenges owing to the lack of preventive and therapeutic drugs that are novel and effective. Urolithin A (UA) is a gut microbial metabolite of ellagic acid that has demonstrated neuroprotective effects in multiple neurological disease models. Nonetheless, the neuromodulatory role of UA in schizophrenia is yet to be elucidated. Wistar rat pups were separated from their mothers for 24 h on postnatal days (PNDs) 9–10 to establish an early-life stress model. The pups were pretreated with UA at different administration times (2, 4, and 6 weeks) and doses (50, 100, and 150 mg/kg) from adolescence (PND29). Behavioral tests were performed after the end of the administration. Subsequently, hippocampal samples were collected for histopathological and molecular evaluations. Male offspring rats subjected to maternal separation exhibited increased sensitivity to prepulse inhibition and cognitive impairment, accompanied by severe neuroinflammation and impaired neurogenesis. However, UA attenuated maternal separation-induced prepulse inhibition deficits and cognitive impairments and restored hippocampal neurogenesis in a dose-dependent manner. Furthermore, UA pretreatment preserved dendritic spine density, synapses, and presynaptic vesicles. In addition, it exerted anti-inflammatory effects by inhibiting microglial activation and expression of the proinflammatory cytokines tumor necrosis factor-α, interleukin-6, and interleukin-1β. Potential mechanisms included upregulation of brain-derived neurotrophic factor protein expression and activation of the extracellular signal-regulated kinase signaling pathway. This study is the first preclinical evaluation of the effects of UA on cognitive impairment in schizophrenia. The findings suggest that changes in cognitive function linked to schizophrenia are driven by the interaction among neuroinflammation, neurogenesis, and synaptic plasticity and that UA has the potential to reverse these processes. These observations provide evidence for future clinical trials of UA as a dietary supplement for preventing schizophrenia.
研究领域:
神经科学
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药理学
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精神病学
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DOI
PubMed
高影响因子
SCHIZOPHRENIA BULLETIN
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2025
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IF 4.8
Fan Rui,Pu Jianlin,Zhang Jin,Yu Minglan,Wang Tingting,Geng Xiaoqi,Dong Wei,Ma Rong,Wang Binglong,Wu Jianfei,Liu Kezhi,Hashimoto Kenji,Xiang Bo
BackgroundSocial withdrawal is a core symptom of schizophrenia (SCZ), yet its underlying molecular mechanisms remain unclear. Gα13 (GNA13), a G protein alpha subunit, has been implicated in SCZ susceptibility. This study investigated the role of Gα13 in social behavior by overexpressing it in the medial prefrontal cortex (mPFC) pyramidal neurons of mice.Study DesignIn this study, we first constructed CRE recombinase overexpressing Gα13 gene mice using CRISPR/Cas9 technology, tested the social behaviors by three-box socialization test, detected the changes of neuronal activities during social activities in mice by calcium signal fiber-optic recordings, observed the changes of dendritic spines by Golgi staining, applied RNA sequencing (RNA-Seq) to find the relevant targets, and observed whether it could reverse the abnormalities by pharmacological experiments social behavior. The electrophysiological characteristics of Gα13 overexpression were investigated using the whole-cell membrane clamp technique, followed by assessment of the severity of SCZ patients and social withdrawal using the PANSS scale and measurement of human plasma Gα13 protein levels using the ELISA technique, and the clinical correlation between the two was assessed.Study ResultsGα13 overexpression (Gα13-OE) mice exhibited significant social deficits in the three-chamber test, showing reduced sociability but normal social novelty recognition. Fiber photometry recordings revealed decreased neuronal activity during social interactions, and Golgi staining showed reduced dendritic spine density in mPFC pyramidal neurons. RNA-Seq identified downregulation of Adcyap1, affecting the cAMP/PKA signaling pathway and NMDA receptor (NMDAR) function. Pharmacological activation of Adcyap1 with PACAP-38 or NMDAR with D-cycloserine rescued the social deficits and restored synaptic function. Conversely, knockdown of Gα13 in an MK-801-induced SCZ mouse model ameliorated social behavior abnormalities. Clinically, patients with SCZ exhibited elevated plasma levels of Gα13, which positively correlated with the severity of social withdrawal symptoms measured by the PANSS G16 item.ConclusionsThese findings suggest that overexpression of Gα13 in the mPFC impairs social behavior by disrupting neuronal function and synaptic plasticity via the Adcyap1/cAMP/PKA/NMDAR pathway. Targeting Gα13 may offer a novel therapeutic strategy for addressing social deficits in SCZ.
研究领域:
神经生物学
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精神病学
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分子神经科学
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信号转导
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行为神经科学
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转化医学
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突触生物学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Zhengyuan Huang,Guanghui Chen,Zhongyu Ren,Ling Xiao,Ziyue Chen,Yinping Xie,Gaohua Wang,Benhong Zhou
The management of cognitive impairments in schizophrenia presents a considerable challenge, with a strong association between neuroinflammation and its progression. Urolithin A (UA) demonstrates important anti-inflammatory properties in multiple neurological disease models, contributing to the enhancement of cognitive deficits. However, it remains uncertain if UA can produce comparable neuroregulatory effects in female rat models of schizophrenia. Eight-week-old female Sprague Dawley rats received either 0.1 mg/kg of MK801 or volume-matched saline via intraperitoneal injection for 5 consecutive days. Furthermore, they were administered 150 mg/kg of UA through oral gavage for 4 weeks. Behavioral assessments were performed to evaluate cognitive function and behavior after UA treatment. Immunofluorescence staining was employed to assess microglial activity in the hippocampus, while Western blot analysis was conducted to investigate the expression of neuroinflammation-associated proteins. Prolonged exposure to MK801 induces schizophrenia-like behaviors and cognitive deficits in female rats. It also elevates the expression of NLRP3, Caspase-1, IL-1β, and IL-18 proteins in the hippocampus, accompanied by the activation of microglial cells. However, UA treatment can reverse the expression of these inflammatory proteins and the activation of microglial cells induced by MK801. This is the first study to evaluate the effects of UA on behavior and cognition in a female rat model of schizophrenia. The findings indicate that UA mitigates MK-801-induced cognitive deficits in female rats by inhibiting neuroinflammation and microglial activation via modulation of the NLRP3 signaling pathway. These findings offer preclinical data endorsing the possible application of UA as a dietary supplement to prevent cognitive deficits in schizophrenia.
研究领域:
神经科学
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药理学
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行为科学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2024
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IF 4.4
Feng Zijin,Hu Zhijing,Li Lei,Yu Minquan,Zhang Yiting,Jing Peng,Xu Xiangqing,Wu Jinhui,Hu Yiqiao,Xu Xiangyang
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.
研究领域:
药理学
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精神病学
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神经科学
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DOI
PubMed
高影响因子
Journal of Neuroinflammation
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2024
·Vol. 21
·期 1
·1-18
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IF 9.3
Su Xi,Wang Guanyu,Liu Senqi,Li Jinming,Shao Minglong,Yang Yongfeng,Song Meng,Han Yong,Li Wenqiang,Lv Luxian
Autophagy is crucial for synaptic plasticity and the architecture of dendritic spines. However, the role of autophagy in schizophrenia (SCZ) and the mechanisms through which it affects synaptic function remain unclear. In this study, we identified 995 single nucleotide polymorphisms (SNPs) across 19 autophagy-related genes that are associated with SCZ. Gene Set Enrichment Analysis (GSEA) of data from the Gene Expression Omnibus public database revealed defective autophagy in patients with SCZ. Using a maternal immune activation (MIA) rat model, we observed that autophagy was downregulated during the weaning period, and early-life activation of autophagy with rapamycin restored abnormal behaviors and electrophysiological deficits in adult rats. Additionally, inhibition of autophagy with 3-Methyladenine (3-MA) during the weaning period resulted in aberrant behaviors, abnormal electrophysiology, increased spine density, and reduced microglia-mediated synaptic pruning. Furthermore, 3-MA treatment significantly decreased the expression and synaptosomal content of complement, impaired the recognition of C3b and CR3, indicating that autophagy deficiency disrupts complement-mediated synaptic pruning. Our findings provide evidence for a significant association between SCZ and defective autophagy, highlighting a previously underappreciated role of autophagy in regulating the synaptic and behavioral deficits induced by MIA.
研究领域:
神经科学
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分子生物学
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行为科学
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遗传学
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DOI
PubMed
高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
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2023
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IF 8.4
Zhenru Li,Lili Liang,Wenfu Lin,Yan Huang,Tiansheng Huang,Wei Wang,Jun Ma,Jie Li,Li-Peng Sun,Bai-Ou Guan
Dopamine (DA) is a biomarker of many psychiatric diseases, such as schizophrenia and Parkinson's disease. Most current DA detection research adopts electrochemical method , which suffers interferences caused by many analogs with similar structures or redox potentials . To realize highly sensitive and selective DA sensing, herein we propose an optofluidic-laser-based DA sensor. Via the competitive adsorption mechanism, rhodamine 6G (Rh6G) is fixed on graphene oxide (GO) and replaced by DA in the sample, with the re-excited Rh6G serving as the gain medium of the optofluidic laser. As the DA concentration increases, more Rh6G is released into the sample, which induces an increase in the relative slope efficiency of the optofluidic laser and a reduction in the laser threshold. Both the relative slope efficiency and threshold attain a suitable linear relationship with the DA concentration within the 5–800 μM range. Under ideal circumstances, the detection limit of the biosensor is 0.3 µM. Moreover, the optofluidic laser-based biosensor achieves favorable selectivity for DA detection, proving the advantages of using optical laser sensors for DA detection in complex samples.
研究领域:
生物医学工程
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分析化学
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光学
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纳米技术
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DOI
高影响因子
MICROCHEMICAL JOURNAL
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2023
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IF 4.8
Chao Chen,Jiayue Ren,Pengcheng Zhao,Jin Zhang,Yongjun Hu,Junjie Fei
Dopamine (DA) is an important neurotransmitter in human’s brain, which has direct connection to diseases like Parkinson’s disease, schizophrenia, etc. Therefore, the sensitive and rapid quantitative detection of DA is essential for medical diagnosis and disease prevention. To construct a novel electrochemical sensor for DA detection, nickel-based metal–organic frameworks (Ni–MOF) were synthesized through a hydrothermal method and combined with β-cyclodextrin. Under optimal experimental conditions, the sensor exhibited a wide linear detection range (0.7–310.2 μM) and a low detection limit (0.227 μM). Furthermore, the sensor exhibited satisfactory stability and accuracy in an electrochemical study involving human serum and dopamine hydrochloride injection samples containing DA, and the redox mechanism of the sensor was elucidated. Overall, this study presents a novel electrochemical sensor based on cyclodextrins and MOFs for DA detection.
研究领域:
分析化学
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神经科学
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电化学
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生物传感器
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）