CN109432078A - Mcc950或其衍生物在制备预防或治疗辐射所致认知障碍药物中的应用 - Google Patents
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Abstract
本发明提供了MCC950或其衍生物在制备预防或治疗辐射所致认知障碍药物中的应用。本发明研究结果为：辐射后小鼠学习记忆明显下降，采用MCC950处理后，小鼠学习记忆能力得到明显改善，表明NLRP3炎症小体抑制剂MCC950的确有防止辐射导致的认知障碍。NLRP3炎症小体抑制剂MCC950对于临床医疗尤其是放射科，以及核意外等情况具有很好的预防保护作用，特别适合放疗病人，预防及治疗放疗病人由于辐射引起的记忆力减退、学习能力减弱等认知障碍，具有极大的推广价值。
Description
技术领域
本发明涉及医药技术领域，特别涉及MCC950或其衍生物在制备预防或治疗辐射所致认知障碍药物中的应用。
背景技术
随着核能和辐射能在疾病的诊治、核能发电发热、科学研究、军事等各个领域的广泛应用，人们接触电离辐射的机会日益增多，电离辐射致机体损伤及其防治越来越受到人们的关注。电离辐射可以加速衰老的进程，可诱发神经元发生退行性病变，其中，放射性认知功能障碍是临床放射治疗或意外受到电离辐射后常见的放射性脑损伤，其临床表现主要为空间记忆、言语记忆、注意力及解决新问题的能力下降，也有1.9％-5.1％的患者最终发展为痴呆。这对于儿童肿瘤患者的影响更为严重，例如手术加放射治疗的儿童髓母细胞瘤患者，成年时认知的能力仅为同龄人的50％-60％。对于放射性认知损伤仍缺乏长期有效的预防和治疗手段。因此，寻找防治辐射所致认知损伤的新药物，对于改善放射性脑损伤患者的生活质量具有重要的临床意义。
NLRP3炎性小体具有调控机体慢性炎症反应的功能，其组成包括NLRP3(NLRfamily，pyrin domaincontaining 3)、凋亡相关斑点样蛋白(Apoptosis-associatedspeck-like protein containing CARD，ASC)和半胱氨酸天冬氨酸蛋白酶-1(Cysteine-requiring aspartate protease-1，Caspase-1)，是内源性或外源性危险信号的胞质内感受器。作为固有免疫细胞内的危险信号感受器之一，NLRP3能被多种病原体相关分子模式(PAMP)或损伤相关分子模式(DAMP)所激活，形成多亚基的炎性小体，同时诱发细胞发生炎症性死亡，从而触发强烈的炎症反应，是机体固有免疫防御系统的重要组成部分。
MCC950是一种有效的、选择性NLRP3抑制剂，CAS号为256373-96-3，分子式为C20H23N2O5S.Na，分子量426.46，结构式如式I所示。在骨髓来源的巨噬细胞中MCC950的IC50为7.5nM。
但是，NLRP3炎症小体抑制剂MCC950能否作为改善辐射所致认知损伤的药物，尚未见报道。
发明内容
有鉴于此，本发明提供了MCC950或其衍生物在制备预防或治疗辐射所致认知障碍药物中的应用。该药物能够作为改善辐射所致认知损伤的药物。
为了实现上述发明目的，本发明提供以下技术方案：
本发明提供了MCC950或其衍生物在制备预防或治疗辐射所致认知障碍药物中的应用。
在本发明中，预防或治疗辐射所致认知障碍为提高辐射后生物体的新事物分辨率。
在本发明中，预防或治疗辐射所致认知障碍为提高辐射后生物体的新位置分辨率。
作为优选，预防或治疗辐射所致认知障碍药物的剂量为1～100mg/kg。
优选地，预防或治疗辐射所致认知障碍药物的剂量为5～50mg/kg。
在本发明提供的具体实施例中，治疗辐射所致认知障碍药物的剂量为10mg/kg。
作为优选，预防或治疗辐射所致认知障碍药物还包括药学上可接受的辅料。
作为优选，预防或治疗辐射所致认知障碍药物的剂型为注射给药剂型。
在本发明提供的实施例中，注射给药剂型为注射液或粉针剂。
作为优选，注射给药剂型的输注方式为静脉内输注、腹膜内输注、皮下输注或肌肉输注。
在本发明中，预防或治疗辐射所致认知障碍药物的剂型为胃肠道给药剂型。
本发明提供了MCC950或其衍生物在制备预防或治疗辐射所致认知障碍药物中的应用。本发明研究结果为：辐射后小鼠学习记忆明显下降，采用MCC950处理后，小鼠学习记忆能力得到明显改善，表明NLRP3炎症小体抑制剂MCC950的确有防止辐射导致的认知障碍。NLRP3炎症小体抑制剂MCC950对于临床医疗尤其是放射科，以及核意外等情况具有很好的预防保护作用，特别适合放疗病人，预防及治疗放疗病人由于辐射引起的记忆力减退、学习能力减弱等认知障碍，具有极大的推广价值。
附图说明
图1是本发明具体实施方式的实施例1NLRP3炎症小体抑制剂MCC950对辐射小鼠认知行为影响的统计结果图；其中A示各组新物体识别实验结果，B示各组新异位置辨别实验结果。
具体实施方式
本发明公开了MCC950或其衍生物在制备预防或治疗辐射所致认知障碍药物中的应用，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。
本发明通过行为学实验证明了NLRP3炎症小体抑制剂MCC950对辐射诱导的认知损伤具有明显的保护作用。
在学习记忆行为检测中，NLRP3炎症小体抑制剂MCC950能够增加辐射小鼠的新事物分辨率以及新位置分辨率。
因此，NLRP3炎症小体抑制剂MCC950可以用作改善辐射后认知障碍的药物制备。
本发明提供的MCC950或其衍生物在制备预防或治疗辐射所致认知障碍药物中的应用中所用原料药或辅料均可由市场购得。
下面结合实施例，进一步阐述本发明：
实施例1
本实施例采用新物体辨别实验、新异位置辨别实验考察NLRP3炎症小体抑制剂MCC950对辐射小鼠的学习记忆行为的影响。
动物：36只雌性昆明小鼠，3月龄，体重25g左右。动物饲养在室温(22±2)℃，湿度(45％～65％)和明暗交替(12h:12h)的环境中，自由摄食和饮水。
动物分组与处理：
(1)正常对照组(Control，n＝12)：小鼠在相同的辐射环境下，给予0Gy吸收剂量；
(2)辐射致认知损伤组(IR，n＝12)：小鼠接受137Cs-γ射线全身辐射至吸收剂量4Gy致放射性认知损伤，剂量率1.118Gy/min；
(3)MCC950干预组(IR+MCC950，n＝12)：小鼠给予137Cs-γ射线全身辐射至吸收剂量4Gy，同时，在辐射后第三周给予腹腔注射MCC950(10mg/kg)，持续至行为学检测结束。
所有学习记忆行为检测，均在辐射后第5周开始。
(一)新物体识别实验
新物体识别实验(Novel Object Recognition，NOR)是一种非奖赏性的、简单的认知记忆实验，在实验前不需要对动物进行学习训练，让动物在自由活动状态下进行学习记忆测试，能更近似地模拟人类的学习记忆行为。实验动物若保留了对旧物体的记忆，便会用更多的时间探究新物体：相反，则对两个物体的探究时间无差异。该实验包括探索和识别两个阶段。
探索阶段：在旷场(40cm×40cm×40cm)对称部位放置形状及材质相同的两个物体A和B，将小鼠由旷场正中放入，熟悉物体5min后取出小鼠，间隔24h后进行识别期的检测。
识别阶段：将物体A更换为形状及材质不同的物体C，且保持原来的位置不变，再次将小鼠放入旷场内自由探索，摄像相机记录小鼠5min内对物体C的探索时间(Timeexploring novelobeject，TN)和对物体A的探索时间(Time exploring familiarobeject，TF)。小鼠对新事物的分辨率用以下公式进行计算：(TN-TF)/(TN+TF)×100％，该指标越高说明小鼠记忆越好。试验结果如图1A所示。
结果：在NOR实验中，与正常对照组相比，辐射致认知损伤组小鼠对新物体的分辨率降低，而MMC950干预组小鼠对新物体的分辨率高于辐射致认知损伤组。上述结果表明，MMC950能够改善辐射致认知损伤小鼠的学习记忆能力。
(二)新异位置辨别实验
新异位置辨别(Novel Place Recognition，NOP)：此实验基于啮齿类动物对新异环境的天然探究的自然习性，能够有效地反映动物对新异环境的识别记忆能力。该实验包括探索和识别两个阶段。
探索阶段：在旷场(40cm×40cm×40cm)对称部位放置形状及材质相同的两个物体A和B，将小鼠由旷场正中放入，熟悉物体5min后取出小鼠，间隔24h后进行识别期的检测。
识别阶段：变动旷场中其中一个物体B的位置，且保持另一个物体A的位置不变，再次将小鼠放入旷场内自由探索，摄像相机记录小鼠5min内对位置变动物体B的探索时间(Time exploring novelPlace object，TN)和对位置不动的物体A的探索时间(Timeexploring familiar Place object，TF)。小鼠对物体B新异位置的分辨率用以下公式进行计算：(TN-TF)/(TN+TF)×100％，若小鼠记忆良好记住原物体B的位置，在识别期会利用更多的时间探索新位置处的B物体，所以该指标越高说明小鼠记忆越好。试验结果如图1B所示。
结果：在新异位置辨别实验中，与正常对照组相比，辐射致认知损伤组小鼠对新异位置的分辨率降低，而MMC950干预组小鼠对新异位置的分辨率高于辐射致认知损伤组。上述结果表明，MMC950能够改善辐射致认知损伤小鼠的空间辨别能力。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (10)
1.MCC950或其衍生物在制备预防或治疗辐射所致认知障碍药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述预防或治疗辐射所致认知障碍为提高辐射后生物体的新事物分辨率。
3.根据权利要求1所述的应用，其特征在于，所述预防或治疗辐射所致认知障碍为提高辐射后生物体的新位置分辨率。
4.根据权利要求1所述的应用，其特征在于，所述预防或治疗辐射所致认知障碍药物的剂量为1～100mg/kg。
5.根据权利要求1所述的应用，其特征在于，所述预防或治疗辐射所致认知障碍药物的剂量为5～50mg/kg。
6.根据权利要求1所述的应用，其特征在于，所述预防或治疗辐射所致认知障碍药物还包括药学上可接受的辅料。
7.根据权利要求1所述的应用，其特征在于，所述预防或治疗辐射所致认知障碍药物的剂型为注射给药剂型。
8.根据权利要求7所述的应用，其特征在于，所述注射给药剂型为注射液或粉针剂。
9.根据权利要求7所述的应用，其特征在于，所述注射给药剂型的输注方式为静脉内输注、腹膜内输注、皮下输注或肌肉输注。
10.根据权利要求1所述的应用，其特征在于，所述预防或治疗辐射所致认知障碍药物的剂型为胃肠道给药剂型。
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| US11542255B2 (en) | 2017-08-15 | 2023-01-03 | Inflazome Limited | Sulfonylureas and sulfonylthioureas as NLRP3 inhibitors |
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