CN115381805A - 丁酸及其衍生物或其药学上可接受的盐在制备治疗缺氧缺血性脑病的产品中的用途 - Google Patents
丁酸及其衍生物或其药学上可接受的盐在制备治疗缺氧缺血性脑病的产品中的用途 Download PDFInfo
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Abstract
本发明涉及医药技术领域，本发明提供的丁酸及其衍生物或其药学上可接受的盐在制备治疗缺氧缺血性脑病的产品中的用途，首次在HIBD模型大鼠粪便中发现丁酸产生菌及丁酸代谢途径异常，进一步研究发现采用丁酸及其衍生物或其药学上可接受的盐干预新生的HIBD模型大鼠，HIBD大鼠大脑皮层和海马的病理损伤及学习记忆相关的行为学恢复，并促进了肠道内容物与代谢途径相关菌群的恢复，说明丁酸及其衍生物或其药学上可接受的盐具有制备缓解、辅助治疗或治疗缺氧缺血性脑病的产品中的用途。
Description
技术领域
本发明涉及医药技术领域，具体涉及一种丁酸及其衍生物或其药学上可接受的盐在制备治疗新生儿缺氧缺血性脑病的产品中的用途。
背景技术
新生儿缺氧缺血性脑病(hypoxie-ischemic encephalopathy，HIE)是指在围产期窒息而导致脑的缺氧缺血性损害。缺氧缺血性脑损伤(Hypoxie ischemic brain damage，HIBD)是患者窒息后产生的一种严重并发症状，具有较高的病死率与致残率，新生儿HIBD是围生期因为窒息所引起的脑损伤，严重的可造成永久性的神经功能损害，是儿童神经系统损伤的常见原因之一。在临床上主要表现为意识障碍、肌张力及原始反射的改变，严重可出现惊厥、脑水肿、颅内高压等症状。
既往关于新生儿缺氧缺血性脑病(HIE)的临床以及动物模型研究，还未有关于丁酸或其药学上可接受的衍生物缓解或治疗新生儿缺氧缺血性脑损伤的相关研究和报道。
发明内容
因此，本发明要解决的技术问题在于提供一种丁酸及其衍生物或其药学上可接受的盐在制备治疗缺氧缺血性脑病的产品中的用途。
为此，本发明提供了如下的技术方案：
丁酸及其衍生物或其药学上可接受的盐在制备缓解、辅助治疗或治疗缺氧缺血性脑病的产品中的用途。
可选的，所述的缺氧缺血性脑病包括缺氧缺血性脑损伤。
可选的，所述的缺氧缺血性脑病包括未成熟大脑缺氧缺血性脑病；
可选的，包括新生儿缺氧缺血性脑病。
可选的，所述的缺氧缺血性脑病包括未成熟大脑缺氧缺血性脑损伤；
可选的，包括新生儿缺氧缺血性脑损伤。
可选的，所述的用途包括在制备缓解、辅助治疗或治疗缺氧缺血性脑病引起的大脑皮层和/或海马体的病理损伤的产品中的用途。
可选的，所述的用途包括在制备缓解、辅助治疗或治疗缺氧缺血性脑病引起的学习记忆相关的行为学障碍的产品中的用途。
可选的，所述的用途包括制备缓解、辅助治疗或治疗缺氧缺血性脑病引起的肠道内容物和/或代谢途径相关菌群紊乱的产品中的用途。
可选的，在制备提升缺氧缺血性脑病引起的大脑皮层中丁酸浓度水平低的产品中的用途。
可选的，所述的丁酸及其衍生物或其药学上可接受的盐包括丁酸、丁酸钠、丁酸钾或丁酸钙；
可选的，所述的产品包括药物或食品；
可选的，所述的食品包括功能性食品或保健品。
一种缓解、辅助治疗或治疗缺氧缺血性脑病的药物制剂，包括以丁酸及其衍生物或其药学上可接受的盐为活性成分；
可选的，还包括制剂允许的药物赋形剂或载体；
可选的，所述药物制剂的形式包括液体制剂和固体制剂；
可选的，所述药物制剂包括注射剂、片剂、胶囊剂或颗粒剂。
本发明技术方案，具有如下优点：
1.本发明提供的丁酸及其衍生物或其药学上可接受的盐在制备缓解、辅助治疗或治疗缺氧缺血性脑病的产品中的用途，首次在HIBD模型大鼠粪便中发现丁酸产生菌及丁酸代谢途径异常，进一步研究发现采用丁酸及其衍生物或其药学上可接受的盐干预新生的HIBD模型大鼠，HIBD大鼠大脑皮层和海马的病理损伤及学习记忆相关的行为学恢复，并促进了肠道内容物与代谢途径相关菌群的恢复，说明丁酸及其衍生物或其药学上可接受的盐具有制备缓解、辅助治疗或治疗缺氧缺血性脑病的产品中的用途。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案，下面将对具体实施方式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，下面描述中的附图是本发明的一些实施方式，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是本发明实验例中各组大鼠大脑皮层及海马组织的H&E染色；
图2是本发明实验例中各组大鼠水迷宫试验第5天代表性通路的结果和试验第6天代表性泳道的结果；
图3是本发明实验例中各组大鼠逃避潜伏期检测结果；与假手术组比较*<0.05；与HIBD模型组比较，#<0.05，##<0.01；
图4是本发明实验例中各组大鼠穿越平台次数检测结果；与假手术组比较*表示p<0.05；与HIBD模型组比较，#表示p<0.05，##表示p<0.01；
图5是本发明实验例中各组大鼠(除了HIBD+生理盐水组)的大鼠大脑皮层中丁酸浓度检测结果；误差条表示SD，与假手术组比较*表示p<0.05；与HIBD模型组比较，#表示p<0.05，##表示p<0.01；
图6是本发明实验例中假手术组与HIBD组大鼠粪便显著性差异代谢物热图；
图7是本发明实验例中各组大鼠(除了HIBD+生理盐水组)的大鼠粪便菌群丰度柱状图。
具体实施方式
提供下述实施例是为了更好地进一步理解本发明，并不局限于所述最佳实施方式，不对本发明的内容和保护范围构成限制，任何人在本发明的启示下或是将本发明与其他现有技术的特征进行组合而得出的任何与本发明相同或相近似的产品，均落在本发明的保护范围之内。
实施例中未注明具体实验步骤或条件者，按照本领域内的文献所描述的常规实验步骤的操作或条件即可进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规试剂产品。
实验例
1、动物及分组
将新生的大鼠(Wistar大鼠，7天幼仔，雌雄不限，SPF级，购自维通利华公司)随机分成假手术组、HIBD模型组、HIBD+生理盐水组、HIBD+丁酸钠组。
假手术组：除不进行单侧颈总动脉结扎手术和缺氧，其余条件与HIBD模型组一致。
HIBD模型组：缺血缺氧模型参考经典的RiceVannucci方法(Rice JE 3rd,V.R.,Brierley JB.The influence of immaturity on hypoxic-ischemic brain damage inthe rat.Ann Neurol.9,131-141(1981).)：大鼠水合氯醛麻醉后，将其固定于无菌动物手术台上，行颈部正中切口(5～10mm)，切开皮肤后用眼科镊精细分离左侧颈前肌群，暴露颈动脉鞘，用玻璃分针轻轻将颈总动脉与迷走神经分离，以5－0缝合线单线结扎颈总动脉并确保无血流通过后缝合伤口，整个手术过程时间控制在5min内。手术完成后置于笼内母鼠旁休息1h，将幼鼠置于含8％O2和92％N2的密闭缺氧箱内2小时。
HIBD+生理盐水组：自HIBD造模成功日起，灌胃生理盐水，剂量为100μL，每日1次，连续2周。
HIBD+丁酸钠组：自HIBD造模成功日起，灌胃丁酸钠(100mg/kg)，剂量为100μL，每日1次，连续2周。
2、检测方法及结果
(1)测序及质谱检测
通过16s高通量测序及GC-MS质谱检测HIBD模型组(6只)和假手术组(6只)大鼠的肠道的内容物(粪便)，结果如图6所示，与假手术组相比，HIBD组大鼠粪便中丁酸盐代谢通路(KEGG)及相关代谢物下调，发现HIBD模型组大鼠的粪便中丁酸产生菌数量明显减少且丁酸代谢途径富集异常。
(2)大鼠的大脑皮层及海马组织的H&E染色
当采用丁酸钠治疗2周后，取各组的大鼠(每组3只)处死，取脑组织福尔马林固定后切片进行H&E染色，结果如图1所示，相对HIBD模型组，HIBD+生理盐水组的大鼠大脑皮层及海马组织病理损伤未得到任何的改善，而HIBD+丁酸钠组的大鼠大脑皮层及海马组织病理损伤得到改善，说明采用丁酸钠干预能够缓解或治疗新生HIBD大鼠大脑皮层及海马组织病理损伤。
(3)学习记忆相关行为学的实验
当采用丁酸钠治疗2周后，取各组的大鼠(每组3只)进行水迷宫试验(实验大鼠被放置在一个圆形水池中，水中加入不透明的、无毒的白色颜料，水池中包含一个隐藏的逃生平台。实验内容包括定位航行和空间探索。定位航行是随机的将动物从水迷宫的四个象限中放入，使其在水中游泳并找到逃生平台，用视频跟踪软件记录动物寻找到隐藏平台的时间(逃避潜伏期)及路径。空间探索是定位航行后撤去逃生平台，观察动物穿过原平台位置的次数和时间，考查动物对原平台的记忆。)，试验第5天代表性通路的结果和试验第6天代表性泳道的结果如图2所示，各组的大鼠的逃避潜伏期检测结果如图3所示，各组的大鼠的穿过前一个平台位置的次数如图4所示，数据处理：数据使用GraphPad Prism(Version9.2.0)和SPSS 20.0(IBM，美国)进行分析。组间比较采用t检验或方差分析。
通过比较可以得出，相对HIBD模型组，HIBD+生理盐水组的大鼠的学习记忆相关行为学实验结果没有差异，而HIBD+丁酸钠组的大鼠的学习记忆相关行为学实验结果具有显著性差异，说明采用丁酸钠干预能够恢复新生HIBD大鼠学习记忆相关行为学。
(4)大脑皮层丁酸含量
当采用丁酸钠治疗2周后，取各组(除了HIBD+生理盐水组)的大鼠(每组6只)，采用液相色谱串联质谱(LC-MS/MS)分析方法定量检测大脑皮层丁酸含量(本实验采用UPLC-ESI-MS/MS分析方法，对目标代谢物进行定性定量检测，具体分析条件和分析方法如下。色谱条件：进样量：5μL；流速：0.35mL/min；流动相：A(0.1％甲酸-水溶液)，B(乙腈)；梯度洗脱方法：0min A/B(90:10，V/V)，1min A/B(90:10，V/V)，2min A/B(75:25，V/V)，6min A/B(65:35，V/V)，6.5min A/B(5:95，V/V)，7.8min A/B(5:95，V/V)，7.81min A/B(90:10，V/V)，8.5min A/B(90:10，V/V)。质谱条件：气帘气：35(psi)；碰撞诱导电离(collision-activated dissociation，CAD)参数：medium；正离子喷雾电压：5500V；负离子喷雾电压：-4500V；离子源温度：450℃；柱温：40℃；离子源：Gas1:50(psi)；Gas2:60(psi)。)，数据处理：根据取样与(或)稀释倍数等参数，对代谢物浓度信息进行进一步计算，最终得到实际样本中各代谢物的绝对含量信息。计算公式如下：样品代谢物含量(ng/g)＝N1*N2*(C*V)/M)；注：C：样本中代谢物峰面积带入标准曲线计算得到的浓度值(ng/mL)；V：定容体积：0.3mL；M：称取的样本质量(g)；N1：稀释倍数(1)；N2：换算系数(1：样本与标准品衍生化量比值)。
结果如图5所示，说明采用丁酸钠能够通过血脑屏障进入大脑，提高新生HIBD大鼠靶器官脑内的丁酸浓度。
(5)肠道内容物与代谢途径相关菌群
当采用丁酸钠治疗2周后，取各组(除了HIBD+生理盐水组)的大鼠(每组5只)，采用16s高通量测序及GC-MS质谱检测HIBD模型组(5只)和假手术组(9只)大鼠的肠道的内容物(粪便)。结果如图7所示，与假手术组相比，HIBD组大鼠粪便中丁酸产生菌下调，并在丁酸盐干预后上调，说明采用丁酸钠干预能促进HIBD肠道内容物与代谢途径相关菌群的恢复。
显然，上述实施例仅仅是为清楚地说明所作的举例，而并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (10)
1.丁酸及其衍生物或其药学上可接受的盐在制备缓解、辅助治疗或治疗缺氧缺血性脑病的产品中的用途。
2.根据权利要求1所述的用途，其特征在于，所述的缺氧缺血性脑病包括缺氧缺血性脑损伤。
3.根据权利要求1或2所述的用途，其特征在于，所述的缺氧缺血性脑病包括未成熟大脑缺氧缺血性脑病；
可选的，包括新生儿缺氧缺血性脑病。
4.根据权利要求1-3任一项所述的用途，其特征在于，所述的缺氧缺血性脑病包括未成熟大脑缺氧缺血性脑损伤；
可选的，包括新生儿缺氧缺血性脑损伤。
5.根据权利要求1-4任一项所述的用途，其特征在于，所述的用途包括在制备缓解、辅助治疗或治疗缺氧缺血性脑病引起的大脑皮层和/或海马体的病理损伤的产品中的用途。
6.根据权利要求1-5任一项所述的用途，其特征在于，所述的用途包括在制备缓解、辅助治疗或治疗缺氧缺血性脑病引起的学习记忆相关的行为学障碍的产品中的用途。
7.根据权利要求1-6任一项所述的用途，其特征在于，所述的用途包括在制备缓解、辅助治疗或治疗缺氧缺血性脑病引起的肠道内容物和/或代谢途径相关菌群紊乱的产品中的用途；
可选的，在制备提升缺氧缺血性脑病引起的大脑皮层中丁酸浓度水平低的产品中的用途。
8.根据权利要求1-7任一项所述的用途，其特征在于，所述的丁酸及其衍生物或其药学上可接受的盐包括丁酸、丁酸钠、丁酸钾或丁酸钙。
9.根据权利要求1-7任一项所述的用途，其特征在于，所述的产品包括药物或食品；
可选的，所述的食品包括功能性食品或保健品。
10.一种缓解、辅助治疗或治疗缺氧缺血性脑病的药物制剂，其特征在于，包括以丁酸及其衍生物或其药学上可接受的盐为活性成分；
可选的，还包括制剂允许的药物赋形剂或载体；
可选的，所述药物制剂的形式包括液体制剂和固体制剂；
可选的，所述药物制剂包括注射剂、片剂、胶囊剂或颗粒剂。
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