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Fast-onset antidepressant targeting the nNOS-SERT interaction in the DRN

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Chinese Journal of Natural Medicines 2023年第1期21卷 1-2页

作者： GUAN Xin PANG Tao State Key Laboratory of Natural Medicines New Drug Screening CenterChina Pharmaceutical UniversityNanjing 210009China

Major depressive disorder is one of the most deleterious mental disorders with a high suicide rate,incidence and recurrence rate,which is manifested as continuous depression,retardation of thinking as well as loss of ... 详细信息

关键词： Depression nNOS SERT Antidepressant Fast-onset

nNOS-mediated protein-protein interactions:promising targets for treating neurological and neuropsychiatric disorders

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The Journal of Biomedical Research 2021年第1期35卷 1-10页

作者： Yuanyuan Gu Dongya Zhu Department of Pharmacology School of PharmacyNanjing Medical UniversityNanjingJiangsu 211166China Institution of Stem Cell and Neuroregeneration School of PharmacyNanjing Medical UniversityNanjingJiangsu 211166China

Neurological and neuropsychiatric disorders are one of the leading causes of disability worldwide and affect the health of billions of people.Nitric oxide(NO),a free gas with multitudinous bioactivities,is mainly produced from the oxidation of L-arginine by neuronal nitric oxide synthase(nNOS)in the brain.Inhibiting nNOS benefits a variety of neurological and neuropsychiatric disorders,including stroke,depression and anxiety disorders,posttraumatic stress disorder,Parkinson’s disease,Alzheimer’s disease,chronic pain,and drug addiction.Due to critical roles of nNOS in learning and memory and synaptic plasticity,direct inhibition of nNOS may cause severe side effects.Importantly,interactions of several proteins,including post-synaptic density 95(PSD-95),carboxyterminal PDZ ligand of nNOS(CAPON)and serotonin transporter(SERT),with the PSD/Disc-large/ZO-1 homologous(PDZ)domain of nNOS have been demonstrated to influence the subcellular distribution and activity of the enzyme in the brain.Therefore,it will be a preferable means to interfere with nNOS-mediated proteinprotein interactions(PPIs),which do not lead to undesirable effects.Herein,we summarize the current literatures on nNOS-mediated PPIs involved in neurological and neuropsychiatric disorders,and the discovery of drugs targeting the PPIs,which is expected to provide potential targets for developing novel drugs and new strategy for the treatment of neurological and neuropsychiatric disorders.

关键词： nNOS PSD-95 CAPON SERT protein-protein interaction neurological and neuropsychiatric disorder

Chinese herbal medicine enhances sexual function and c-Fos/nNOS expression in the nucleus accumbens of orchidectomized rats

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Journal of Traditional Chinese Medicine 2016年第3期36卷 347-352页

作者： Liu Hongyu Cui Jianmei Zhai Haifeng Xue Jinjuan Wang Xiaoyang Institute of Sport and Exercise Medicine North University of China National Institute on Drug Dependence Peking University School of Physical Education Shanxi University

OBJECTIVE: To determine whether the central nervous system is involved in the effect of Chinese herbal medicine on sexual function recovery in orchidectomized rats.METHODS: Orchidectomized rats were administered intragastrically with a decoction of "kidneynourishing" Chinese herbal medicine once per day for 28 days. Accessory genital organ weight, plasma testosterone, and mating behavior were investigated. The expression of c-Fos and neuronal nitric oxide synthase(n NOS) in neuronal cells in the nucleus accumbens(NAc) was analyzed by immunohistochemistry.RESULTS: There was a decrease in accessory genital organ weight, plasma testosterone, and sexual behavior, as well as a low number of c-Fos-positive cells and a large n NOS-positive cell area in orchidectomized rats. Administration of the herbal medicine increased accessory genital organ weight, testosterone level, mating behavior, and c-Fos-positive cell number, while it decreased the n NOS-positive cell area in orchidectomized rats.CONCLUSION: An increase of plasma testosterone after administration of "kidney-nourishing" herbal medicine might contribute to the elevated sexual function and activity in orchidectomized rats. In addition, a central nervous system mechanism, such as the functional alteration of NAc, might be involved.

关键词： c-fos nNOS 雄性大鼠伏隔核中药神经元型一氧化氮合酶去睾丸中枢神经系统

Moutan Cortex Radicis inhibits the nigrostriatal damage in a 6-OHDA-induced Parkinson's disease model

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Chinese Journal of Natural Medicines 2018年第7期16卷 490-498页

作者： Yeong-Gon Choi Yeon-Mi Hong Li-Hua Kim Sujung Yeo Sabina Lim Laboratory of Neurodegenerative Diseases Ilsong Institute of Life Science Hallym University Research Group of Pain and Neuroscience WHO Collaborating Center for Traditional Medicine East-West Medical Research Institute Kyung Hee University Department of Applied Korean Medicine College of Korean Medicine Kyung Hee University Department of Meridian and Acupoint College of Korean Medicine Sang Ji University

The traditionally used oriental herbal medicine Moutan Cortex Radicis [MCR; Paeonia Suffruticosa Andrews(Paeoniaceae)] exerts anti-inflammatory, anti-spasmodic, and analgesic effects. In the present study, we investigated the therapeutic effects of differently fractioned MCR extracts in a 6-hydroxydopamine(OHDA)-induced Parkinson's disease model and neuro-blastoma B65 cells. Ethanol-extracted MCR was fractionated by n-hexane, butanol, and distilled water. Adult Sprague-Dawley rats were treated first with 20 μg of 6-OHDA, followed by three MCR extract fractions(100 or 200 mg·kg^(-1)) for 14 consecutive days. In the behavioral rotation experiment, the MCR extract-treated groups showed significantly decreased number of net turns compared with the 6-OHDA control group. The three fractions also significantly inhibited the reduction in tyrosine hydroxylase-positive cells in the substantia nigra pars compacta following 6-OHDA neurotoxicity. Western blotting analysis revealed significantly reduced tyrosine hydroxylase expression in the substantia nigra pars compacta in the 6-OHDA-treated group, which was significantly inhibited by the n-hexane or distilled water fractions of MCR. B65 cells were exposed to the extract fractions for 24 h prior to addition of 6-OHDA for 30 min; treatment with n-hexane or distilled water fractions of MCR reduced apoptotic cell death induced by 6-OHDA neurotoxicity and inhibited nitric oxide production and neuronal nitric oxide synthase expression. These results showed that n-hexane-and distilled water-fractioned MCR extracts inhibited 6-OHDA-induced neurotoxicity by suppressing nitric oxide production and neuronal nitric oxide synthase activity, suggesting that MCR extracts could serve as a novel candidate treatment for the patients with Parkinson's disease.

关键词： Anti-inflammatory agent Neuroblastoma B65 cells 6-Hydroxydopamine Nitric oxide nNOS

矿物药青礞石对戊四氮点燃癫痫大鼠干预作用研究

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中药材 2016年第1期39卷 155-159页

作者：吴露婷刘圣金吴德康喻斌王宇华王瑞杨江南京中医药大学药学院/江苏省中药资源产业化过程协同创新中心/中药资源产业化与方剂创新药物国家地方联合工程研究中心江苏南京210023 江苏省中医院江苏南京210029

目的:探讨青礞石对戊四氮点燃癫痫大鼠的干预作用。方法:将戊四氮点燃成功的癫痫模型大鼠给药后取脑组织海马区,采用HE染色显微观察组织病理学改变,免疫组化法检测nNOS蛋白表达,黄嘌呤氧化酶法检测T-SOD活性、硫代巴比妥酸法检测MDA含... 详细信息

目的:探讨青礞石对戊四氮点燃癫痫大鼠的干预作用。方法:将戊四氮点燃成功的癫痫模型大鼠给药后取脑组织海马区,采用HE染色显微观察组织病理学改变,免疫组化法检测nNOS蛋白表达,黄嘌呤氧化酶法检测T-SOD活性、硫代巴比妥酸法检测MDA含量、定磷法检测Na+,K+-ATPase及Ca2+,Mg2+-ATPase活性。结果:青礞石粉末、药渣及水煎液均能降低大鼠海马区的病变程度、提高T-SOD活性、降低MDA含量、提高Na+,K+-ATPase及Ca2+,Mg2+-ATPase活性、降低nNOS的蛋白表达,其作用强度依次为:粉末>药渣>水煎液。结论:青礞石具有抗癫痫作用,其机制可能是通过提高脑组织的抗氧化能力,清除氧自由基,保护膜功能,维持脑内离子浓度动态平衡,抑制脑部异常放电,最终达到治疗癫痫的效果。

关键词：矿物药青礞石癫痫海马 nNOS ATP酶 T-SOD MDA

小鼠髓过氧化物酶(MPO)基因克隆分析及真核表达载体的构建

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中国兽医学报 2021年第1期41卷 129-136,142页

作者：甘泽王琪王媛媛赵彩英李怡娜张全伟马友记张勇赵兴绪甘肃农业大学动物医学学院甘肃兰州730070 甘肃农业大学生命科学与技术学院甘肃兰州730070 甘肃农业大学动物科学技术学院甘肃兰州730070

髓过氧化物酶(myeloperoxidase,MPO)是一种血红素辅基蛋白酶,是血红素过氧化物酶超家族成员之一,参与多种疾病的发生和发展过程。本研究旨在克隆小鼠MPO基因CDS全长序列,检测该基因在小鼠神经细胞的表达谱。首先利用RT-PCR法与克隆载体... 详细信息

髓过氧化物酶(myeloperoxidase,MPO)是一种血红素辅基蛋白酶,是血红素过氧化物酶超家族成员之一,参与多种疾病的发生和发展过程。本研究旨在克隆小鼠MPO基因CDS全长序列,检测该基因在小鼠神经细胞的表达谱。首先利用RT-PCR法与克隆载体克隆小鼠MPO基因CDS全长序列,对其进行生物信息学分析;然后构建真核表达载体pEGFP-C1-MPO,瞬时转染小鼠神经元细胞,通过qRT-PCR、Western blot和免疫荧光检测MPO在神经细胞的表达及分布规律。结果显示,小鼠MPO基因CDS全长2171 bp,编码718个氨基酸,与章鱼、美洲灰熊、马、人、非洲爪蟾、扬子鳄等物种的氨基酸序列同源性均高于79.25%。转染细胞后,试验组MPO的mRNA和蛋白表达水平极显著高于阴性对照组(PnNOS的mRNA水平显著高于对照组(PnNOS表达,抑制NADPH的表达,这为今后深入研究MPO的功能奠定理论基础。

关键词：小鼠 MPO基因 nNOS NADPH

运动预干预对睡眠剥夺大鼠学习记忆及海马nNOS表达的影响

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神经解剖学杂志 2019年第3期35卷 317-322页

作者：崔建梅郭燕兰李中华杨洁于芳苏晓云中北大学体育学院太原030051 山西医科大学汾阳学院汾阳030001

目的:探讨跑台运动预干预对完全睡眠剥夺(TSD)大鼠空间学习记忆能力、海马单胺类神经递质水平和神经元型一氧化氮合酶(nNOS)表达的影响。方法:将40只大鼠随机分为对照组(CON)、运动组(EX)、完全睡眠剥夺组(TSD)及睡眠剥夺运动组(EX+TSD... 详细信息

目的:探讨跑台运动预干预对完全睡眠剥夺(TSD)大鼠空间学习记忆能力、海马单胺类神经递质水平和神经元型一氧化氮合酶(nNOS)表达的影响。方法:将40只大鼠随机分为对照组(CON)、运动组(EX)、完全睡眠剥夺组(TSD)及睡眠剥夺运动组(EX+TSD)。除CON组及TSD组大鼠,EX组和EX+TSD组大鼠进行跑台运动预干预4周,运动结束后建立大鼠72 h睡眠剥夺模型(小平台水环境法),然后运用八臂迷宫实验(ERM)评估大鼠空间学习记忆能力,用高效液相-电化学法检测大鼠海马单胺类神经递质多巴胺(DA)、去甲肾上腺素(NE)、5-羟色胺(5-HT)的表达水平,用免疫组化法检测海马一氧化氮合酶(nNOS)神经元的表达。结果:(1)与CON组比较,ERM实验中TSD组大鼠工作记忆错误次数(WME)、参考记忆错误次数(RME)均显著增多,正确反应的次数(CN)减少,完成八臂迷宫时间显著延长(P nNOS阳性细胞平均光密度显著增加(P 0. 05),海马nNOS阳性细胞平均光密度显著下降(P nNOS活性、减弱高浓度NO的神经毒性纠正TSD大鼠单胺类神经系统紊乱,对睡眠剥夺引起的海马神经元损害具有保护作用有关。

关键词：跑台运动睡眠剥夺学习记忆单胺类神经递质 nNOS 大鼠

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PDZ结构域有望成为新药靶点

中国新药杂志 2019年第11期28卷 1325-1329页

作者：朱志颖秦亚娟厉廷有南京医科大学药学院南京211166

PDZ结构域是蛋白质中最常见的肽结合区域之一,它涉及许多关键信号通路。以突触后致密蛋白-95(PSD-95) PDZ结构域为靶点,设计合成的Tat-NR2B9C和ZL006,显示神经保护活性;以神经元型一氧化氮合酶(nNOS) PDZ结构域为靶点,设计合成的ZLc-002... 详细信息

PDZ结构域是蛋白质中最常见的肽结合区域之一,它涉及许多关键信号通路。以突触后致密蛋白-95(PSD-95) PDZ结构域为靶点,设计合成的Tat-NR2B9C和ZL006,显示神经保护活性;以神经元型一氧化氮合酶(nNOS) PDZ结构域为靶点,设计合成的ZLc-002,显示抗焦虑活性。本文重点介绍PDZ结构域的结构、分类及有望以含PDZ结构域的蛋白为靶点开发出治疗急性缺血性脑卒中和焦虑症的新药。

关键词： PDZ结构域 PSD-95 nNOS Tat-NR2B9C ZL006 ZLc-002

nNOS PDZ抑制剂的合成及其神经保护作用研究

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南京医科大学学报（自然科学版） 2014年第3期34卷 314-322页

作者：马玉丁屹蔡鋆鑫常磊朱东亚厉廷有南京医科大学药学院江苏南京211166 南京医科大学心血管转化医学协同创新中心江苏南京210029

目的:合成nNOS PDZ抑制剂并评价其神经保护作用。方法:根据nNOS PDZ结构域配体结合部位多碱性中心的结构特点设计并合成多系列双羧酸及其酯类化合物,用谷氨酸诱导的神经元细胞乳酸脱氢酶释放模型评价化合物的神经保护作用。结果:合成了1... 详细信息

目的:合成nNOS PDZ抑制剂并评价其神经保护作用。方法:根据nNOS PDZ结构域配体结合部位多碱性中心的结构特点设计并合成多系列双羧酸及其酯类化合物,用谷氨酸诱导的神经元细胞乳酸脱氢酶释放模型评价化合物的神经保护作用。结果:合成了18个目标化合物,其中N-(2-甲氧羰基乙酰基)-D-缬氨酸甲酯(1)、N-(2-羧基乙酰基)-D-缬氨酸甲酯(2)、N-(2-甲氧羰基乙酰基)-L-缬氨酸甲酯(7)、N-(2-羧基乙酰基)-L-缬氨酸(9)显示较强的神经保护作用。结论:nNOS PDZ结构域抑制剂具有神经保护作用。

关键词：神经保护剂 nNOS 乳酸脱氢酶