CN112773800B - 哌啶-1-二硫代甲酸-3-甲基-1,4-二氧-1,4-二氢萘-2-甲基酯的用途 - Google Patents
哌啶-1-二硫代甲酸-3-甲基-1,4-二氧-1,4-二氢萘-2-甲基酯的用途 Download PDFInfo
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Abstract
本发明公开了一种哌啶‑1‑二硫代甲酸‑3‑甲基‑1,4‑二氧‑1,4‑二氢萘‑2‑甲基酯的用途,是在治疗帕金森疾病中的应用。本发明实验结果发现,帕金森模型(PD)小鼠采取灌胃方式给予PKM2‑IN‑1,发现该药物可显著缓解PD相关症状,如恢复黑质部位多巴胺能神经元数量,提高中脑部位酪氨酸羟化酶的表达,提高小鼠运动能力和嗅觉功能。
Description
技术领域
本发明涉及一种化合物哌啶-1-二硫代甲酸-3-甲基-1,4-二氧-1,4-二氢萘-2-甲基酯的用途。
背景技术
帕金森病(PD)又称为震颤性麻痹,是一种仅次于阿尔茨海默病之后、严重影响人类生存质量的第二大神经退行性疾病。据统计,全世界每800人中就有1人患有帕金森,到2030年,由于老龄化进程的加速,帕金森患病率将翻一番,预计超过900万患者。患者每年的直接医疗费用预计超过10,000美元,对家庭和社会造成了沉重的负担。帕金森具有进行性、多发性和起病隐匿等特点,主要表现为行动迟缓、肌强直、静止性震颤和姿势不稳。帕金森的主要病理学特征主要表现为黑质部位多巴胺能神经元细胞的减少。脑内产生多巴胺的细胞逐渐丧失了影响神经系统的功能,使患者控制肌肉的能力受到限制。临床对于帕金森的治疗,主要以多巴胺替代疗法为主。长期使用该疗法可引起多种不良反应,如不安、失眠、幻觉等精神症状。因此,寻找新的PD治疗药物具有巨大的经济利益和社会价值。
发明内容
本发明的目的在于提供一种哌啶-1-二硫代甲酸-3-甲基-1,4-二氧-1,4-二氢萘-2-甲基酯的用途。
本发明的技术解决方案是:
一种哌啶-1-二硫代甲酸-3-甲基-1,4-二氧-1,4-二氢萘-2-甲基酯在制备治疗帕金森疾病制剂中的应用。
本发明得到了哌啶-1-二硫代甲酸-3-甲基-1,4-二氧-1,4-二氢萘-2-甲基酯在治疗帕金森疾病中的应用。本发明的实验结果,帕金森模型(PD)小鼠采取灌胃方式给予PKM2-IN-1,发现该药物可显著缓解PD相关症状,如恢复黑质部位多巴胺能神经元数量,提高中脑部位酪氨酸羟化酶的表达,提高小鼠运动能力和嗅觉功能。
附图说明
下面结合附图和实施例对本发明作进一步说明。
图1是化合物哌啶-1-二硫代甲酸-3-甲基-1,4-二氧-1,4-二氢萘-2-甲基酯(Piperdine-1-carbodithioic acid-3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-ylmethyl ester)结构式。
图2是哌啶-1-二硫代甲酸-3-甲基-1,4-二氧-1,4-二氢萘-2-甲基酯(PKM2-IN-1)减轻帕金森模型小鼠运动功能障碍示意图。其中:A:实验流程;B:悬尾实验;C:爬杆实验;D:嗅觉实验。PKM2-IN-1:哌啶-1-二硫代甲酸-3-甲基-1,4-二氧-1,4-二氢萘-2-甲基酯;MPTP:N-甲基-4-苯基-1,2,3,6-四氢化吡啶(N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)。*p<0.05,**p<0.01,one-way ANOVA分析。
图3是哌啶-1-二硫代甲酸-3-甲基-1,4-二氧-1,4-二氢萘-2-甲基酯(PKM2-IN-1)缓解帕金森模型小鼠黑质部位多巴胺能神经元的丢失示意图。其中:A:黑质部位多巴胺能神经元形态学分析。利用TH抗体进行免疫组织化学分析。B:中脑部位TH蛋白表达量分析。蛋白表达量利用western blot方法进行分析。TH:酪氨酸羟化酶(tyrosine hydroxylase);Vehicle:对照组;PKM2-IN-1:哌啶-1-二硫代甲酸-3-甲基-1,4-二氧-1,4-二氢萘-2-甲基酯;MPTP:N-甲基-4-苯基-1,2,3,6-四氢化吡啶(N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)。**p<0.01,***p<0.001,##p<0.01,one-way ANOVA分析。
具体实施方式
一种哌啶-1-二硫代甲酸-3-甲基-1,4-二氧-1,4-二氢萘-2-甲基酯在制备治疗帕金森疾病制剂中的应用。
实验步骤
1.帕金森动物模型制备
12周龄C57BL/6J雄性小鼠,采用腹腔注射神经毒素MPTP(N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine)方法诱导PD模型小鼠。在给药前三天,每天对小鼠进行转棒,爬杆等一系列的行为学训练。尽量挑选运动能力在同一水平的小鼠,避免个体差异造成的影响,分为两组。一组为生理盐水组,另一组为MPTP组。接着对其行腹腔注射MPTP(20mg/kg/day),连续注射一周,再进行行为学评估。与对照小鼠(注射同等体积的生理盐水)相比,行为学具有显著下降的小鼠被认为是诱导成功的PD模型小鼠,用于后续实验。
2.给药处理
哌啶-1-二硫代甲酸-3-甲基-1,4-二氧-1,4-二氢萘-2-甲基酯溶于玉米油。采用灌胃给药方式处理小鼠,给药剂量为50mg/kg/day,每天一次,连续给药7天。对照小鼠给予同等体积的玉米油。
3.小鼠悬尾实验
小鼠悬尾实验中不动时间可以反映抑郁状态,具体方法是将小鼠尾部后1/3处用胶带固定,悬挂于50cm高的泡沫盒上,使小鼠头部距离台面15cm,然后进行10min录像,观察小鼠在这段时间内不动的时间。
4.爬杆实验
制作一个直径1cm,长50cm并且顶端固定有一个直径为1.5cm的软木小球的杆,并且缠上纱布以增加摩擦,将杆竖直放置,将小鼠放到自制爬杆顶端的小球上,然后记录动物从开始运动到完全转为头向下直到返回到杆底部的时间,每次检测间隔5分钟,共检测3次取平均值。在尾静脉注射之前三天,每天在同样时间对小鼠进行爬杆训练,把差异较大的小鼠剔除以减小实验误差。
5.嗅觉功能实验
嗅觉实验检测前提前喂食老鼠奶酪,在嗅觉测试前禁食20h,测试过程中将老鼠放进干净垫料的笼盒,分别在中间,左上,右上,左下,右下依次在垫料下2cm埋乳酪,检测老鼠找到奶酪的时间。
6.黑质部位多巴胺能神元形态学分析
利用组织化学方法对实验小鼠黑质部位酪氨酸羟化酶阳性细胞进行染色,主要操作步骤如下:1.取材的小鼠脑组织放于4%多聚甲醛中,放于4℃冰箱24小时;2.1X PB配制20%,30%蔗糖,依次脱水24小时,如组织未沉入底部适当将时间延长;3.脱水脑组织切片处理,调节厚度为12μm,37℃烘箱过夜,-20℃保存;4.染色前60℃烘片2小时,5.PBS洗3次,每次5分钟;6.封闭液封闭,37℃,30分钟;6.PBS洗2次,内源性过氧化氢酶阻断剂5分钟;7.PBS洗2次,非特异性染色阻断剂30分钟,37℃烘箱;8.与TH抗体(1:200)4℃冰箱过夜;9.PBS洗2次,加生物素标记的羊抗鼠/兔IgG,37℃,1小时;10.PBS洗2次,加链霉卵白素-过氧化物酶,37℃,1小时;11.PBS洗2次,进行DAB显色;12.酒精脱水,依次为50%酒精,70%酒精,80%酒精,95%酒精两道,100%酒精两道,每道5分钟;13.无水乙醇和二甲苯,二甲苯透明三道,每道5分钟,中性树脂封片后用显微镜观察拍照。TH阳性细胞数量用StereoInvestigator软件统计分析。
7.黑质部位蛋白样品制备及表达水平检测
组织裂解液配方:25mM Tris-HCl,pH 7.4;10mM NaF;10mM Na4P2O7;2mM Na3VO4;1mM EGTA;1mM EDTA;1%NP-40;10μg/ml Leupeptin;10μg/ml Aprotinin;2mM PMSF;20nMOkadaic acid。用台式匀浆器(Polytron,PT2100)匀浆,样品于4℃旋转裂解1小时后离心(13000rpm,4℃)20分钟,离心后小心去除上层脂质,其余上清转至另一离心管并再次离心。这一过程重复2次以彻底去除蛋白样品中的脂质。样品蛋白含量用蛋白测定试剂盒测定,根据所得结果将所有样品的蛋白浓度调至相同水平,加入上样缓冲液,混匀后于100℃煮5分钟,冷却至室温用于western blot分析。
将上述步骤所得的样品用聚丙烯酰胺凝胶电泳(SDS-PAGE)分离,并将胶上蛋白转至PVDF膜。转膜结束后的PVDF膜用含5%牛血清白蛋白的TBST(Tris-buffered salinesolution/Tween)缓冲液室温封闭1小时。封闭后的PVDF与一抗共孵过夜(4℃)。与一抗作用结束后,用TBST洗PVDF膜三次,再与二抗室温作用1小时。二抗作用结束后用TBST洗三次。最后PVDF膜用化学发光反应体系(chemiluminescence assay system,Roche)反应,并曝光至X胶片(Kodak)。各蛋白表达水平定量用软件Quantity-One(Bio-Rad)分析。
Claims (1)
1.一种哌啶-1-二硫代甲酸-3-甲基-1,4-二氧-1,4-二氢萘-2-甲基酯在制备治疗帕金森疾病制剂中的应用。
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AU2021314940A AU2021314940B2 (en) | 2021-01-25 | 2021-09-05 | Use of piperdine-1-carbodithioic acid-3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-ylmethyl ester |
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