CN116549632A - 抗Lingo-1抗体Opicinumab的新用途及针对新用途的药物 - Google Patents
抗Lingo-1抗体Opicinumab的新用途及针对新用途的药物 Download PDFInfo
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Abstract
本发明公开了抗Lingo‑1抗体Opicinumab的新用途及针对新用途的药物,本发明提供了抗Lingo‑1抗体Opicinumab在特异性抑制幻觉作用中的新用途及包含抗Lingo‑1抗体Opicinumab的药物,本发明首次发现并验证了Opicinumab在特异性抑制幻觉作用中的应用,为本领域抗幻觉药物的开发奠定了理论基础。
Description
技术领域
本发明属于生物医药技术领域,具体地,本发明涉及抗Lingo-1抗体Opicinumab的新用途及针对新用途的药物。
背景技术
据2017年世界卫生组织统计,全球约有3.22亿抑郁症患者,而抑郁症患者近十年的增速为18%,抑郁症患者中的自杀率高达6%。目前市售的传统抗抑郁药物通常需要长达几周甚至几个月后才能起效,并且仅有50%的抑郁症患者治疗后完全康复,35%发展为复发性抑郁障碍,15%会发展为药物抵抗从而无药可用。近年来,多种经典致幻剂在抑郁症治疗方面展现出了一定的潜能。经典致幻剂是一类作用于5-HT受体的精神活性物质,主要通过激活5-HT2A受体诱导感觉和情绪的变化以及幻觉作用,其中,天然的经典致幻剂裸盖菇素(Psilocybin)于2019年被美国FDA授予作为治疗重度抑郁症和药物抵抗性抑郁症的突破性疗法。美国Ⅱ期临床研究结果表明,裸盖菇素在一天内可以极大地改善抑郁症患者的相关症状,且效果可持续三个月以上。但是,经典致幻剂本身的致幻副作用极大地限制了它们的临床研究和广泛应用。因此,全世界的科学家一直致力于寻找和研发在保证经典治疗剂快速起效的治疗作用的同时能够抑制其诱导的幻觉作用这一副反应的药物。
抗Lingo-1抗体Opicinumab又称为BIIB033,是一种靶向细胞因子Lingo-1的人源化抗体。Lingo-1是一种跨膜信号蛋白,主要在神经元及少突胶质细胞中表达。研究表明,Lingo-1是在髓鞘形成过程中的主要负调控因子。Nogo受体复合物能够抑制神经元的生长,而Lingo-1在Nogo受体复合物中是以完整形式存在的,到目前为止,细胞外信号通过Lingo-1介导抑制髓鞘形成的机制还不明确。Opicinumab可以维持髓鞘的正常形态和功能,修复损伤的髓鞘,恢复神经功能,被认为是首个可以治愈多发性硬化症(Multiple sclerosis,MS)的潜力新药,而不仅仅是延缓疾病进展。此外,Opicinumab也能够用于临床治疗急性视神经炎,有临床前研究发现Opicinumab注射到中枢神经系统中可诱导强大的髓鞘再生。然而,目前尚未见Opicinumab在特异性抑制经典致幻剂诱导的幻觉作用中的应用。
发明内容
基于此,为了克服现有技术中存在的不足之处,本发明的目的在于公开抗Lingo-1抗体Opicinumab的新用途及针对新用途的药物,即抗Lingo-1抗体Opicinumab在特异性抑制幻觉作用中的新用途及包含抗Lingo-1抗体Opicinumab的药物。
本发明采用如下技术方案实现上述目的:
本发明的第一方面提供了Lingo-1拮抗剂在制备特异性抑制幻觉作用的药物中的用途。
进一步,所述Lingo-1拮抗剂为Opicinumab。
进一步,所述幻觉作用为5HT2A受体介导的幻觉作用。
进一步,所述药物包含有效量的Opicinumab。
在本发明中,所述幻觉为5HT2A受体介导的幻觉,即经典致幻剂作用于5-HT受体,通过激活5-HT2A受体诱导产生的幻觉作用。所述经典致幻剂包括但不限于:2,5-二甲氧基-4-甲基苯丙胺(DOM)、赛洛西滨(Psilocybin)、赛洛辛(Psilocin)、2,5-二甲氧基-4-碘苯丙胺(DOI)、麦角酰二乙胺(LSD)、N,N-二甲基色胺(DMT)。此外,所述幻觉作用并不局限于经典致幻剂诱导产生的幻觉作用,其他致幻剂(例如,酒精、吗啡等)诱导产生的病理性的幻觉作用均在本发明所述的经典致幻剂的保护范围内。
在本发明中,所述Opicinumab为一种靶向细胞因子Lingo-1的人源化抗体,在本发明的具体实施方案中,所述Opicinumab优选为购自于武汉科斯坦生物科技有限公司、货号为CSD00391的Opicinumab。
进一步,在本发明的具体实施方案中,本发明以经典致幻剂DOM或Psilocin诱导的甩头小鼠模型为例,代表性地研究了本发明所述的Opicinumab对致幻剂诱导的幻觉作用的影响,所述致幻剂并不局限于本发明所列出的具体致幻剂,只要是能够引起幻觉作用的致幻剂均在本发明的保护范围内。在本发明的具体实施方案中,所述致幻剂优选为作用于5-HT受体通过激活5-HT2A受体诱导产生幻觉作用的经典致幻剂。
进一步,本发明所采用的甩头小鼠模型是目前本领域最常用的研究致幻行为的动物模型。甩头反应(HTR)是一种头部快速的左右旋转行为,在给予大鼠和小鼠5-羟色胺能致幻剂或其他5-HT2A激动剂后出现,甩头反应被广泛用作5-HT2A受体激活的行为测定。小鼠的甩头反应效果和人类致幻效果之间存在很强的正相关性,也即甩头反应能够指征幻觉行为的产生。
本发明的第二方面提供了一种用于特异性抑制幻觉的药物组合物。
进一步,所述药物组合物包含有效量的Opicinumab。
进一步,所述药物组合物还包含药学上可接受的赋形剂。
进一步,所述药学上可接受的赋形剂包括填充剂、崩解剂、粘合剂、表面活性剂。
进一步,所述填充剂包括乳糖、糊精、微晶纤维、淀粉、山梨醇、甘露醇、预胶化淀粉。
进一步,所述崩解剂包括交联聚维酮、交联羧甲基纤维素钠、羧甲基淀粉钠、羟丙基纤维素。
进一步,所述粘合剂包括淀粉浆、淀粉浆钠、羟丙甲纤维素、聚维酮。
进一步,所述表面活性剂包括十二烷基磺酸钠、十六烷基硫酸钠、硬脂酸、油酸、月桂酸。
进一步,所述药学上可接受的赋形剂还包括润滑剂,优选地,所述润滑剂包括硬脂酸镁、滑石粉、聚乙二醇等。
进一步,所述药物组合物中还可以加入药学上可接受的助悬剂、助溶剂、矫味剂、防腐剂、抗氧化剂和稳定剂等;
优选地,所述助悬剂可以是阿拉伯胶、西黄蓍胶、桃胶、甲基纤维素、羧甲基纤维素钠、羟丙基纤维素、硅皂土等;
优选地,所述助溶剂可以是盐酸、磷酸、丙酸、醋酸、乳酸、枸橼酸、酒石酸、硼酸、葡萄糖醛酸、葡萄糖酸、乳糖酸、苹果酸、苏糖酸、葡庚糖酸、2,5-二羟基苯甲酸、酸式氨基酸等;
优选地,所述矫味剂可以是糖精钠、甜蜜素、阿斯巴甜、乙酰舒泛-k、甘油、山梨醇、甘露醇、蔗糖、单糖浆、芳香糖浆等;
优选地,所述防腐剂可以是苯酚、甲酚、氯甲酚、麝香草酚、苯甲酸及其盐类、山梨酸及其盐类、硼酸及其盐类、丙酸、甲醛、戊二醛、苯甲醇、苯乙醇、三氯叔丁醇、氯仿、氯己定等;
优选地,所述抗氧化剂和稳定剂可以是亚硫酸、亚硫酸盐、亚硫酸氢盐、焦亚硫酸盐、连二亚硫酸盐、硫代硫酸盐、硫脲、谷胱甘肽、二巯基丙醇、巯基乙酸及盐、硫代乳酸及盐、硫代二丙酸及盐、没食子酸及盐、咖啡酸或其药用盐、阿魏酸或其药用盐、二叔丁基对苯酚、2,5-二羟基苯甲酸或其盐、水杨酸或其盐、抗坏血酸及抗坏血酸盐、异抗坏血酸及异抗坏血酸盐、烟酰胺、酒石酸、磷酸盐、醋酸药用盐、柠檬酸盐、EDTA及EDTA盐等。
在具体的实施方案中,具体选用什么赋形剂、助悬剂、助溶剂、矫味剂、防腐剂、抗氧化剂和稳定剂和本发明所述的药物组合物进行搭配,根据所需要制成的制剂而定,制成普通的制剂时,选用何种赋形剂、助悬剂、助溶剂、矫味剂、防腐剂、抗氧化剂和稳定剂是本领域技术人员所熟知的。
进一步,所述药物/药物组合物的适合的给药剂量根据制剂化方法、给药方式、患者的年龄、体重、性别、病态、饮食、给药时间、给药途径、排泄速度及反应灵敏性之类的因素而可以进行多种处方,熟练的医生通常能够容易地决定处方及处方对所希望的治疗有效的给药剂量。
进一步,所述有效量,是指可对人和/或动物产生治疗效果且可被人和/或动物所接受的量。例如,药物治疗上或药学上有效量是指产生需要的治疗效果所需要的药物的量,治疗效果可以通过临床试验结果、模型动物研究和/或体外研究的结果来反映。药学上有效量取决于几个因素,包括但不限于:治疗对象的特征因素(如治疗对象的身高、体重、性别、年龄和用药史等)、罹患疾病的严重程度。本发明中所述的活性成分Opicinumab与医学上可以接受的载体和/或辅料(用于治疗给药的载体和/或载体,它们本身并不是必要的活性成分,且施用后没有过分的毒性)可以组成药物组合物或药物制剂,这些药物组合物或药物制剂可以根据需要制备成口服制剂、注射剂、片剂、粉制剂、胶囊剂、分散片、缓释制剂等各种需要的剂型。在本发明的具体实施方案中,所述有效量是指对经典致幻剂诱导产生的幻觉作用具有抑制或减轻的作用且能够被患者所接受的量。
进一步,所述药物/药物组合物的给药方式包括但不限于:皮下注射、肌肉注射、静脉注射、口服、直肠给药、阴道给药、鼻腔给药、透皮给药、结膜下给药、眼球内给药、眼眶给药、眼球后给药、视网膜给药、脉络膜给药、鞘内注射、腹腔注射。
进一步,所述治疗有效量的本发明的药物/药物组合物可用于相关疾病或病症(如经典致幻剂诱导产生的幻觉)的单一用药或联合用药治疗。本领域技术人员能够理解,在实际给药时的用量可高于或低于实施例中记载的有效剂量范围。针对某一对象(如哺乳动物:人)的治疗有效量和具体治疗方案可受诸多因素的影响,包括所用活性成分(Opicinumab)的药效活性、给药对象的年龄、体重、一般情况、性别、饮食、给药时间、疾病易感性、疾病进程以及收治医师的判断等。此外,本领域技术人员清楚药物的给药方式、给药剂型、给药剂量受患者的年龄、体重、性别、病态、饮食、给药时间、排泄速度及反应灵敏性等众多因素的影响,因此,本发明中所述的药物/药物组合物的给药方式、给药剂型、给药剂量并不只局限于本发明中所列举出的给药方式、给药剂型、给药剂量。
进一步,本发明中所述的药物/药物组合物中还可包括其它可用于抑制或减轻幻觉作用的物质。
此外,本发明还提供了一种用于特异性抑制幻觉作用的方法,所述方法包括如下步骤:给有需要的受试者施用有效量的Opicinumab或本发明第二方面所述的药物组合物。
进一步,所述受试者是指任何动物,还指人类和非人类的动物。非人类的动物包括所有脊椎动物,例如,哺乳动物,如非人灵长类动物(特别是高等灵长类动物)、绵羊、狗、啮齿类动物(如小鼠或大鼠)、豚鼠、山羊、猪、猫、兔、牛、和任何家畜或宠物;以及非哺乳动物,如鸡,两栖类,爬行动物等。在本发明的具体实施方案中,所述受试者优选为人。
附图说明
图1为经典致幻剂DOM和Psilocin、非致幻型5-HT2A受体激动剂Lisuride和TBG腹腔给药小鼠后大脑皮层中Nogo-A和RhoA蛋白表达量变化的结果图;
图2为经典致幻剂DOM和Psilocin、非致幻型5-HT2A受体激动剂Lisuride和TBG腹腔给药小鼠后大脑皮层中Nogo-A和RhoA蛋白磷酸化变化的结果图;
图3为Opicinumab对经典致幻剂DOM诱导的小鼠甩头行为的影响结果图,其中,每组n=8-10,数据表示为平均值±SEM,*P<0.05,**P<0.01,***P<0.001,****P<0.0001,数据使用单因素方差分析(One way ANOVA)和Dunnett's检验进行分析;
图4为Opicinumab对经典致幻剂Psilocin诱导的小鼠甩头行为的影响结果图,其中,每组n=8-10,数据表示为平均值±SEM,*P<0.05,**P<0.01,***P<0.001,****P<0.0001,数据使用单因素方差分析(One way ANOVA)和Dunnett's检验进行分析;
图5为P75 NTR抑制剂TAT-Pep5对经典致幻剂DOM诱导的小鼠甩头行为的影响结果图,其中,每组n=6,数据表示为平均值±SEM,*P<0.05,**P<0.01,***P<0.001,****P<0.0001,数据使用单因素方差分析(One way ANOVA)和Dunnett's检验进行分析。
具体实施方式
下面结合具体实施例,进一步阐述本发明,仅用于解释本发明,而不能理解为对本发明的限制。本领域的普通技术人员可以理解为:在不脱离本发明的原理和宗旨的情况下可以对这些实施例进行多种变化、修改、替换和变型,本发明的范围由权利要求及其等同物限定。下列实施例中未注明具体条件的实验方法,通常按照常规条件或按照厂商所建议的条件实施检测。
实施例1Western Blot检测致幻剂作用后Nogo-A、RhoA的变化1、实验材料
本实施例中使用到的实验试剂、实验抗体和实验仪器分别见下表1-3。
表1实验试剂
表2实验抗体
表3实验仪器
本实施例中主要试剂配置:
10×电泳液running buffer:将电泳液:双蒸水按1:9配置。
10×电转液transfer buffer:将电转液:甲醇:双蒸水按1:2:7配置。
10×TBST:将TBST:双蒸水按1:9配置。
5%脱脂奶粉:取2g脱脂奶粉,加40mL的1×TBST充分溶解。
5% BSA:取2g BSA,加40mL的1×TBST充分溶解。
过硫酸铵:取1.00g过硫酸铵,溶于10mL双蒸水中。
2、Western Blot检测致幻剂作用后Nogo-A、RhoA的变化
本实施例所采用的样品为经典致幻剂DOM(1mg/kg)和Psilocin(0.5mg/kg)和非致幻型5-HT2A受体激动剂Lisuride(T61065-上海陶术生物科技有限公司)(0.1mg/kg)和TBG(军事医学研究院毒物药物研究所合成)(20mg/kg)腹腔给药小鼠(斯贝福(北京)生物技术有限公司,C57,雄性,18-22g,6-8周)后10min时大脑皮层的蛋白提取物。采用Western Blot实验检测上述样品中Nogo-A和RhoA蛋白的表达量变化。具体Western Blot实验方法如下:
(1)制胶
①选下缘平滑的玻璃板,清洗玻璃板和梳子后使用蒸馏水冲洗并吹干。
②厚、薄两块玻璃板对齐后放入夹中卡紧,垂直卡在架子。操作时要使两块玻璃板下边缘对齐,以免漏胶。
③按聚丙烯酰胺凝胶配方配制所需的分离胶,加入TEMED后立即摇匀即可灌胶。10%分离胶配方见下表4,5%浓缩胶的配方见下表5。
表4 10%分离胶配方
表5 5%浓缩胶配方
(2)灌胶与上样
①灌胶时,用枪沿玻璃板一侧加入,待胶面升到距离短板上沿15mm左右即可。然后加一层水,液封后的胶面凝的更快。灌胶时开始可快一些,胶面快达所需高度时要放慢速度。胶水液封是要很慢并且从左到右均匀一层,否则胶会被冲变型。
②当水和胶之间有一条折线时(室温下,大约20min),说明胶已凝。再等3min使胶充分凝固就可倒去上层水并用滤纸吸干。
③按聚丙烯酰胺凝胶配方配制5%的浓缩胶,加入TEMED后立即摇匀即可灌胶。将剩余空间从一侧加入灌满浓缩胶然后将梳子插入浓缩胶中。插梳子要使梳子一侧先插下去,再缓慢将另一侧插下,最后检查梳子是否水平。
④胶凝后,用蒸馏水冲洗一下凝胶,将其放入电泳槽中。薄玻璃板在内侧,厚玻璃板在外侧。若只跑一块胶,电泳槽的另一边要放置一块替代玻璃板的塑料板。
⑤将内槽加满新的电泳液后开始准备上样,内槽电泳液至少要没过内侧玻璃板,外槽加约3cm高电泳液没过玻璃板下沿即可。两手分别捏住梳子的两边垂直向上轻轻将其拔岀,用l mL移液枪对加样孔进行吹打冲洗,加样是用移液器吸取样品,枪尖插至加样孔上方两板间隙处缓慢加入样品。未加样的孔需用1×loading buffer补齐。
(3)电泳
①选择恒压80V进行电泳,样品进入分离胶后可将电压调至120V加快速度。电泳至溴酚蓝跑到胶的下边缘即可终止电泳。
(4)转膜
①准备一块PVDF膜,面积略大于所要转印的胶面面积。转印一块胶需要8张薄滤纸或4张厚滤纸(8×10cm)。如果是PVDF膜,使用前需用甲醇活化30-60s且转膜液中配方含甲醇。
②在加有电转液的玻璃大皿里放入转膜用的夹子、两块海绵、滤纸和膜。将夹子打开使黑的一面保持水平。在上面垫一张海绵纸,用手按压海绵,赶出气泡,使电转液浸透海绵。在垫子上垫两层厚滤纸,一手固定滤纸一手赶去其中的气泡。
③将玻璃板撬掉后剥,切除下边缘由于挤压变形的胶,将浓缩胶剥离干净。小心剥离分离胶盖于滤纸上,轻轻用手赶去气泡,将膜盖于胶上,盖下后不可移动。再盖上滤纸,海绵,将夹子夹好。
④将夹子放入电转槽中,胶在负极,膜在正极(黑-黑,红-白)。利用冰块使电转体系处于低温环境中,200mA恒流转移2h。
⑤转完后用镊子将膜取出,用TBST冲洗1次,从边上倒,防止冲走蛋白。
(5)抗体孵育
①首先将膜置于封闭液(5%脱脂牛奶或BSA)中常温摇动1-4h或4℃过夜。
②用5%的BSA将一抗按一定比例稀释。加入一抗稀释液,常温摇动1-4h或4℃过夜。
③回收一抗,用TBST溶液常温下洗膜3-4次,每次5min。
④用5%的牛奶将二抗按一定比例稀释(常用1:5000),加入二抗稀释液,常温摇床孵育1h。
⑤弃二抗,用TBST洗3-4次,5min/次。
(6)显影
①将膜蛋白面朝上置于黑板上,显影液A/B液1:1混匀(换枪头)后滴加在膜上,充分覆盖。
②将黑板放入曝光机器中,在白光条件下拍摄Marker,在自发光条件下曝光目的条带。
(7)数据统计
使用Photoshop、ImageJ以及GraphPad Prism进行数据分析。
3、实验结果
经典致幻剂DOM(1mg/kg)和Psilocin(0.5mg/kg)、非致幻型5-HT2A受体激动剂Lisuride(0.1mg/kg)和TBG(20mg/kg)腹腔给药小鼠后10min时大脑皮层的蛋白提取物中Nogo-A和RhoA蛋白的表达量变化结果见图1,结果显示,Nogo-A蛋白的变化量不明显,DOM和Psilocin给药后RhoA蛋白的量呈上调趋势。表明RhoA蛋白在经典致幻剂的急性作用中可能通过改变蛋白量而发挥作用,而Nogo-A蛋白可能不是通过改变蛋白量而发挥作用,而是可能通过蛋白修饰或其他形式的变化而发挥作用。
实施例2Phos-tag凝胶电泳检测致幻剂作用后Nogo-A、RhoA的变化1、实验材料
本实施例中使用到的实验试剂、实验抗体和实验仪器分别见下表6-8。
表6实验试剂
表7实验抗体
表8实验仪器
本实施例中的主要试剂配置:
1×电泳液running buffer:将电泳液:双蒸水按1:9配置。
1×电转液transfer buffer:将电转液:甲醇:双蒸水按1:2:7配置。1×TBST:将TBST:双蒸水按1:9配置。
5%脱脂奶粉:取2g脱脂奶粉,加40mL的1×TBST充分溶解。
5%BSA:取2g BSA,加40mL的1×TBST充分溶解。
过硫酸铵:取1.00g过硫酸铵,溶于10mL双蒸水中。
Phosbind:10mg Phosbind溶于0.10mL甲醇和3.2mL蒸馏水中。
10mmol/L Mncl2+:10mg溶于5mL蒸馏水。
10mmol/L EDTA:350mg EDTA溶于120mL电转液中。
2、实验方法
本实施例所采用的样品为经典致幻剂DOM(1mg/kg)和Psilocin(0.5mg/kg)和非致幻型5-HT2A受体激动剂Lisuride(T61065-上海陶术生物科技有限公司)(0.1mg/kg)和TBG(军事医学研究院毒物药物研究所合成)(20mg/kg)腹腔给药小鼠(斯贝福(北京)生物技术有限公司,C57,雄性,18-22g,6-8周)后10min时大脑皮层的蛋白提取物。采用Phos-tag凝胶电泳检测上述样品中Nogo-A和RhoA蛋白的磷酸化变化。具体Phos-tag凝胶电泳检测实验方法如下:
(1)制胶
①选下缘平滑的玻璃板,清洗玻璃板和梳子后使用蒸馏水冲洗并吹干。
②厚、薄两块玻璃板对齐后放入夹中卡紧,垂直卡在架子。操作时要使两块玻璃板下边缘对齐,以免漏胶。
③按聚丙烯酰胺凝胶配方配制所需的分离胶,加入TEMED后立即摇匀即可灌胶。10%分离胶配方见下表9,5%浓缩胶的配方见下表10。
表9 10%分离胶配方
表10 5%浓缩胶配方
(2)灌胶与上样
①灌胶时,用枪沿玻璃板一侧加入,待胶面升到距离短板上沿15mm左右即可。然后加一层水,液封后的胶面凝的更快。灌胶时开始可快一些,胶面快达所需高度时要放慢速度。胶水液封是要很慢并且从左到右均匀一层,否则胶会被冲变型。
②当水和胶之间有一条折线时(室温下,大约20min),说明胶已凝。再等3min使胶充分凝固就可倒去上层水并用滤纸吸干。
③按聚丙烯酰胺凝胶配方配制5%的浓缩胶,加入TEMED后立即摇匀即可灌胶。将剩余空间从一侧加入灌满浓缩胶然后将梳子插入浓缩胶中。插梳子要使梳子一侧先插下去,再缓慢将另一侧插下,最后检查梳子是否水平。
④胶凝后,用蒸馏水冲洗一下凝胶,将其放入电泳槽中。薄玻璃板在内侧,厚玻璃板在外侧。若只跑一块胶,电泳槽的另一边要放置一块替代玻璃板的塑料板。
⑤将内槽加满新的电泳液后开始准备上样,内槽电泳液至少要没过内侧玻璃板,外槽加约3cm高电泳液没过玻璃板下沿即可。两手分别捏住梳子的两边垂直向上轻轻将其拔岀,用l mL移液枪对加样孔进行吹打冲洗,加样是用移液器吸取样品,枪尖插至加样孔上方两板间隙处缓慢加入样品。未加样的孔需用1×loading buffer补齐。
(3)电泳
①选择恒压80V进行电泳,样品进入分离胶后可将电压调至120V加快速度。电泳至溴酚蓝跑到胶的下边缘即可终止电泳。
(4)洗膜
电泳后,转膜之前,需要使用螯合剂(EDTA)从凝胶中除去锰离子(Mn2+)。此步骤可提高磷酸化和非磷酸化蛋白转移到PVDF膜上的转移效率。
①电泳后,将凝胶在含有1-10mmol/L EDTA的普通转移缓冲液中浸泡至少10分钟,同时轻轻摇动。(10分钟×1-3次)。根据凝胶厚度等调整EDTA缓冲液的处理时间和温度(例如:1.5mm厚:处理20分钟×两次)。
②将凝胶在不含EDTA的普通转移缓冲液中浸泡10分钟,同时轻轻摇动(10分钟×1次)。
(5)转膜
①准备一块PVDF膜,面积略大于所要转印的胶面面积。转印一块胶需要8张薄滤纸或4张厚滤纸(8×10cm)。如果是PVDF膜,使用前需用甲醇活化30-60s且转膜液中配方含甲醇。
②在加有电转液的玻璃大皿里放入转膜用的夹子、两块海绵、滤纸和膜。将夹子打开使黑的一面保持水平。在上面垫一张海绵纸,用手按压海绵,赶出气泡,使电转液浸透海绵。在垫子上垫两层厚滤纸,一手固定滤纸一手赶去其中的气泡
③将玻璃板撬掉后剥,切除下边缘由于挤压变形的胶,将浓缩胶剥离干净。小心剥离分离胶盖于滤纸上,轻轻用手赶去气泡,将膜盖于胶上,盖下后不可移动。再盖上滤纸,海绵,将夹子夹好。
④将夹子放入电转槽中,胶在负极,膜在正极(黑-黑,红-白)。利用冰块使电转体系处于低温环境中,200mA恒流转移2h。
⑤转完后用镊子将膜取出,用TBST冲洗1次,从边上倒,防止冲走蛋白。
(6)抗体孵育
①首先将膜置于封闭液(5%脱脂牛奶或BSA)中常温摇动1-4h或4℃过夜。
②用5%的BSA将一抗按一定比例稀释。加入一抗稀释液,常温摇动1-4h或4℃过夜。
③回收一抗,用TBST溶液常温下洗膜3-4次,每次5min。
④用5%的牛奶将二抗按一定比例稀释(常用1:5000),加入二抗稀释液,常温摇床孵育1h。
⑤弃二抗,用TBST洗3-4次,5min/次。
(7)显影
①将膜蛋白面朝上置于黑板上,显影液A/B液1:1混匀(换枪头)后滴加在膜上,充分覆盖。
②将黑板放入曝光机器中,在白光条件下拍摄Marker,在自发光条件下曝光目的条带。
(8)数据统计
使用Photoshop、ImageJ以及GraphPad Prism进行数据分析。
3、实验结果
根据Phos-Tag实验原理,如同一种蛋白出现两条距离相近的条带,则上条带为发生磷酸化修饰的蛋白量,下条带为未发生磷酸化修饰的蛋白量。上、下两条条带为总的该蛋白的蛋白量。
检测经典致幻剂DOM(1mg/kg)和Psilocin(0.5mg/kg)、非致幻型5-HT2A受体激动剂Lisuride(0.1mg/kg)和TBG(20mg/kg)腹腔给药小鼠后,10分钟时小鼠大脑皮层的蛋白提取物样品中Nogo-A和RhoA蛋白的磷酸化变化结果图见图2,结果显示,Nogo-A蛋白仅检测到一条条带,则Nogo-A蛋白的磷酸化变化不明显。RhoA蛋白检测到两条条带,上面为发生磷酸化的蛋白量,下条带为未发生磷酸化变化的蛋白量,可以得到Psilocin组的RhoA磷酸化变化呈下降趋势。表明RhoA蛋白在经典致幻剂的急性作用中可能通过改变蛋白量以及发生磷酸化修饰而发挥作用。而Nogo-A蛋白可能不是通过磷酸化修饰而发挥作用。
实施例3 Opicinumab对经典致幻剂诱导的幻觉作用的抑制研究
1、实验材料
实验动物:SPF级C57小鼠,雄性,体重20-22g;由斯贝福(北京)生物技术有限公司提供,实验动物生产许可证,SCXK(京)2019-0010。实验动物饲养于军事医学研究院行为中心,8-10只/笼。12h昼夜交替室温(22±2℃),湿度(40±20℃)%,自由饮水摄食,实验前适应环境三天。
实验试剂:本实施例中使用到的实验试剂见下表11。
实验器材:本实施例中使用到的实验器材见下表12。
表11实验试剂
表12实验器材
本实施例中的主要试剂配置:
DOM溶液配置:称取适量样品溶于生理盐水,配置成0.1mg/mL,适用于小鼠腹腔注射。
Psilocin溶液配置:称取适量样品溶于1% DMSO和99%生理盐水,配置成0.5mg/mL,使用生理盐水稀释成0.05mg/mL,适用于小鼠腹腔注射。
抗Lingo-1抗体Opicinumab溶液配置:购买的母液为5mg/mL,使用PBS梯度稀释成3mg/mL和1mg/mL,用于小鼠侧脑室注射。
P75 NTR抑制剂TAT-Pep5溶液配制:称取适量样品溶于生理盐水,配置成1mg/mL,梯度稀释成0.2mg/mL和0.04mg/mL,用于小鼠侧脑室注射。
2、甩头反应实验验证Opicinumab对经典抑制剂诱导的幻觉作用的抑制效果
(1)Opicinumab对经典抑制剂诱导的幻觉作用的影响
甩头反应(HTR)是一种头部快速的左右旋转行为,在给予大鼠和小鼠5-羟色胺能致幻剂或其他5-HT2A激动剂后出现,甩头反应被广泛用作5-HT2A受体激活的行为测定。在经典致幻剂研究中,甩头反应是目前最常用的动物模型。小鼠的甩头反应效果和人类致幻效果之间存在很强的正相关性,也即甩头反应能够指征幻觉行为的产生。
本实施例中所述实验小鼠首先使用上述工具药物(Opicinumab)进行侧脑室给药。等待30分钟后,腹腔注射经典致幻剂DOM或Psilocin。注射完毕后立即放入透明箱中进行甩头反应行为的观察并进行人工计数,行为测试进行15或30分钟。
其中,DOM的药物剂量为1mg/kg,使用腹腔注射的方式进行注射;Psilocin的剂量为0.5mg/kg,使用腹腔注射的方式进行注射。工具药物(Opicinumab)选择低(5μg/5μL)、中(15μg/5μL)、高(25μg/5μL)三个剂量,均使用侧脑室注射的方式进行注射,在致幻剂给药前30min进行注射。侧脑室注射给药体积为5μL,腹腔注射给药体积为0.2mL/20g。
(2)P75 NTR抑制剂TAT-Pep5对经典抑制剂诱导的幻觉作用的影响
本实施例进一步验证了P75 NTR抑制剂TAT-Pep5对经典致幻剂DOM诱导的小鼠甩头行为的影响。实验中DOM的药物剂量为1mg/kg,使用腹腔注射的方式进行注射。TAT-Pep5选择低(0.2μg/5μL)、中(1μg/5μL)、高(5μg/5μL)三个剂量,均使用侧脑室注射的方式进行注射,在DOM给药前30min进行注射。
3、实验结果
Opicinumab对经典抑制剂诱导的幻觉作用的抑制效果见图3和图4,图3和图4中的左图显示Opicinumab具有显著的甩头行为抑制作用,且呈现出剂量梯度式的变化,表明Opicinumab能够显著抑制经典致幻剂诱导的小鼠甩头行为,也即本发明所述的Opicinumab对经典致幻剂诱导的幻觉作用具有显著的抑制作用;图3和图4中的右图为甩头反应15或30分钟内的甩头次数变化,每5分钟累计计数一次,结果显示在致幻剂给药后大约5到10分钟时Opicinumab给药组与对照组开始出现明显的甩头次数差异。以上结果进一步表明Opicinumab能够应用于特异性抑制幻觉作用的药物的制备中。
P75 NTR抑制剂TAT-Pep5对经典致幻剂诱导的小鼠甩头行为影响的结果图见图5,图5中的左图显示低、中和高剂量的TAT-Pep对小鼠的甩头行为都没有明显的抑制或上调作用,表明在Nogo-A/RhoA信号通路中,P75 NTR受体及其下游的RhoA激活并不参与到幻觉效应中;图5中的右图为甩头实验30分钟内的甩头次数变化,每5分钟累计计数一次,可见四组的甩头次数曲线均没有明显的差异,也即并不是抑制Nogo-A/RhoA信号通路中的蛋白均能抑制幻觉作用。
上述实施例的说明只是用于理解本发明的方法及其核心思想。应当指出,对于本领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也将落入本发明权利要求的保护范围内。
Claims (10)
1.Lingo-1拮抗剂在制备特异性抑制幻觉作用的药物中的用途。
2.根据权利要求1所述的用途,其特征在于,所述Lingo-1拮抗剂为Opicinumab。
3.根据权利要求2所述的用途,其特征在于,所述幻觉作用为5HT2A受体介导的幻觉作用。
4.一种用于特异性抑制幻觉的药物组合物,其特征在于,所述药物组合物包含有效量的Opicinumab。
5.根据权利要求4所述的药物组合物,其特征在于,所述药物组合物还包含药学上可接受的赋形剂。
6.根据权利要求5所述的药物组合物,其特征在于,所述药学上可接受的赋形剂包括填充剂、崩解剂、粘合剂、表面活性剂。
7.根据权利要求6所述的药物组合物,其特征在于,所述填充剂包括乳糖、糊精、微晶纤维、淀粉、山梨醇、甘露醇、预胶化淀粉。
8.根据权利要求6所述的药物组合物,其特征在于,所述崩解剂包括交联聚维酮、交联羧甲基纤维素钠、羧甲基淀粉钠、羟丙基纤维素。
9.根据权利要求6所述的药物组合物,其特征在于,所述粘合剂包括淀粉浆、淀粉浆钠、羟丙甲纤维素、聚维酮。
10.根据权利要求6所述的药物组合物,其特征在于,所述表面活性剂包括十二烷基磺酸钠、十六烷基硫酸钠、硬脂酸、油酸、月桂酸。
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WO2015182232A1 (ja) * | 2014-05-29 | 2015-12-03 | クラシエ製薬株式会社 | 抗幻覚剤 |
WO2018204764A1 (en) * | 2017-05-05 | 2018-11-08 | Camp4 Therapeutics Corporation | Identification and targeted modulation of gene signaling networks |
CN109862911A (zh) * | 2016-07-13 | 2019-06-07 | 比奥根Ma公司 | Lingo-1拮抗剂的剂量方案和用于治疗脱髓鞘病症的用途 |
US20220042035A1 (en) * | 2018-02-14 | 2022-02-10 | Generation Bio Co. | Non-viral dna vectors and uses thereof for antibody and fusion protein production |
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WO2015182232A1 (ja) * | 2014-05-29 | 2015-12-03 | クラシエ製薬株式会社 | 抗幻覚剤 |
CN109862911A (zh) * | 2016-07-13 | 2019-06-07 | 比奥根Ma公司 | Lingo-1拮抗剂的剂量方案和用于治疗脱髓鞘病症的用途 |
WO2018204764A1 (en) * | 2017-05-05 | 2018-11-08 | Camp4 Therapeutics Corporation | Identification and targeted modulation of gene signaling networks |
US20220042035A1 (en) * | 2018-02-14 | 2022-02-10 | Generation Bio Co. | Non-viral dna vectors and uses thereof for antibody and fusion protein production |
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