CN115844885B - nat10小分子抑制剂在制备治疗缺血性脑卒中药物中的应用 - Google Patents
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Abstract
本发明公开NAT10小分子抑制剂在制备治疗缺血性脑卒中药物中的应用,属于医药技术领域本发明基于C57BL/6J小鼠构建光化学诱导的血栓栓塞型PT脑缺血动物模型,并于3~7天给予NAT10小分子抑制剂Remode l i n,通过尼氏染色评估Remode l i n对梗死体积的影响,通过错步实验、圆筒实验和黏附移除实验评估Remode l i n对感觉运动功能的影响。结果发现,Remode l i n能够显著减小梗死体积,有效改善脑缺血小鼠的感觉运动功能,有望开发为缺血性脑卒中的潜在治疗药物。
Description
技术领域
本发明属于医药技术领域,具体涉及NAT10小分子抑制剂在制备治疗缺血性脑卒中药物中的应用。
背景技术
脑卒中是由突发的局部脑血管阻塞或破裂引起的神经功能障碍疾病,具有高发病率、高死亡率、高致残率、高复发率的特征,是导致全球成年人永久性残疾的主要原因,是我国成年人死亡的首位原因。脑卒中包括出血性脑卒中和缺血性脑卒中,其中缺血性脑卒中约占卒中总数的70%,临床治疗仍以血管再通为主。目前尚无有效促进卒中后脑修复或改善长期预后的治疗方案和药物,即使及时溶栓也无法显著减轻缺血后的神经功能损伤。因此,如何促进卒中后脑修复及增强神经功能重建是目前亟待解决的科学难题。
随着表观遗传修饰检测技术和精准医疗理念的发展,研究人员开始从表观遗传修饰层面挖掘缺血性脑卒中潜在的治疗靶点,包括非编码RNA、磷酸化、甲基化和乙酰化等。N-乙酰转移酶NAT10作为调控乙酰化水平的核心酶之一,能够通过调控tRNA和mRNA的乙酰化水平,参与有丝分裂、癌症和衰老等生理病理过程,在疾病进展中发挥重要作用。NAT10小分子抑制剂Remodelin化学结构式如图3所示,分子式为C15H15BrN4S,分子量为363.28,目前未见报道NAT10小分子抑制剂可以治疗缺血性脑卒中。
发明内容
针对现有临床药物治疗效果的不足,本发明的目的在于提供NAT10小分子抑制剂在制备治疗缺血性脑卒中药物中的应用。
本发明的目的可以通过以下技术方案实现:
一种治疗缺血性脑卒中的药物,包括NAT10抑制剂。
进一步的,所述药物还包括药学上可接受的载体。
进一步的,所述药物的剂型为片剂、颗粒剂、胶囊剂或注射剂。
进一步的,所述药物中还包含其他治疗缺血性脑卒中的有效成分。
进一步的,所述的NAT10抑制剂为remodelin。
NAT10小分子抑制剂在制备治疗缺血性脑卒中药物中的应用。
进一步的,所述药物的给药浓度为5mg/kg。
进一步的,所述药物的给药途径为灌胃给药。
进一步的,所述NAT10抑制剂为remodelin。
本发明的有益效果:
本发明通过NAT10小分子抑制剂Remodelin在制备治疗缺血性脑卒中药物中的应用。结果发现,Remodelin能够显著减小梗死体积,有效改善脑缺血小鼠的感觉运动功能,有望开发为缺血性脑卒中的潜在治疗药物。
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,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是本发明实施例提供的实施例1NAT10小分子抑制剂remodelin对脑皮层缺血小鼠梗死体积的影响结果图;
图2是本发明实施例提供的实施例2NAT10小分子抑制剂remodelin对脑皮层缺血小鼠感觉运动功能的影响结果图;
图3是本发明NAT10小分子抑制剂Remodelin化学结构式。
具体实施方式
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,所描述的实施例仅仅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它实施例,都属于本发明保护的范围。
一种NAT10小分子抑制剂在制备治疗缺血性脑卒中药物中的应用,下面根据具体实施例对本申请作出详细说明。
实施例1评估NAT10小分子抑制剂remodelin对脑皮层缺血小鼠梗死体积的影响。
实验动物:8-10周龄SPF级C57BL/6J雄性小鼠,体重25~30g。所有小鼠生活于可自由饮食饮水的饲养笼中,控制光照进行12h昼夜交替。
实验分组:实验共设两组:模型组(手术组)+0.05%DMSO(n=5),模型组+Remodelin(n=5)。
实验模型:光化学诱导的血栓栓塞型(PT)脑缺血模型
PT模型是一种利用光敏剂在皮层微血管中形成血栓诱导局灶性皮层缺血的脑卒中模型。首先将小鼠用2%异氟烷麻醉并以俯卧位固定于立体定位仪。在手术过程中用恒温毯将直肠温度控制在37.0±0.5℃。暴露颅骨,清除结缔组织,并保持表面干燥。尾静脉注射玫瑰红(30mg/kg)5分钟后,以12,000lux冷光源照射距bregma1.5mm处的感觉运动区(直径2mm),时长5分钟。最后缝合创口并给予抗炎处理。
动物处理:PT小鼠脑缺血3-7天通过灌胃连续给予0.2ml0.05%DMSO或remodelin(5mg/kg),并于第8天检测梗死体积。
梗死体积测定:取卒中8天鼠脑,冰冻切片(50μm,每只小鼠收集6组平行切片)后根据试剂盒说明(碧云天)进行尼氏染色,明场显微镜获取图片,应用ImageJ统计梗死面积,梗死面积(mm2)=健侧面积(mm2)-损伤侧非梗死面积(mm2)。梗死体积(mm3)=梗死面积(mm2)×脑片厚度(mm)×6。
结果如图1所示,NAT10小分子抑制剂可以显著减小脑梗死体积。
实施例2探究NAT10小分子抑制剂remodelin对脑缺血小鼠感觉运动功能的影响。
实验动物:同实施例1。
实验分组:实验共设四组:假手术组+0.05%DMSO(n=10),假手术组
+Remodelin(n=10),模型组+0.05%DMSO(n=10),模型组+Remodelin(n=10)。
实验模型:同实施例1。假手术小鼠仅注射玫瑰红,未进行光照。
动物处理:PT小鼠脑缺血3~7天通过灌胃连续给予0.2ml0.05%DMSO或remodelin(5mg/kg),并于第8天进行网格实验、圆通实验和粘纸实验。
网格实验:将小鼠置于32cm×20cm×50cm(长×宽×高)网格上,待适应1min后记录小鼠左前肢行走100步内出错的次数。以下两种情形被视为行走出错:1)小鼠左前肢穿入网格孔,无法支撑身体;2)小鼠静止时,左前肢腕部与网格水平。小鼠左前肢出错百分率(%)=左前肢出错次数/(左前肢出错次数+左前肢正确步数)×100%。
圆筒实验:将小鼠置于直径9cm,高度15cm的透明树脂玻璃圆筒内,录像记录3min。当小鼠站立时,分别记录右前肢、左前肢及双侧前肢同时碰触筒壁的次数。小鼠在该项试验中得分=(右前肢-左前肢)/(右前肢+左前肢+双侧前肢)接触次数,得分越高说明双侧肢体的不对称程度越明显。
粘纸实验:将直径5mm的圆形标签贴在小鼠两侧前肢腕关节远端桡骨处,分别记录小鼠两侧前肢移除标签的时间。如果小鼠在3min内无法移除标签,则视为无法移除粘附物。小鼠感觉运动功能不对称性的评估公式:延迟时间(sec)=左前肢移除标签的时间(sec)-右前肢移除标签的时间(sec)。
结果如图2所示,给予Remodelin可以降低脑缺血小鼠在网格上行走时的出错率、增加使用左前患肢的使用、减少移除粘纸的时间,表明NAT10小分子抑制剂能够促进脑缺血小鼠感觉运动功能修复。
所述NAT10小分子抑制剂remodelin为上海碧云天生物技术有限公司生产的试剂,其产品编号为SD1163,分子式为C15H15BrN4S,分子量为363.28,CAS号为1622921-15-6,同时本发明所用试剂或仪器均可在市场获得。
在本说明书的描述中,参考术语“一个实施例”、“示例”、“具体示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中,对上述术语的示意性表述不一定指的是相同的实施例或示例。而且,描述的具体特征、结构、材料或者特点可以在任何的一个或多个实施例或示例中以合适的方式结合。
以上显示和描述了本发明的基本原理、主要特征和本发明的优点。本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明精神和范围的前提下,本发明还会有各种变化和改进,这些变化和改进都落入要求保护的本发明范围内。
Claims (1)
1.Remodelin在制备治疗缺血性脑卒中的药物中的应用。
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