CN117298086B - 索法酮在制备预防和/或治疗nlrp3炎性小体介导的疾病的药物中的应用 - Google Patents
索法酮在制备预防和/或治疗nlrp3炎性小体介导的疾病的药物中的应用 Download PDFInfo
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- CN117298086B CN117298086B CN202311614553.1A CN202311614553A CN117298086B CN 117298086 B CN117298086 B CN 117298086B CN 202311614553 A CN202311614553 A CN 202311614553A CN 117298086 B CN117298086 B CN 117298086B
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Abstract
本发明涉及生物医药技术领域，具体提供了一种索法酮在制备预防和/或治疗NLRP3炎性小体介导的疾病的药物中的应用。索法酮能在体外抑制NLRP3炎性小体的活化，在体内可以改善NLRP3炎症小体介导的疾病模型动物的病理状态，索法酮可通过共价结合直接与NLRP3结合，从而抑制NLRP3炎性小体的激活。由于索法酮来源于中药活性成分，且是临床上一直在应用的药物，其副作用较小，安全性可控，因而可作为抗痛风性关节炎、自身免疫性脑病、2型糖尿病等NLRP3炎症小体介导的疾病的潜在药物进行后续开发，缩短了新药开发的周期，具有较强的转化价值。
Description
技术领域
本发明涉及生物医药技术领域，具体涉及索法酮在制备预防和/或治疗NLRP3炎性小体介导的疾病的药物中的应用。
背景技术
固有免疫是机体抵抗外源病原体及清除体内异物的第一道防线。机体通过模式识别受体识别病原相关分子模式（PAMPs）及损伤相关分子模式（DAMPs）。
炎性小体是存在于胞浆内的一类模式识别受体，是机体对外源性危险信号及内源性损伤信号的感受器，NLRP3是研究最广泛的一类炎症小体。NLRP3蛋白通过与凋亡相关斑点样蛋白（ASC）及半胱氨酸蛋白酶-1（caspase-1）组装成复合物的形式来执行功能。活化的NLRP3炎性小体一方面通过剪切白介素-1β（IL-1β）及白介素-18（IL-18）前体形式形成有活性的IL-1β及IL-18，进一步促进炎症级联反应，另一方面还可以剪切GSDMD诱导细胞焦亡的发生。
NLRP3炎性小体活化剂多种多样，细菌病毒、环境中的粉尘颗粒，机体内代谢产物以及细胞死亡释放的物质均可诱导NLRP3炎性小体的活化。由于NLRP3激活剂的广泛性，因此其在多种疾病的发生发展过程中起着重要的作用。
痛风是一种无菌炎症，由于尿酸代谢功能的障碍，导致尿酸结晶（MSU）在关节等组织中积累，进而特异性地活化NLRP3炎症小体，NLRP3基因缺失后尿酸结晶诱导的关节炎明显减轻。
多发性硬化症也是一种NLRP3相关的自身免疫性炎症性疾病，其特征为髓鞘反应性CD4+T细胞浸润中枢神经系统，攻击少突胶质细胞并诱导脱髓鞘作用。多发性硬化症作为一种慢性脱髓鞘疾病，近年来其发病率逐渐上升，并且以青壮年时期发病居多，复发率、致残率极高，极大地影响患者的工作、生活质量。实验性自身免疫性脑脊髓炎（EAE）是模拟人类多发性硬化症的常用小鼠模型。在实验性自身免疫性脑脊髓炎中脊髓中NLRP3表达量明显升高，当NLRP3基因缺失后，实验性自身免疫性脑脊髓炎病程变慢，病情明显缓解。
2型糖尿病是一种胰岛素相对不足的糖尿病，以胰岛素敏感性降低为特征。2型糖尿病是一种慢性疾病，伴随着慢性炎症的发生。在持续的慢性炎症过程中NLRP3持续被活化。NLRP3激活产物IL-1β在胰岛素抵抗过程中起着重要的作用，IL-1β作用于胰岛，能够诱导胰岛β细胞死亡及功能丧失，并且能够抑制胰岛素信号的传递，促进胰岛素抵抗。
目前临床治疗NLRP3炎性小体活化导致的疾病主要通过抑制IL-1β的功能来实现，如IL-1β的受体拮抗剂/阻断剂或者IL-1β的单克隆抗体等。由于NLRP3炎性小体活化还会促进IL-18、HMBG1等除IL-1β外其他炎症因子的成熟及分泌且还可以导致细胞焦亡的发生，针对IL-1β靶向作用不强，甚至还会对机体正常的生理功能造成影响，产生一系列的副作用。
目前已报道的NLRP3抑制剂有外源性的小分子化合物如MCC950、BAY 11-7082等，天然产物提取物如雷公藤、胡萝卜硫素及异甘草素等，内源性代谢物如β-羟基丁酸等。这些抑制剂通过影响NLRP3炎性小体激活的上游信号抑制NLRP3炎性小体的激活或者通过靶向NLRP3炎性小体中的其他组成蛋白来抑制NLRP3炎性小体的组装，因此，这些抑制剂特异性不强。
索法酮是中药广豆根中提取、合成的有效成分，属异戊二烯基查耳酮衍生物，能增加胃血流量，扩张胃粘膜血管，增加胃组织耗氧量，促进胃粘膜修复，增加胃壁构成成分，增加胃组织内前列腺素含量，其作用机理为抑制前列腺素分解酶-5-羟基前列腺素脱氢酶的活性。本品主要通过增强防御因子而对消化道溃疡发挥良好效果，临床主要用于治疗胃溃疡与胃炎。作为临床上在应用的药物，索法酮的安全性在临床上得以验证，发现其新的药理作用，可缩短抗痛风性关节炎、自身免疫性脑病及2型糖尿病等NLRP3炎性小体介导的疾病的研发周期，增加了其成药的可能性。
发明内容
发明目的：针对于上述现有技术的不足，本发明公开了索法酮在制备用于治疗/预防NLRP3炎性小体介导疾病（痛风性关节炎、自身免疫性脑病、2型糖尿病）药物的应用。
为实现上述目的，本发明提供如下技术方案：
本发明提供了索法酮在制备预防和/或治疗NLRP3炎性小体介导的疾病的药物中的应用。
索法酮的结构式如下：
对于上述药物，索法酮作为活性成分可通过口服、注射、喷射、滴鼻、滴眼、渗透、吸收、物理或化学介导的方法导入机体如肌肉、皮内、皮下、静脉、粘膜组织；或是被其他物质混合或包裹后导入机体。
优选地，所述NLRP3炎性小体介导的疾病包括痛风性关节炎、自身免疫性脑病、2型糖尿病。
优选地，所述应用为索法酮在制备预防和/或治疗关节炎药物中的应用。
优选地，所述应用为索法酮在制备预防和/或治疗自身免疫性脑病药物中的应用。
优选地，所述应用为索法酮在制备预防和/或治疗2型糖尿病中的应用。
优选地，所述索法酮作为唯一活性成分在制备预防和/或治疗NLRP3炎性小体介导的疾病的药物中的应用。
优选地，所述预防和/或治疗NLRP3炎性小体介导的疾病的药物以索法酮（活性成分）作为唯一成分制成，或所述预防和/或治疗NLRP3炎性小体介导的疾病的药物以索法酮作为唯一活性成分并与药学上允许的一种或多种药学上可接受的载体制成；
所述药学上可接受的载体为药学上可接受的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂中的一种或多种；所述药物为口服试剂或者非口服试剂。具体的，可以按照常规方法将本发明的药物制成片剂、胶囊剂、丸剂、粉末剂、栓剂、膏剂及溶液剂和混悬剂，其中优选的是适用于胃肠道给药的胶囊剂和片剂。在制备适用于口服给药的胶囊剂、片剂、丸剂和粉末剂时，可以使用蔗糖、乳糖、玉米淀粉、微晶纤维素、羧甲基纤维素作为载体或赋形剂。
优选地，所述预防和/或治疗NLRP3炎性小体介导的疾病是指防止所述疾病发生、消除已发生的疾病症状、延缓已发生的疾病发展和/或逆转病理过程。
优选地，所述索法酮的立体异构体、索法酮的外消旋体或索法酮的盐在制备预防和/或治疗NLRP3炎性小体介导的疾病的药物中的应用。
本发明中，所述索法酮可以抑制LPS及ATP处理的巨噬细胞中NLRP3炎性小体激活产物IL-1β的产生；
所述索法酮可以抑制LPS及ATP处理的巨噬细胞中NLRP3炎性小体激活所导致的乳酸脱氢酶的释放；
所述索法酮可以抑制LPS及ATP处理的巨噬细胞中NLRP3炎性小体激活标志物半胱氨酸蛋白酶-1/半胱氨酸蛋白酶前体-1的表达；
所述索法酮可以直接与NLRP3蛋白结合；
所述索法酮作为预防和/或治疗痛风性关节炎、自身免疫性脑病、2型糖尿病等NLRP3介导的疾病的药物能够明显缓解痛风性关节炎、自身免疫性脑病、2型糖尿病等NLRP3介导的疾病的病理状况。
本发明的有益效果是：
1、本发明首次将索法酮应用于经典且广泛认可的痛风性关节炎、自身免疫性脑病、2型糖尿病等NLRP3介导的疾病的细胞及动物模型，相关实验证明索法酮可以抑制巨噬细胞中NLRP3炎性小体的激活进而具有预防和/或治疗抗痛风性关节炎、自身免疫性脑病、2型糖尿病等NLRP3介导的疾病的作用。
2、由于索法酮是临床上已经应用的药物，发现其新的药理作用有利于其作为抗痛风性关节炎、自身免疫性脑病、2型糖尿病等NLRP3炎性小体介导的疾病的潜在药物进行后续开发，有利于临床转化，具有重大的转化价值。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为实施例1中各组巨噬细胞中的培养基上清中IL-1β的含量的示意图；
图2为实施例1中各组的巨噬细胞中乳酸脱氢酶释放率的示意图；
图3为实施例1中各组的巨噬细胞中半胱氨酸蛋白酶-1/半胱氨酸蛋白酶前体-1的表达变化示意图；
图4为实施例2中检测索法酮的特异性探针上与NLRP3纯蛋白结合的荧光信号的结果图；
图5为实施例3中索法酮与尿酸结晶诱导的关节肿胀程度的关系图；
图6为实施例3中索法酮与关节中IL-1β的分泌量的关系图；
图7为实施例4中索法酮与改善自身免疫性脑病的临床评分结果的关系图；
图8为实施例4中索法酮与自身免疫性脑病小鼠体重的关系图；
图9为实施例4中索法酮与自身免疫性脑病小鼠脑组织中单核细胞群数量的关系图；
图10为实施例5中索法酮与2型糖尿病各组小鼠空腹血糖水平的示意图；
图11为实施例5中索法酮与2型糖尿病各组小鼠胰岛素抵抗指数的示意图；
图12为实施例5中索法酮与2型糖尿病各组小鼠的糖耐量的示意图。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
细胞模型：
BMDMs（骨髓来源的巨噬细胞）细胞诱导分化：取6周龄的C57BL/6J雄性小鼠胫骨中的骨髓，裂解红细胞，在细胞中加入含10% L929细胞培养基上清的DMEM完全培养基，继续培养5天后即可得到BMDMs细胞。(本发明中均采用此方法获得BMDMs细胞）
将BMDMs细胞接种在6孔板中，设置对照组、模型组及给药组。在细胞中加入500ng/ml LPS处理3h后，加入5mM ATP继续处理1h，建立NLRP3炎性小体激活模型、对照组：只添加LPS；给药组：在LPS处理的同时加入不同浓度的索法酮（200、100、50μM）。ATP处理结束后，收集各组培养基上清，采用ELISA试剂盒检测培养基上清中IL-1β的含量；采用乳酸脱氢酶检测试剂盒，检测各组乳酸脱氢酶释放变化；收集细胞裂解液，进行WB实验检测半胱氨酸蛋白酶-1/半胱氨酸蛋白酶前体-1蛋白表达的变化。
动物模型建立：
C57BL/6J小鼠购买于斯贝福（北京）生物技术有限公司，为正常饲养小鼠，8周龄，小鼠生长过程处于同一环境，且喂养同样的食物。
1、关节炎模型构建：
取8周龄C57BL/6J小鼠，进行称重，然后进行分组。给药组左膝关节注射索法酮100mg/kg，对照组左膝关节注射相同体积的溶剂。30min后，给药组及模型组左膝关节注射尿酸结晶（0.5 mg，溶于20 μl无菌PBS），右膝关节注射等体积无菌PBS。24h后测量左右膝关节的宽度，然后颈椎脱臼处死小鼠，将左膝关节取出，放置于含有200 μlopti-MEM（1%双抗）的12板中培养1h。将培养上清用ELISA试剂盒检测各组IL-1β的含量。
2、自身免疫性脑病模型构建：
用生理盐水将MOG35-55 稀释为10mg/ml，并按1:1等体积加入完全弗氏佐剂结核菌素H37Ra，终浓度为4mg/ml）混合。充分乳化后按照每只250μg/0.1ml于小鼠脊柱两侧分四点进行皮下注射，免疫当天及第2天（48h）分两次腹腔注射0.5ml PTX（500ng/只），建立自身免疫性脑病模型（EAE）。实验设置正常组、对照组及给药组，给药组按照索法酮100mg/kg进行灌胃给药。22天后，各组小鼠进行临床评分及称量体重，之后处死小鼠，收集小鼠脑部组织，将脑组织研磨成单细胞悬液，加入30% Percoll细胞分离液，分离单核细胞，采用PE-CD4、FITC-CD8、APC-CD11b流式抗体孵育单核细胞，流式上机分析细胞比例。
3、2型糖尿病动物模型构建：
1%链脲佐菌素（Streptozotocin，STZ）溶液配制
A液：0.21g柠檬酸加10ml ddH2O，B液：0.294g柠檬酸钠加10 ml ddH2O。将A液和B液按1:1比例混合，调节缓冲液pH值至4.4，为了避免pH值偏移缓冲液要现配现用，溶解STZ前缓冲液于0.22μm除菌过滤器中过滤，后放冰上预冷。避光条件下精确称量和分装STZ，实验前20min内与配制好的檬酸-柠檬酸钠缓冲液按1g：100ml轻轻晃动混配成1% STZ溶液，配制过程需要保持避光且在冰浴中进行。
采用高脂饲料喂养5周龄C57BL/6J小鼠，6周后小鼠过夜禁食12h，腹腔注射50mg/kg预冷的1% STZ溶液，连续3天，对照组小鼠腹腔注射相同剂量的缓冲液，稳定一周后，测量小鼠空腹血糖＞11.1mM即为造模成功，造模成功后继续给予60%的高脂饲料喂养8周，同时给药组灌胃给索法酮100mg/kg。8周后，采用血糖仪测量小鼠尾尖静脉空腹血糖，收集小鼠血清采用胰岛素检测试剂盒检测血清中胰岛素含量，胰岛素抵抗程度应用稳态模型胰岛素抵抗指数（HOMA-IR）值进行评价。HOMA-IR计算公式如下：HOMA-IR=空腹血糖水平（mM）×空腹胰岛素水平（mU/ml）/22.5。进行糖耐量实验实验（OGTT）小鼠灌胃给予20%的葡萄糖溶液（2g/kg），持续监测0、30、60、90、120min时小鼠尾静脉的血糖，糖耐量实验期间小鼠可自由饮水，避免对小鼠过度刺激。
实施例1：索法酮可以抑制巨噬细胞中NLRP3炎性小体的激活
ELISA检测细胞培养基上清中IL-1β的含量，如图1所示，结果显示索法酮（SOF）可以抑制巨噬细胞中NLRP3炎性小体激活产物IL-1β的产生。
乳酸脱氢酶试剂盒检测巨噬细胞中乳酸脱氢酶的含量，如图2所示，结果显示索法酮（SOF）可以抑制巨噬细胞中NLRP3炎性小体激活所导致的乳酸脱氢酶的释放。
WB实验检测巨噬细胞中激活标志物半胱氨酸蛋白酶-1/半胱氨酸蛋白酶前体-1的表达变化，如图3所示，结果显示索法酮（SOF）可以抑制巨噬细胞中NLRP3炎性小体激活标志物半胱氨酸蛋白酶-1/半胱氨酸蛋白酶前体-1的表达。
实施例2：索法酮可以直接与NLRP3蛋白结合
采用索法酮的特异性探针（本实验室自己合成）与NLRP3纯蛋白孵育，进行“点击化学”反应在复合物上标记上荧光染料，SDS-PAGE分离蛋白，利用远红外扫胶仪检测探针上的荧光信号，如图4所示，结果显示索法酮的特异性探针可以与NLRP3纯蛋白结合，证明索法酮可以直接与NLRP3蛋白结合。
实施例3：索法酮可以治疗痛风性关节炎
采用尿酸结晶关节注射C57BL/6J小鼠诱导急性关节炎，观察索法酮对尿酸结晶诱导的关节炎的作用。图5结果显示索法酮能够明显缓解尿酸结晶诱导的关节肿胀；ELISA试剂盒检测关节中IL-1β的分泌增加，如图6所示，结果显示索法酮可减少关节中IL-1β的分泌。
实施例4：索法酮可以治疗自身免疫性脑病
建立自身免疫性脑病模型22天后，A：对小鼠进行临床评分，如图7所示，结果显示索法酮可以改善自身免疫性脑病的临床评分；B：称量小鼠体重，如图8所示，结果显示索法酮具有体重保护作用；C：采用流式细胞技术检测小鼠脑组织中单核细胞群的比例变化，如图9所示，结果显示索法酮可以减少脑组织中单核细胞的浸润。
实施例5：索法酮可以治疗2型糖尿病
建立2型糖尿病动物模型，给药8周后，A：采用血糖仪检测各组小鼠空腹血糖水平，如图10所示，结果显示索法酮给药组可以显著降低2型糖尿病模型小鼠的空腹血糖水平；B：采用胰岛素检测试剂盒检测血清中空腹胰岛素水平，并计算胰岛素抵抗指数（HOMA-IR），结果如图11所示，索法酮给药后可以显著降低胰岛素抵抗指数；C：进行糖耐量（OGTT）实验，各组小鼠给予20%葡萄糖溶液（2g/kg）灌胃，持续监测0、30、60、90、120min 血糖，如图12所示，结果显示索法酮给药后可以显著降低葡萄糖负荷后的血糖水平。
以上实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的精神和范围。
Claims (4)
1.索法酮在制备预防和/或治疗NLRP3炎性小体介导的疾病的药物中的应用；所述NLRP3炎性小体介导的疾病为痛风性关节炎、自身免疫性脑病或2型糖尿病。
2.根据权利要求1所述的应用，所述索法酮作为唯一活性成分在制备预防和/或治疗NLRP3炎性小体介导的疾病的药物中的应用。
3.根据权利要求2所述的应用，其特征在于，所述药物还包括药学上可接受的载体；所述药物为口服试剂。
4.根据权利要求1-3中任一项所述的应用，其特征在于，所述药物中索法酮的形式还可以为索法酮的盐。
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