CN116370608B - Il-33在长期抑郁引起的记忆损伤治疗中的应用 - Google Patents
Il-33在长期抑郁引起的记忆损伤治疗中的应用 Download PDFInfo
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- CN116370608B CN116370608B CN202310541996.6A CN202310541996A CN116370608B CN 116370608 B CN116370608 B CN 116370608B CN 202310541996 A CN202310541996 A CN 202310541996A CN 116370608 B CN116370608 B CN 116370608B
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Abstract
本发明公开了IL‑33在长期抑郁引起的记忆损伤治疗中的应用。本发明提供了IL‑33在制备治疗记忆损伤的药物组合物中的应用及一种治疗长期抑郁引起的记忆损伤的药物组合物,通过使用含有有效量IL‑33的药物组合物,可以维护海马神经的发生,明显改善长期抑郁引起的记忆损伤,具有良好的临床应用前景。
Description
技术领域
本发明属于生物医药领域,涉及IL-33在长期抑郁引起的记忆损伤治疗中的应用。
背景技术
抑郁症又称抑郁障碍,以显著而持久的心境低落为主要临床特征,是心境障碍的主要类型。尤其是,长期的中度或重度抑郁症可能成为一个严重的疾患,患者可能会受极大影响,在工作以及在学校和家庭生活中表现不佳,包括学习记忆障碍、情绪情感障碍,最严重时,抑郁症可引致自杀。每年因其自杀死亡人数估计高达100万人。抑郁症已成为世界第四大疾病,而长期抑郁引起的记忆损伤也逐渐成为威胁人们身体健康的常见疾病之一。近年来大量文献报道,慢性应激导致的长期抑郁不仅对大脑的结构及功能都有着不利影响,而且与学习记忆损伤的形成以及神经精神疾病的发生发展有着密切联系。慢性应激通过损伤HPA轴的负反馈平衡,激活海马糖皮质激素受体,增加神经细胞的代谢,减少神经细胞的存活和再生,此外,通过促进树突萎缩,影响长时程增强和认知功能,从而诱发神经精神疾病。因此,如何治疗长期抑郁引起的记忆损伤成为亟待解决的问题。
目前有多种活性物质可用于治疗抑郁症,例如血清素再摄取抑制剂(SRI)、去甲肾上腺素再摄取抑制剂(NERI)、血清素-去甲肾上腺素再摄取双重抑制剂(SNRI)、单胺氧化酶抑制剂(MAQI)、磷酸二酯酶-4(PDE4)抑制剂等。但是,现有药物对许多患者仍然没有治疗效果或治疗效果不佳。因此,筛选治疗长期抑郁引起的记忆损伤的药物,对于改善记忆损伤,治疗抑郁,提高人们的生活生存质量具有重要的意义。
发明内容
为了弥补现有技术的不足,本发明的目的在于提供一种治疗长期抑郁引起的记忆损伤的药物组合物及其应用。
为了实现上述目的,本发明采用如下技术方案:
本发明的第一方面提供了IL-33在制备治疗记忆损伤的药物组合物中的应用。
进一步,所述药物组合物包括有效量的IL-33促进剂。
进一步,所述促进剂特异性促进IL-33的表达水平。
进一步,所述促进剂为IL-33的过表达载体或IL-33蛋白。
进一步,所述促进剂提升记忆能力、增加海马神经发生。
进一步,所述药物组合物还包括药学上可接受的载体。
进一步,所述药物组合物的给药途径为经胃肠道给药、直肠给药、注射给药、粘膜给药和鼻腔给药中的任意一种。
进一步,所述药物组合物的给药途径为鼻腔给药。
进一步,所述记忆损伤为长期抑郁引起的记忆损伤。
本发明的第二方面提供了一种治疗记忆损伤的药物组合物,所述药物组合物包括有效量的IL-33促进剂。
进一步,所述促进剂特异性促进的IL-33表达水平。
进一步,所述促进剂为IL-33的过表达载体或IL-33蛋白。
进一步,所述药物组合物还包括药学上可接受的载体。
进一步,所述药物组合物的剂型包括液体剂型或固体剂型。
进一步,所述液体剂型包括鼻喷雾剂、滴鼻剂、通过雾化器的气雾剂或注射制剂;所述固体剂型包括片剂、胶囊剂、小药囊、糖衣丸、粉末、颗粒剂、锭剂或粉末。
进一步,所述药物组合物的剂型为液体剂型。
进一步,所述液体剂型为滴鼻剂。
进一步,所述记忆损伤为长期抑郁引起的记忆损伤。
本发明的第三方面提供了一种治疗记忆损伤的药盒,所述药盒包括本发明的第二方面所述的药物组合物、任选地容器和说明书。
本发明的第四方面提供了IL-33在筛选治疗记忆损伤的候选药物中的应用。
进一步,所述筛选治疗记忆损伤的候选药物的方法如下:用待筛选物质处理表达或含有IL-33基因或其编码的蛋白的培养体系;和检测所述体系中IL-33基因或其编码的蛋白的表达或活性;其中,当所述待筛选物质促进IL-33基因或其编码的蛋白的表达水平或活性时,该待筛选物质是治疗记忆损伤的候选药物。
进一步,所述记忆损伤为长期抑郁引起的记忆损伤。
本发明的第五方面提供了一种筛选治疗记忆损伤的候选药物的方法,所述方法如下:用待筛选物质处理表达或含有IL-33基因或其编码的蛋白的培养体系;和检测所述体系中IL-33基因或其编码的蛋白的表达或活性;其中,当所述待筛选物质促进IL-33基因或其编码的蛋白的表达水平或活性时,该待筛选物质是治疗记忆损伤的候选药物。
进一步,所述记忆损伤为长期抑郁引起的记忆损伤。
本发明的第六方面提供了一种构建记忆损伤、海马神经发生障碍的动物模型的方法,所述方法包括敲除IL-33受体ST2基因。
进一步,所述动物包括哺乳动物。
进一步,所述哺乳动物包括狗、猪、兔或啮齿目动物。
进一步,所述啮齿目动物包括小鼠、大鼠、仓鼠、豚鼠。
进一步,所述动物为小鼠。
进一步,所述记忆损伤为长期抑郁引起的记忆损伤。
本发明的第七方面提供了本发明的第六方面所述的方法构建的动物模型在筛选治疗记忆损伤、增加海马神经发生的药物中的应用。
进一步,所述筛选治疗记忆损伤、增加海马神经发生的药物的方法如下:向所述动物模型施用测试药物;检测动物模型中记忆损伤、海马神经发生的相关症状和/或指标,并与对照组进行比较;所述动物模型中记忆损伤、海马神经发生的相关症状有显著改善,则表示该测试药物是潜在治疗记忆损伤、增加海马神经发生的药物。
进一步,所述记忆损伤为长期抑郁引起的记忆损伤。
本发明的第八方面提供了一种筛选治疗记忆损伤、增加海马神经发生的药物的方法,所述方法如下:向所述动物模型施用测试药物;检测动物模型中记忆损伤、海马神经发生的相关症状和/或指标,并与对照组进行比较;所述动物模型中记忆损伤、海马神经发生的相关症状有显著改善,则表示该测试药物是潜在治疗记忆损伤、增加海马神经发生的药物。
进一步,所述记忆损伤为长期抑郁引起的记忆损伤。
本发明的优点和有益效果:
本发明首次发现了IL-33可以用于治疗长期抑郁引起的记忆损伤。使用IL-33可以较好的治疗长期抑郁引起的记忆损伤,维护海马神经的发生。
附图说明
图1为IL-33受体ST2基因敲除影响海马神经发生的结果图,其中1A是小鼠BrdU掺入后海马BrdU和NeuN免疫荧光染色代表图,1B是小鼠BrdU掺入后左海马BrdU+神经元计数结果图,1C是小鼠BrdU掺入后右海马BrdU+神经元计数结果图;
图2为水迷宫实验检测结果图,其中2A是水迷宫1-4天找到平台的潜伏期结果图,2B是第5天撤掉平台后在NW区域穿梭次数的结果图,2C是第5天撤掉平台后在NW区域停留时间的结果图,2D是第5天撤掉平台后在平台所在位置穿梭次数的结果图,2E是第5天撤掉平台后在平台所在位置停留时间的结果图;
图3为IL-33滴鼻处理2周提升CUMS小鼠记忆能力的结果图,其中3A是滴鼻处理前水迷宫1-4天找到平台的潜伏期的结果图,3B是滴鼻处理后水迷宫1-4天找到平台的潜伏期的结果图,3C是滴鼻处理前在撤掉平台的NW区域穿梭次数和停留时间的结果图,3D是滴鼻处理后在撤掉平台的NW区域穿梭次数和停留时间的结果图,3E是滴鼻处理前在撤掉平台的平台所在位置穿梭次数和停留时间的结果图,3F是滴鼻处理后在撤掉平台的平台所在位置穿梭次数和停留时间的结果图;
图4为IL-33滴鼻处理2周增加CUMS小鼠海马神经发生的结果图,其中4A是小鼠BrdU掺入后海马BrdU和NeuN免疫荧光染色代表图,4B是小鼠BrdU掺入后左海马BrdU+神经元计数结果图;4C是小鼠BrdU掺入后右海马BrdU+神经元计数结果图。
具体实施方式
本发明通过广泛而深入的研究,发现IL-33受体ST2基因敲除影响海马神经的发生;IL-33滴鼻处理长期慢性不可预见性应激(CUMS)小鼠能够提升CUMS小鼠的记忆能力和增加CUMS小鼠的海马神经发生。
除非另有定义,否则本文使用的所有技术和科学术语的含义与本发明所属领域的普通技术人员通常所理解的含义相同。否则,本文所用的某些术语具有本说明书中所述的含义。
在本发明中,术语“记忆损伤”、“记忆障碍”、“学习障碍”、“学习记忆障碍”、“认知障碍”可互换使用,应被理解为包括任何认知疾病或病症。引起这种认知疾病或病症的非限制性例子包括注意力缺陷病症(ADD)、注意力缺陷多动症(ADHD)、阅读障碍、与年龄相关的记忆损伤和学习障碍、健忘症、轻度认知损伤、认知损伤型非痴呆性前阿尔茨海默病、自闭症、肌张力障碍及抽动秽语综合症、痴呆、与年龄相关的认知下降、认知衰退、中度精神损伤、由衰老所致的精神衰退、影响脑电波强度和/或脑部葡萄糖利用的病状、紧张、焦虑症、集中和注意力障碍、情绪恶化、一般认知及心理健康、神经退行性病症、激素失调、抑郁或它们的任意组合。在本发明的具体实施例中,引起记忆损伤的疾病或病症为抑郁;进一步,抑郁为长期抑郁。
本发明提供了治疗记忆损伤的产品,所述产品包含有效量的IL-33促进剂;和药学上可接受的载体。
作为可选择的实施方案,所述促进剂是指任何可增加IL-33蛋白的活性、提高IL-33基因或蛋白的稳定性、上调IL-33蛋白的表达、增加IL-33蛋白有效作用时间、或促进IL-33基因的转录和翻译的物质,这些物质均可用于本发明,作为对于上调IL-33有用的物质,从而可用于治疗记忆损伤。例如所述的促进剂包括核酸促进剂,蛋白促进剂。在一些实施方案中,所述促进剂上调IL-33蛋白的表达,包括但不限于过表达IL-33的载体、IL-33蛋白或其活性肽。
在本发明中,术语“载体”是指任何赋形剂、稀释剂、填充剂、盐、缓冲剂、稳定剂、增溶剂、油、类脂、含脂质囊泡、微球体、脂质体包囊或本领域公知的用于药物制剂的其他材料。应当理解,载体特征将取决于具体应用的施用途径。如本发明所使用,术语“药学上可接受的载体”是指不干扰根据本发明的药物组合物的效果或根据本发明的药物组合物的生物活性的非毒性材料。用药学上可接受的载体配制药物活性成分是本领域已知的,例如Remington:《药学的科学和实践》(The Science and Practice ofPharmacy)(例如第21版(2005年),以及任何以后的版本)。药学上可接受的载体的非限制性实例包括:盐(例如酸式盐/阴离子盐、碱盐/阳离子盐)、赋形剂、缓冲剂、稀释剂、增溶剂、张度调节剂、表面活性剂、防腐剂、等渗剂、稳定剂和螯合剂。一种或多种药学上可接受的载体可用于配制本发明的药物组合物。
在本发明的一个实施方案中,药学上可接受的载体包括酸式盐/阴离子盐。酸式盐/阴离子盐的非限制性实例包括但不限于乙酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、酒石酸氢盐、溴化物、依地酸钙、樟脑磺酸盐、碳酸盐、氯化物、柠檬酸盐、二盐酸盐、依地酸盐、乙二磺酸盐、依托酸盐、乙磺酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、谷氨酸盐、对羟乙酰氨基苯胂酸盐、己基间苯二酚盐、海巴明、氢溴酸盐、盐酸盐、羟萘酸盐、碘化物、羟乙基磺酸盐、乳酸盐、乳糖酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基溴化物、甲基硝酸盐、甲基硫酸盐、粘液酸盐、萘磺酸盐、硝酸盐、双羟萘酸盐、泛酸盐、磷酸盐/二磷酸盐、聚半乳糖醛酸盐、水杨酸盐、硬脂酸盐、次乙酸盐、琥珀酸盐、硫酸盐、鞣酸盐、酒石酸盐、茶氯酸盐、甲苯磺酸盐和三乙碘化物。
在本发明的一个实施方案中,药学上可接受的载体包括碱盐/阳离子盐。碱盐/阳离子盐的非限制性实例包括但不限于铝、2-氨基-2-羟甲基-丙烷-1,3-二醇(也已知为三(羟甲基)氨基甲烷、氨基丁三醇或“TRIS”)、氨、苄星青霉素、叔丁胺、氯普鲁卡因、胆碱、环己胺、二乙醇胺、乙二胺、锂、L-赖氨酸、镁、葡甲胺、N-甲基-D-葡糖胺、哌啶、钾、普鲁卡因、奎宁、钠、三乙醇胺或锌。
在本发明的一个实施方案中,药学上可接受的载体包括缓冲剂。缓冲剂的非限制性实例包括但不限于精氨酸、天冬氨酸、二羟乙基甘氨酸、柠檬酸盐、磷酸氢二钠、富马酸、甘氨酸、双甘氨肽、组氨酸、赖氨酸、马来酸、苹果酸、乙酸钠、碳酸钠、磷酸二氢钠、磷酸钠、琥珀酸盐、酒石酸、三嗪和三(羟甲基)氨基甲烷以及它们的混合物。
在本发明的一个实施方案中,药学上可接受的载体包括防腐剂。防腐剂的非限制性实例包括但不限于苄索氯铵、苯甲酸、苄醇、溴代硝基丙二醇、4-羟基苯甲酸丁酯、氯丁醇、氯甲酚、氯己啶、氯苯甘油醚、邻甲酚、间甲酚、对甲酚、4-羟基苯甲酸乙酯、咪脲、4-羟基苯甲酸甲酯、苯酚、2-苯氧基乙醇、2-苯基乙醇、4-羟基苯甲酸丙酯、脱氢乙酸钠、硫柳汞以及它们的混合物。
在本发明的一个实施方案中,药学上可接受的载体包括等渗剂。等渗剂的非限制性实例包括但不限于氨基酸(诸如甘氨酸、组氨酸、精氨酸、赖氨酸、异亮氨酸、天冬氨酸、色氨酸和苏氨酸)、糖醇(诸如甘油、1,2-丙二醇、丙二醇)、1,3-丙二醇和1,3-丁二醇)、聚乙二醇(例如,PEG400)以及它们的混合物。等渗剂的另一个实例包括糖。糖的非限制性实例可以是单糖、二糖或多糖,或水溶性葡聚糖,包括例如果糖、葡萄糖、甘露糖、山梨糖、木糖、麦芽糖、乳糖、蔗糖、海藻糖、葡聚糖、支链淀粉、糊精、环糊精、α和β-HPCD、可溶性淀粉、羟乙基淀粉和羧甲基纤维素钠。等渗剂的另一个实例是糖醇,其中术语“糖醇”被定义为具有至少一个-OH基团的C(4-8)烃。糖醇的非限制性实例包括甘露糖醇、山梨醇、肌醇、半乳糖醇、己六醇、木糖醇和阿拉伯糖醇。包含本段中列出的每种等渗剂的药物构成本发明的可供选择的实施方案。
在本发明的一个实施方案中,药学上可接受的载体包括螯合剂。螯合剂的非限制性实例包括但不限于柠檬酸、天冬氨酸、乙二胺四乙酸(EDTA)的盐以及它们的混合物。
在本发明的一个实施方案中,药学上可接受的载体包括稳定剂。稳定剂的非限制性实例包括羧基-/羟基纤维素及其衍生物(诸如HPC、HPC-SL、HPC-L和HPMC)、环糊精、2-甲基硫基乙醇、聚乙二醇(诸如PEG 3350)、聚乙烯醇(PVA)、聚乙烯基吡咯烷酮、盐(诸如氯化钠)、含硫的物质,诸如硫代甘油或巯基乙酸。
在本发明的一个实施方案中,药学上可接受的载体包括一种或多种表面活性剂,优选一种表面活性剂、至少一种表面活性剂或两种不同的表面活性剂。术语“表面活性剂”是指任何由水溶性部分(亲水性)和脂溶性和部分(亲脂性)组成的分子或离子。例如,表面活性剂选自:阴离子表面活性剂、阳离子表面活性剂、非离子表面活性剂和/或两性离子表面活性剂。
用于任何药物制剂的赋形剂必须符合预期的施用途径并且与活性成分相容。
在本发明的一个实施方案中,药物为液体制剂。液体制剂的一个优选实例为水性制剂,即包含水的制剂。液体制剂包括但不限于溶液、悬浮液、乳液、微乳液或凝胶。水性制剂通常包含至少50%w/w的水,或至少60%w/w、70%w/w、75%w/w、80%w/w、85%w/w、90%w/w或至少95%w/w的水。
在一个实施方案中,可将药物配制为可注射的,其可例如经由注射装置(例如,注射器或输液泵)注射。注射可例如皮下、肌内、腹膜内或静脉内递送。
在另一个实施方案中,药物为固体制剂,例如冷冻干燥或喷雾干燥的药物,其可按原样使用,或在使用前由医师或患者添加溶剂和/或稀释剂。固体剂型可包括片剂,诸如压片和/或包衣片,以及胶囊剂(例如硬明胶胶囊或软明胶胶囊)。药物组合物也可为例如用于重构的小药囊、糖衣丸、粉末、颗粒剂、锭剂或粉末的形式。
在一个实施方案中,药物可在鼻腔内、颊内或舌下递送。在本发明的具体实施方案中,药物在鼻腔递送。
适用于鼻腔给药的制剂,其中载体为固体,包括例如具有粒度在约20至约500微米范围内的粗粉,其作为干粉给药,或在吸入器装置中通过鼻腔通道从靠近鼻子的粉末容器快速吸入。其中所述载体为供施用的液体(例如,鼻喷雾剂、滴鼻剂或通过雾化器的气雾剂)的合适制剂,包括所述制剂的水溶液或油溶液。
对于本领域的技术人员还将显而易见的是,本发明的药物的有效剂量将根据期望的效果而变化。因此,本领域技术人员可容易地确定待施用的最佳剂量,并且最佳剂量将随所使用的具体化合物、给药方式、制剂强度和疾病状况的进展而变化。另外,与接受治疗的具体受治疗者相关的因素,包括受治疗者年龄、体重、饮食和给药时间,将导致需要将剂量调整至适当的治疗水平。
根据具体实施方案,有效量或有效剂量是指足以实现下列效应中的一者、两者、三者、四者、或更多者的治疗量:(i)减少或改善欲被治疗的疾病、障碍、或病症的严重程度或与其相关的症状;(ii)减少所治疗疾病、障碍或病症或与之相关的症状的持续时间;(iii)预防所治疗疾病、障碍或病症或与之相关的症状发展;(iv)引起所治疗疾病、障碍或病症或与之相关的症状消退;(v)防止所治疗疾病、障碍或病症或与之相关的症状发展或发作;(vi)防止所治疗疾病、障碍或病症或与之相关的症状复发;(vii)减少患有所治疗疾病、障碍或病症或与之相关的症状的受试者的住院治疗;(viii)减少患有所治疗疾病、障碍或病症或与之相关的症状的受试者的住院时间;(ix)提高患有所治疗疾病、障碍或病症或与之相关的症状的受试者的存活;(xi)抑制或减少受试者中所治疗疾病、障碍或病症或与之相关的症状;和/或(xii)增强或改善另一种疗法的预防或治疗效果。
治疗有效量或剂量可根据各种因素,诸如欲被治疗的疾病、障碍、或病症、给药方式、目标部位、受试者的生理状态(包括例如年龄、体重、健康)而变化,不论受试者是人或动物、给药的其他药物,以及是否为治疗性治疗。
在本发明中,术语“治疗”是指(1)防止易感或尚未显示病症的受试者出现症状或疾病;(2)抑制疾病或阻止其发展或复发;或(3)改善或导致疾病或病症消退。如本领域所理解的,“治疗”是用于获得有益的或期望的结果(包括临床结果)的方法。出于本技术的目的,有益的或期望的结果可以包括但不限于减轻或改善一个或多个症状、病症(包括疾病)程度的减轻、病症(包括疾病)状态的稳定(即,不恶化),病症(包括疾病)的延迟或减缓、病症(包括疾病)、状态和缓解(无论是部分还是全部)的进展、改善或缓解,无论是否可检测。
本发明的药盒包含药物和信息材料的单独容器、分隔件或隔室。例如,药物可以包含在瓶子、小瓶或注射器中,并且信息材料可以与容器结合而被包含。在一些实施方案中,药盒的单独元件包含在一个单一的、未分开的容器中。例如,药物包含在瓶子、小瓶或注射器中(以标签形式附有信息材料)。在一些实施方案中,药盒包括多个(例如,一包)单独的容器,每个容器包含一个或多个单位剂型(例如,本文所述的剂型)的活性物质。
在本发明中,术语“IL-33”是指白细胞介素33,也被称为NF-HEV或IL-1F11,在人中由IL-33基因所编码。在某些实施例中,IL-33是全长。在另一实施例中,IL-33是成熟的截短IL-33(氨基酸112-270)。最近研究表明全长IL-33是有活性的(Cayrol和Girard,Proc NatlAcad Sci U S A[美国国家科学院院刊]106(22):9021-6(2009);Hayakawa等人,BiochemBiophys Res Commun[生物化学和生物物理学研究通讯]387(1):218-22(2009);Talabot-Ayer等人,J Biol Chem.[生物化学杂志]284(29):19420-6(2009))。然而,N末端处理的或截短的IL-33(包括但不限于aa 72-270、79-270、95-270、99-270、107-270、109-270、111-270、112-270)可具有增强的活性(Lefrancais 2012、2014)。在另一实施例中,IL-33可包括全长IL-33、其片段或IL-33突变体或变体多肽,其中IL-33片段或IL-33变体多肽保留活性IL-33的一些或所有功能特性。
在本发明中,术语“ST2”是指生长刺激表达基因2蛋白(growthstimulationexpressed gene 2),也被称为ST2L、IL-1RL1、T1、Fit-1、DER-4、IL-1R4或ST2α,在人中由ST2基因所编码。
在本发明中,术语“动物”是指除人以外的所有脊椎动物,优选地是哺乳动物,例如狗、猪、兔或啮齿目动物。
作为可选择的实施方案,所述动物是啮齿目动物(也称为啮齿动物)。术语”啮齿”是指系统发育类啮齿动物的任何和所有成员(例如,小鼠,大鼠,松鼠,海狸,土拨鼠,地鼠,田鼠,土拨鼠,仓鼠,豚鼠和刺豚鼠),包括从中衍生的所有后代的任何后代。在一些实施方案中,本公开的啮齿动物包括作为非限制性实例的小鼠、大鼠和仓鼠。在一些实施方案中,本公开的啮齿动物包括作为非限制性实例的小鼠和大鼠。在一些实施方案中,啮齿动物选自总科鼠总科(Muroidea)。在一些实施方案中,本公开的啮齿动物来自选自下列的家族:丽仓鼠科(Calomyscidae)(例如,类小鼠的仓鼠)、仓鼠科(Cricetidae)(例如,仓鼠、新世界大鼠和小鼠、田鼠)、鼠科(Muridae)(真小鼠和大鼠、沙鼠、棘鼠、冠鼠)、马岛鼠科(Nesomyidae)(攀鼠、岩鼠、具尾大鼠、马达加斯加大鼠和小鼠)、刺山鼠科(Platacanthomyidae)(例如,刺棒睡鼠)和鼹形鼠科(Spalacidae)(例如,鼹鼠、竹鼠和鼢鼠)。在一些实施方案中,本公开的啮齿动物选自真小鼠或大鼠(鼠科)、沙鼠、棘鼠和冠鼠。在一些实施方案中,本公开的小鼠来自鼠科(Muridae)的成员。在本发明的具体实施方案中,所述啮齿动物是小鼠。
在本发明中,术语“动物模型”是指具有或显示出疾病或病状的特征的非人类动物。在特定实施方式中,动物模型是哺乳动物模型。在特定实施方式中,动物模型是啮齿目动物模型。在特定实施方式中,啮齿目动物模型是小鼠、大鼠、豚鼠或仓鼠模型。在本发明的具体实施例中,所述动物模型是指小鼠模型。
下面结合附图和实施例对本发明作进一步详细的说明。以下实施例仅用于说明本发明而不用于限制本发明的范围。根据本发明的实质对本发明进行的简单改进都属于本发明要求保护的范围。
实施例1IL-33受体ST2基因敲除对海马神经发生的影响
1、小鼠的来源
IL-33受体ST2基因敲除小鼠(ST2 KO,n=5)由本实验室构建,在本校(华中科技大学)SPF级动物房繁殖,鼠尾DNAPCR鉴定基因型。野生型小鼠(WT,n=5)作为对照组。
ST2 KO小鼠的构建方法:将ST2基因的4和5外显子缺失的成年10周龄雄性BALB/cST2-/-小鼠与雌性C57BL/6进行杂交,再将成年F1代小鼠与C57BL/6杂交;筛选出F2代小鼠中阳性杂合子再与C57BL/6杂交;依次,同前将子代阳性杂合子与C57BL/6杂交,至第10代(小鼠含99.9%C57BL/6基因型)将阳性杂合子自交,可筛选出阳性纯合子C57BL/6ST2-/-,即实验所用ST2 KO小鼠。
ST2 KO小鼠与对照组小鼠同龄、同性别。
2、5-溴脱氧尿苷(BrdU)掺入
BrdU购自Sigma,货号B9285,用PBS配成10mg/mL的浓度,分装冻存于-20℃。每天按照50mg/kg的剂量腹腔注射,一只小鼠约注射125μL,连续5天。接着麻醉小鼠,灌流,制备冰冻切片,冰冻切片冻存于-80℃备用。观察海马NeuNlow神经元BrdU掺入情况可以反映海马神经元的状态。
3、BrdU免疫荧光
1)固定:PBS洗海马冰冻切片3次,每次5min,4%多聚甲醛固定30min。
2)变性:将固定好的海马冰冻切片PBS洗3次,每次5min(摇床转速60rpm);2mol/L的HCl室温下变性60min。
3)中和与封闭:0.1mol/L的硼酸钠(pH8.5)中和10min,PBS冲洗10min,重复3次;3%BSA-0.3%Triton-PBS封闭室温1h。
4)孵一抗:用1%BSA-PBS稀释抗BrdU抗体(Abcam,ab6326)至终浓度为6μg/mL,神经元核抗原(NeuN,Neuronal nuclei)抗体(CST,24307)按照1:200稀释,在海马冰冻切片上滴加150-300μL,4℃湿盒中孵育36h,将孵好一抗的切片PBS洗10min,重复3次。
5)孵二抗:用1%BSA溶液按1:600稀释TRITC结合的goat anti-rat二抗、FITC结合的goat anti-rabbit二抗(中山金桥),37℃湿盒中孵育60min,将孵好二抗的切片PBS洗3次,每次10min,注意避光。
6)染核:每张切片滴加200μL浓度为1μg/mL的DAPI溶液浸染3min,PBS洗2次,每次5min。
7)封片:中性树胶封片,荧光显微镜观察。
4、统计学分析
应用GraphPad Prism 6.01和SPSS19.0软件对所有数据进行统计学分析。计量资料结果以均数±标准差(Mean±SD)或均数±标准误(Mean±SEM)表示,组间均值用t检验统计分析,P<0.05认为差异有统计学意义。
5、实验结果
结果如图1所示,结果显示与野生型小鼠相比,ST2基因敲除小鼠的海马BrdU掺入减少,表明ST2基因敲除抑制海马神经发生,提示IL-33有利于记忆维护。
实施例2长期慢性不可预见性应激(CUMS)对记忆损伤的影响
1、小鼠来源
C57 BL/6小鼠购自维通利华公司。
2、慢性不可预见性应激
C57 BL/6小鼠共应激8周,前4周根据应激程序表(如表1所示)随机给予刺激,应激方式每天随机抽取,上午、下午或夜间各使用一种,但禁水、禁食应间隔进行,进而达到动物无法预料刺激的发生的效果,尽量随机使应激程序满足不可预测性的条件,具体实验操作安排见表1。后面4周重复前四周的程序。
表1慢性不可预知性应激程序表
3、Morris水迷宫
小鼠Morris水迷宫在线检测系统由一个不锈钢喷塑圆柱形水池和图像采集分析系统两部分组成。水池直径为100cm,高38cm。平台直径6cm,高14cm。水温21-22℃,按东南西北四个方向将水池平均划分为4个象限(NE、SE、SW、NW),前4天每天定于固定时间段,每个时间段训练3-4次。训练开始时,将平台置于NW象限,从池壁四个起始点的任一点将小鼠面向池壁放入水池,立即围紧围帘。自由录像记录系统记录小鼠找到平台的时间(逃避潜伏期)和游泳路径,训练时将小鼠分别从四个不同的起始点(不同象限)放入水中。小鼠找到平台后在平台上休息10s再进行下一次试验;如果60s内找不到平台(潜伏期记为60s),则由实验者将其拿上平台,在平台上休息30s再进行下一次试验。每天以小鼠3-4次训练潜伏期的平均值作为小鼠当日的学习成绩。第5天为探索实验,撤去平台,选择平台所在象限对角象限作为入水点,记录60s内小鼠的穿台次数。
4、统计学分析
与实施例1一致。
5、实验结果
结果如图2所示,结果显示与对照组小鼠(Ctrl,n=7)相比,第1-4天适应学习期间的CUMS小鼠(n=15)到达站台的时间均延长,提示慢性应激小鼠学习能力下降;与Ctrl组小鼠相比,第5天测试期的CUMS小鼠进入平台所在象限次数和停留时间均减少,进入平台所在位置次数和停留时间也减少。以上结果表明慢性应激可诱导认知功能损伤。
实施例3IL-33对CUMS小鼠记忆能力的影响
1、IL-33滴鼻处理
配制IL-33溶液(10μg溶于450μL PBS),CUMS组小鼠随机分为2组,CUMS+IL-33组小鼠每日滴鼻IL-33(10μL/只),CUMS+PBS组小鼠每日滴鼻PBS(10μL/只),主要滴加于右侧鼻孔。IL-33滴鼻连续2周后,重复水迷宫第4天、第5天的测试内容。通过BrdU掺入比较了CUMS+PBS组(n=8)和CUMS+IL-33组(n=7)小鼠海马的神经发生。
2、统计学分析
与实施例1一致。
3、实验结果
水迷宫实验结果如图3所示,结果显示与CUMS+PBS组小鼠(n=8)相比,处理后的CUMS+IL-33组小鼠(n=7)在水迷宫中找到平台的时间较短;撤掉平台后,与CUMS+PBS组小鼠相比,处理后的CUMS+IL-33组小鼠进入平台所在象限次数和停留时间均增加,进入平台所在位置次数和停留时间也有增加的趋势。以上结果表明IL-33滴鼻2周可提升CUMS小鼠记忆能力。
BrdU掺入实验结果如图4所示,结果显示IL-33滴鼻处理2周没有改变左侧海马的神经发生,但是增加了右侧海马的神经发生,其位置特征可能与滴鼻主要滴在右侧鼻孔有关。
综上所述,IL-33信号转导维护海马神经发生。IL-33滴鼻处理2周对于长期应激造成的记忆损伤具有一定治疗作用。
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 (14)
1.IL-33在制备治疗长期抑郁引起的记忆损伤的药物组合物中的应用。
2.根据权利要求1所述的应用,其特征在于,所述药物组合物包括有效量的IL-33促进剂。
3.根据权利要求2所述的应用,其特征在于,所述促进剂特异性促进IL-33的表达水平。
4.根据权利要求3所述的应用,其特征在于,所述促进剂为IL-33的过表达载体或IL-33蛋白。
5.根据权利要求4所述的应用,其特征在于,所述促进剂提升记忆能力、增加海马神经发生。
6.根据权利要求1所述的应用,其特征在于,所述药物组合物还包括药学上可接受的载体。
7.根据权利要求1所述的应用,其特征在于,所述药物组合物的给药途径为经注射给药和鼻腔给药中的任意一种。
8.根据权利要求7所述的应用,其特征在于,所述药物组合物的给药途径为鼻腔给药。
9.根据权利要求1所述的应用,其特征在于,所述药物组合物的剂型包括液体剂型或固体剂型。
10.根据权利要求9所述的应用,其特征在于,所述液体剂型包括鼻喷雾剂、滴鼻剂、通过雾化器的气雾剂或注射制剂;所述固体剂型包括颗粒剂或粉末。
11.根据权利要求10所述的应用,其特征在于,所述药物组合物的剂型为液体剂型。
12.根据权利要求10所述的应用,其特征在于,所述液体剂型为滴鼻剂。
13.IL-33在筛选治疗长期抑郁引起的记忆损伤的候选药物中的应用,所述筛选治疗记忆损伤的候选药物的方法如下:用待筛选物质处理表达或含有IL-33基因或其编码的蛋白的培养体系;和检测所述体系中IL-33基因或其编码的蛋白的表达或活性;其中,当所述待筛选物质促进IL-33基因或其编码的蛋白的表达水平或活性时,该待筛选物质是治疗记忆损伤的候选药物。
14.一种筛选治疗长期抑郁引起的记忆损伤的候选药物的方法,其特征在于,所述方法如下:用待筛选物质处理表达或含有IL-33基因或其编码的蛋白的培养体系;和检测所述体系中IL-33基因或其编码的蛋白的表达或活性;其中,当所述待筛选物质促进IL-33基因或其编码的蛋白的表达水平或活性时,该待筛选物质是治疗记忆损伤的候选药物。
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