CN118976027A - 氨基噻唑衍生物在制备治疗神经退行性疾病药物中的应用 - Google Patents
氨基噻唑衍生物在制备治疗神经退行性疾病药物中的应用 Download PDFInfo
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Abstract
本发明涉及医药技术领域，具体公开了一种氨基噻唑衍生物在制备预防、缓解或者治疗神经退行性疾病产品中的应用。本发明使用小分子化合物INNA1605来治疗神经退行性疾病。该化合物可以改善阿尔茨海默病模型小鼠的认知障碍，降低脑内病理性Aβ沉积，通过调控小胶质细胞启动及训练免疫下调炎症反应，减轻神经毒性，对神经元具有保护作用。通过这些作用，INNA1605有望提供一种缓解和治疗神经退行性疾病的有效药物。
Description
技术领域
本发明涉及生物医药技术领域，具体地指一种氨基噻唑衍生物在制备治疗神经退行性疾病药物中的应用。
背景技术
阿尔茨海默病(Alzheimer’s disease，AD)是一种老年化的慢性神经退行性疾病，目前缺乏有效治疗AD的药物。随着人口老龄化，到2050年，预计全球痴呆症患病率将增加两倍。而阿尔茨海默病是痴呆症的主要原因，并迅速成为21世纪最昂贵、危害性大和负担最重的疾病之一。治疗AD的药物研发主要有抗淀粉样β蛋白、抗tau蛋白和抗炎等策略。近年来针对神经炎症开发治疗AD临床药物不再仅专注于Aβ和tau蛋白，而是针对多样的创新靶点，其中神经炎症是重要的开发方向之一。神经炎症被认为是阿尔茨海默病病理学的主要组成部分。
小胶质细胞激活是人脑神经炎症免疫反应的重要部分，是与AD发展相关的关键因素。文献表明，在活化的小胶质细胞存在的情况下，Aβ增强tau蛋白的传播，促进AD的进展。另一方面，早期检测到的小胶质细胞激活具有清除Aβ和保护神经元的作用。小胶质细胞激活对Aβ的作用表现出病程特异性，在AD的进展中具有矛盾效应，提示抗神经炎症的药物干预时机及强度应当动态关注。
训练免疫(Trained immunity)是一种先天免疫记忆特性，先天免疫细胞通过代谢和表观遗传重编程使其功能发生长期改变，导致其对二次刺激的免疫反应过度或不足，并且这种免疫反应是非特异性的。有研究发现通过调节小胶质细胞的免疫记忆对AD中神经炎症及Aβ的清除可产生影响，训练后的小胶质细胞可以促进小鼠AD模型的神经病理，提示调控小胶质细胞的训练免疫是防治AD的一个新方向。
有文献表明，MyD88先天缺陷的情况下，小胶质细胞的早期免疫反应受到抑制可能会阻止它们充分激活以对抗和清除Aβ蛋白。而后天MyD88缺陷抑制小胶质细胞的促炎激活，降低神经毒性炎症反应，维持小胶质细胞的正常功能，这随后减弱了脑内Aβ的负荷。MyD88的先天缺陷与后天缺陷对AD产生相反的作用，表明MyD88对于AD的病程进展有重要作用。由此推测在AD小鼠Aβ形成早期，MyD88通路激活促进小胶质细胞活化减少Aβ沉积，延缓AD病程。而在晚期，Aβ刺激下小胶质细胞受到训练，此时MyD88通路激活训练的小胶质细胞产生过度的神经炎症，从而加重AD神经病理。小胶质细胞的训练免疫可能解释了AD病程中MyD88先天缺陷与后天缺陷所导致效应的矛盾性。综上，MyD88可作为对AD的干预靶点。
小分子化合物INNA1605能特异性的抑制MyD88信号传导，有效减少促炎细胞因子的表达，逆转炎症反应。在前期研究中，已表明MyD88抑制剂对急性过度免疫炎性反应有着良好的抑制作用，减轻急性脑梗塞后再灌注损伤。MyD88抑制剂对于慢性神经毒性炎症参与导致的AD的治疗作用和机制需要进一步研究。目前尚未有INNA1605在阿尔茨海默症治疗有效性方面的研究报道。
发明内容
为了解决上述问题，本发明提供了一种氨基噻唑衍生物在制备治疗神经退行性疾病药物中的应用，并进一步扩展到具有相似机制的神经退行性疾病。本发明首次发现氨基噻唑衍生物对于阿尔茨海默症和抑郁症具有良好的治疗效果，提供一种氨基噻唑衍生物的新用途。
为实现上述目的，本发明采用的技术方案如下：
本发明提供了氨基噻唑衍生物在制备预防、缓解或者治疗神经退行性疾病产品中的应用。
优选地，所述神经退行性疾病为神经毒性炎症参与导致的阿尔茨海默病或抑郁症。
本发明还提供了氨基噻唑衍生物在制备具有神经元保护活性产品上的应用。
本发明还提供了氨基噻唑衍生物在制备降低Aβ蛋白沉积功能的产品中的应用。
本发明还提供了氨基噻唑衍生物在制备调控小胶质细胞启动及训练免疫的产品上的应用。
本发明还提供了氨基噻唑衍生物作为神经元活性保护剂或Aβ蛋白沉积抑制剂或小胶质细胞启动及训练免疫调节剂在制备预防、缓解或者治疗神经退行性疾病产品中的应用。
优选地，所述产品为功能性食品、保健品或药物。
优选地，所述药物包括但不局限注射剂、口服液、片剂、胶囊。
优选地，所述氨基噻唑衍生物为3-(4-(4-苄基哌嗪-1-基)-N-(4-苯基噻唑-2-)丙酰胺，代号为INNA1605，结构式如下：
相比于现有技术，本发明的有益效果为：
本发明涉及使用氨基噻唑衍生物INNA1605来治疗神经退行性疾病。该化合物可以改善阿尔茨海默病模型小鼠的认知障碍，降低脑内病理性Aβ沉积，通过调控小胶质细胞启动及训练免疫下调炎症反应，减轻神经毒性，对神经元具有保护作用。通过这些作用，INNA1605有望提供一种预防、缓解和治疗神经退行性疾病的有效药物。
附图说明
图1为慢性INNA1605干预轻微改善认知功能(Morris水迷宫)；(#p<0.05，##p<0.01vs Control组)；
图2为慢性INNA1605干预显著减少APP/PS1小鼠脑Aβ沉积；9月龄时各组小鼠全脑(A)、皮层(B)、海马(C)区域的代表性免疫组化图像及Aβ斑块的面积百分比(D)；(###p<0.001vs Control组；*p<0.05vs APP/PS1；control组；APP/PS1和APP/PS1+INNA1605组)；
图3为慢性INNA1605干预显著抑制APP/PS1小鼠脑小胶质细胞激活；9月龄时各组小鼠全脑(A)、皮层(B)、海马(C)区域的代表性免疫组化图像及Iba-1阳性的小胶质细胞的面积百分比(D)；(#p<0.05，###p<0.001vs Control组；*p<0.05，**p<0.01vs APP/PS1组；control组；APP/PS1和APP/PS1+INNA1605组)；
图4为慢性INNA1605干预可以显著减轻脑组织内的炎性反应；(A)9月龄各组小鼠皮层组织TNF-α、IL-6、IL-1β、COX2、iNOS和MYD88的mRNA表达水平；(B)9月龄各组小鼠海马组织TNF-α、IL-6、IL-1β、COX2、iNOS和MYD88的mRNA表达水平；(#p<0.05，###p<0.001vsControl组；*p<0.05，**p<0.01，***p<0.001vs APP/PS1组)；
图5为INNA1605可以抑制Aβ诱导的小胶质细胞激活及促炎因子分泌；CCK8试剂盒测定不同浓度INNA1605对小胶质细胞活力的影响；不同浓度INNA1605预处理后，Aβ刺激的小胶质细胞IL-1β、TNF-α、IL-6和COX2等炎性因子的mRNA表达水平；(##p<0.01，###p<0.001vsControl组；*p<0.05，**p<0.01vsAβ组)；
图6为INNA1605剂量依赖性地降低Aβ诱导的神经毒性，显著提高神经元的活力；(A)CCK8试剂盒测定不同浓度INNA1605对神经元活力的影响；(B)不同条件培养基处理的神经元的活力测定；(###p<0.001vs Control-CM组；**p<0.01，***p<0.001vs Aβ-CM组)；
图7为INNA1605抑制了Aβ诱导的小胶质细胞训练免疫，逆转了小胶质细胞的促炎性表观遗传修饰；(*p<0.05，**p<0.01vs Aβ组)；
图8为INNA1605防止新冠病毒突刺蛋白(CSDS-/SARS-907COV-2Spike RBD)诱导的抑郁症行为和神经毒性炎症导致的病理性改变。
具体实施方式
为了更好地解释本发明，以下结合具体实施例进一步阐明本发明的主要内容，但本发明的内容不仅仅局限于以下实施例。
实施例1：INNA1605对阿尔兹海默病的治疗作用。
阿尔兹海默病小鼠模型制作与分组：建立模型：APP/PS1转基因小鼠购于上海斯莱克实验动物有限责任公司，该转基因小鼠在培育至8至9个月龄时自发阿尔兹海默病，无需进行额外处理。
实验分为3组，分别为：
对照组(Control组)：C57BL/6小鼠，给予等剂量的溶剂(ddH2O)；
模型组(APP/PS1组)：APP/PS1转基因小鼠，给予等剂量的溶剂(ddH2O)；
用药组(APP/PS1+INNA1605组)：APP/PS1转基因小鼠，给予INNA1605药物(每天2次，每次25mg/Kg，腹腔注射1次，口服1次)。
在小鼠9个月龄时，进行Morris水迷宫测试，以评估APP/PS1小鼠的空间学习和记忆能力。行为学试验结束后，经深度麻醉，一部分小鼠经开胸充分暴露心脏和主动脉后，20ml注射器接输液针头从心尖插至主动脉内，固定针头，剪开右心房，经主动脉灌注4℃的生理盐水30ml至血液大部分流出后，小心快速分离取出海马和皮层组织，保存于-80℃进行后续生化分析。余下小鼠先灌注4℃生理盐水30ml，再灌注预冷的4％多聚甲醛30ml，然后取出全脑，4％多聚甲醛继续固定48h，经脱水透明、石蜡包埋、切片后进行免疫组织化学分析，通过免疫组织化学染色检测病理性Aβ沉积和小胶质细胞激活水平，RT-PCR检测TNF-α、IL-1β、IL-6、COX-2、iNOS和MyD88的表达水平。
如图1所示，所得到实验结果显示INNA1605治疗后的APP/PS1转基因小鼠其记忆力比模型组小鼠要好，虽然还未达到正常小鼠(即Control组)的记忆水平。通过免疫组化我们也发现，如图2所示，INNA1605治疗后的APP/PS1转基因小鼠其在小鼠全脑、皮层、海马区域脑Aβ沉积明显比模型组少。如图3所示，NNA1605治疗后小鼠全脑、皮层、海马区域Iba-1阳性的小胶质细胞的面积较模型组也明显减少。此外，如图4所示，用药组相较于模型组，其大脑皮层和海马中TNF-a、IL-6、COX-2、iNOS等炎性因子和MyD88表达水平明显下降，提示无论是在疗效上还是在机理上，INNA1605均可作为治疗阿尔兹海默病的新型药物。
实施例2：INNA1605抑制了小胶质细胞训练免疫，从而减轻神经毒性，对神经元具有保护作用。
体外实验采用小胶质细胞系(BV-2)和神经元细胞系(SH-SY5Y)，建立Aβ刺激模型，分为Control组、Aβ组、Aβ+1μM INNA1605组、Aβ+5μM INNA1605组，Aβ+10μM INNA1605组，Aβ+20μM INNA1605组，Aβ刺激24h后，收集BV-2细胞提取mRNA测定IL-1β、TNF-α、IL-6、COX2等促炎介质的表达水平，通过染色质免疫共沉淀和RT-PCR实验检测BV-2细胞的表观遗传修饰变化。此外，收集一部分上清液作为条件培养基用于培养SH-SY5Y细胞，24h后用CCK8试剂盒检测SH-SY5Y细胞的活力。
如图5～6所示，所得到实验结果显示在30μmol/L范围内，INNA1605对BV-2细胞和SH-SY5Y细胞均无明显细胞毒性。与Aβ组相比，INNA1605处理的BV-2细胞活化受到抑制，IL-1β、TNF-a、IL-6、COX2等炎性因子表达水平下降，并且INNA1605以剂量依赖性地方式降低Aβ诱导的神经毒性，显著提高SH-SY5Y细胞的活力。此外，如图7所示，INNA1605抑制了Aβ诱导的小胶质细胞训练免疫，逆转了小胶质细胞的促炎性表观遗传修饰。
实施例3：氨基噻唑衍生物INNA1605用于防治抑郁症。
选择6-7周龄雄性C57BL/6J小鼠和雄性CD-1大鼠建立抑郁症模型，挫败性抑郁症(CSDS)模型：C57BL/6J小鼠每天被不同的CD-1大鼠攻击10分钟，连续10天，晚上两种鼠关在同一个有孔的透明玻璃隔开的笼子里，保持被攻击的压力。实验结果如图8所示，结果表明INNA1605(TJ-M2010-5)明显改善诱导抑郁症行为和脑内神经毒性炎症导致的病理性改变。
根据本发明所提出的技术方案，有证据表明小分子化合物INNA1605具有潜在的抗阿尔茨海默症效果。这种作用是通过抑制小胶质细胞来训练免疫系统，从而降低神经毒性炎症反应，减少Aβ的堆积，并保护神经元。这一发现揭示了INNA1605在治疗阿尔茨海默症中的潜在机制，有助于推动其在市场上的新应用探索和针对阿尔茨海默症药物的研发进程。此外，INNA1605用于防治抑郁症，表明INNA1605在治疗神经退行性疾病的潜力。
其它未说明的部分均属于现有技术。
Claims (9)
1.氨基噻唑衍生物在制备预防、缓解或者治疗神经退行性疾病产品中的应用。
2.根据权利要求1所述的应用，其特征在于：所述神经退行性疾病为神经毒性炎症参与导致的阿尔茨海默病或抑郁症。
3.氨基噻唑衍生物在制备具有神经元保护活性产品上的应用。
4.氨基噻唑衍生物在制备降低Aβ蛋白沉积功能的产品中的应用。
5.氨基噻唑衍生物在制备调控小胶质细胞启动及训练免疫的产品上的应用。
6.氨基噻唑衍生物作为神经元活性保护剂或Aβ蛋白沉积抑制剂或小胶质细胞启动及训练免疫调节剂在制备预防、缓解或者治疗神经退行性疾病产品中的应用。
7.根据权利要求1或3或4或5或6所述的应用，其特征在于：所述产品为功能性食品、保健品或药物。
8.根据权利要求7所述的应用，其特征在于：所述药物包括但不局限注射剂、口服液、片剂、胶囊。
9.根据权利要求1或3或4或5或6所述的应用，其特征在于：所述氨基噻唑衍生物为3-(4-(4-苄基哌嗪-1-基)-N-(4-苯基噻唑-2-)丙酰胺，代号为INNA1605，结构式如下：
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