CN105012313A - 5α-雄甾-3β,5,6β-三醇及其类似物在预防或治疗低压缺氧引起的高原病中的应用 - Google Patents
5α-雄甾-3β,5,6β-三醇及其类似物在预防或治疗低压缺氧引起的高原病中的应用 Download PDFInfo
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Abstract
本发明提供5α-雄甾-3β,5,6β-三醇及其类似物在制备治疗或预防低压缺氧造成的高原病的药物中的应用,从而为高原病的预防与治疗提供一种新药物。研究表明,5α-雄甾-3β,5,6β-三醇处理可以有效减轻低压缺氧引起的食蟹猴脑组织的血管性水肿,并降低脑含水量上升,保护低压缺氧引起的神经元变性损伤,从而可以改善低压缺氧造成的神经功能障碍,用于高原病预防或治疗。
Description
技术领域
本发明涉及化合物5α-雄甾-3β,5,6β-三醇及其类似物的新的药物用途。
背景技术
随着海拔上升,大气压降低且氧分压降低,吸入气氧分压过低导致动脉血氧分压降低,氧含量减少,组织供氧不足。这种低压缺氧(hypobaric hypoxia, HH)主要发生在高原这一特殊环境,也被称作高原低氧(high altitude hypoxia)。
当个体近期到达超过海拔2500米以上地区,在急性低压缺氧(Acute Hypobaric Hypoxia)发生时,如果个体适应不了这种环境变化,会相继发生高原性头痛(High-altitude headache,HAH)、急性高原病(Acute mountain sickness,AMS),并且AMS可进一步发展为高原脑水肿(High altitude cerebral edema,HACE)和高原肺水肿 (High-altitude pulmonary edema, HAPE)。已有大量报道,高原病根据程度不同主要表现出头痛、多言、失眠、步态不稳、受损伤的心智能力、嗜睡、神情恍惚麻木以及共济失调等神经功能上的症状。
目前,针对高原病药物的研发思路主要是靶向提高携氧能力和细胞因子、炎症反应,前者的代表性药物为碳酸酐酶抑制剂如乙酰唑胺,后者代表药物如糖皮质激素和一些抗氧化剂[1],但没有一种药物属于神经保护剂。
5α-雄甾-3β,5,6β-三醇是新发现的神经保护剂[2],其结构式为:
5α-雄甾-3β,5,6β-三醇的分子结构
我们的研究发现,5α-雄甾-3β,5,6β-三醇及其类似物出人意料地可以显著改善低压缺氧处理的神经功能学评分,保护低压缺氧造成的脑部病理损伤,从而有效预防或治疗低压缺氧引起的高原病。
发明内容
本发明的目的在于提供5α-雄甾-3β,5,6β-三醇(在本说明书及附图中也被简称为“YC-6”)及其类似物在制备治疗或预防低压缺氧造成的高原病的药物中的应用,从而为高原病的预防与治疗提供一种新药物。
在本发明的一个实施方式中,所述高原病为由高原性急性低压缺氧引起的急性高原病。
在本发明的另一个实施方式中,所述高原病为高原脑水肿,具体是血管性水肿。
在本发明的另一个实施方式中,所述高原病为神经元损伤,具体是神经元的变性损伤,包括由高原性急性低压缺氧引起的神经元损伤和由高原性慢性低压缺氧引起的神经元损伤。
在本发明的另一个实施方式中,所述药物包含额外的用于治疗或预防低压缺氧造成的高原病的活性成分。
非人灵长类低压缺氧模型动物模型的研究表明,5α-雄甾-3β,5,6β-三醇处理可以显著改善低压缺氧环境下的实验动物的神经功能学评分,对低压缺氧导致的神经功能损伤具有显著保护作用, 表明5α-雄甾-3β,5,6β-三醇对AMS (High altitude cerebral edema)和HACE(High-altitude pulmonary edema)具有预防和治疗效果。
进一步的研究表明,5α-雄甾-3β,5,6β-三醇显著阻断低压缺氧导致的脑含水量上升,电镜形态学和HE染色病理分析表明,5α-雄甾-3β,5,6β-三醇可以减少低压缺氧导致的脑血管源性水肿和神经元空泡样变性损伤,从而预防或治疗高原病。
我们的研究表明,5α-雄甾-3β,5,6β-三醇的结构类似物如胆甾烷-3β,5α,6β-三醇(化合物I)也具有神经保护作用[3]。相似地,我们发现,该化合物也能够有效减轻低压缺氧引起的血管性水肿及神经元变性损伤,从而用于高原病的预防或治疗。其结构式为:
胆甾烷-3β,5α,6β-三醇的分子结构。
同样类似地,5α-雄甾-3β,5,6β-三醇的结构类似物如具有通式A的化合物也具有神经保护作用[4]。相似地,我们发现,该化合物也能够有效减轻低压缺氧引起的血管性水肿,降低脑含水量上升,保护低压缺氧引起的神经元变性损伤,从而用于高原病预的防或治疗。通式A为:
其中R1=R2=R3=OH,R4为具有1至5个(优选2至5个,更优选3至5个)碳原子的直链或支链的烷基或末端烯基(即仅在一个末端具有双键的烯基)。
在本发明的一个实施方式中,在通式A中,R1=R2=R3= OH,R4= CHCH2CH3,即所述化合物是17-亚丙基-雄甾-3β,5α,6β-三醇(化合物II)。
在本发明的一个实施方式中,在通式A中,R1=R2=R3= OH,R4= CH(CH3)2,即所述化合物是17-异丙基-雄甾-3β,5α,6β-三醇(化合物III)。
在本发明的一个实施方式中,在通式A中,R1=R2=R3= OH,R4= CH(CH2)3CH3,即所述化合物是17-丁基-雄甾-3β,5α,6β-三醇(化合物IV)。
5α-雄甾-3β,5,6β-三醇及其类似物的结构上的特征在于都是3β,5α,6β-三羟基甾体类化合物,功能上的特征在于都具备神经保护作用。本发明发现上述5α-雄甾-3β,5,6β-三醇类似物同样能够有效预防或治疗低压缺氧引起的高原病。
附图说明
图1: 5α-雄甾-3β,5,6β-三醇显著改善急性低压缺氧的食蟹猴的神经功能损伤。*:5α-雄甾-3β,5,6β-三醇处理组与溶剂对照组比较,P<0.05。
图2:5α-雄甾-3β,5,6β-三醇减轻急性低压缺氧食蟹猴脑皮层组织的血管性水肿(透射电镜,3900×)。Con:平原对照组;H/R+V:溶剂对照组;H/R+YC-6:5α-雄甾-3β,5,6β-三醇处理组。粗箭头指示大脑额叶皮层组织内的毛细血管,细箭头指示血管周隙VRS。
图3:5α-雄甾-3β,5,6β-三醇减轻低压缺氧食蟹猴脑皮层神经元的变性损伤(HE染色,400×)。Con:平原对照组;H/R+V:溶剂对照组;H/R+YC-6:5α-雄甾-3β,5,6β-三醇处理组。箭头指示变性受损的神经元。
具体实施方式
下面通过具体实施例进一步解释本发明,但是本发明不仅限于实施例中。
5α-雄甾-3β,5,6β-三醇的新用途验证
1. 动物:健康雄性食蟹猴(Macaca fascicularis)17只,6至6.5岁,体重6.8-7.5Kg。实验动物的使用经过实验动物管理与使用委员会和实验动物伦理委员会批准,实验方案符合动物保护、动物福利和伦理原则和规定。
17只雄性食蟹猴随机分为3组(表1):
表1:实验动物分组说明
2. 主要仪器与参数:高原环境模拟低压舱群是模拟高原环境低温低压实验平台体系,可以自动化控制模拟1万米以下任意海拔高度、-30℃以上任意温度的低温低压环境。上升速度为3米/秒(0至6000m);下降时为2米/秒(6000至7500m),舱内温度恒定于22℃,平均空气流速为150 m3/h。
3. 食蟹猴急性低压缺氧模型的制作及给药:
(1)采用低压舱控制模拟7500米海拔高度造成食蟹猴急性缺氧。将饲养于动物房的食蟹猴做好标识然后放入低压舱内饲养1天以适应实验环境。实验开始后通过调节低压舱内气压来模拟3000、4500、6000米海拔高度,每个高度停留30分钟后,以及模拟7500米处理24小时后,按设计剂量和方式给药。7500米处理48小时后,以3米/秒速度将模拟海拔下降到6000米,***麻醉后放血处死动物,并进行解剖、取材、固定。平原对照组的食蟹猴一直饲养于海拔高度为350米的动物房,直到评价和麻醉处死取材。
(2)5α-雄甾-3β,5,6β-三醇处理组的动物在未开始模拟升高前、模拟升至3000米停留30分钟后以及模拟升至4500米停留30分钟后,按10 mg/kg的剂量分别静脉推注葡萄糖生理盐水稀释的5α-雄甾-3β,5,6β-三醇 10 ml;溶剂对照组只静脉推注葡萄糖生理盐水10 ml。
(3)5α-雄甾-3β,5,6β-三醇处理组的动物在低压舱内模拟高度6000米停留30分钟后,5α-雄甾-3β,5,6β-三醇缓释剂按30 mg/kg的剂量分成5点进行骨骼肌肌肉注射;急性高原缺氧模型组只静脉推注葡萄糖生理盐水10ml。
(4)5α-雄甾-3β,5,6β-三醇处理组的动物在低压舱内模拟高度7500米停留24小时后,5α-雄甾-3β,5,6β-三醇注射液按10 mg/kg的剂量用葡萄糖生理盐水稀释至10 ml,一次性静脉推注,并且5α-雄甾-3β,5,6β-三醇缓释剂按30 mg/kg的剂量分成5点进行骨骼肌肌肉注射。急性高原缺氧模型组只静脉推注葡萄糖生理盐水10ml。
4. 检测指标
4.1 动物神经功能评分
根据本实验的特点,动物在低压舱内模拟海拔7500米停留24小时后,以3米/秒速度下降到模拟海拔6000米,按照文献[5]的方法评估并记录食蟹猴的神经功能评分。由两位不了解分组情况且未参与给药的经培训的观察者评估并记录神经功能评分,按平均评分计分。
4.2 左半球脑含水量测量
根据文献[6]介绍的方法进行脑含水量测量。低压舱模拟高度7500米停留48小时后以及平原对照组实验猴,由不了解分组情况且未参与给药的实验者麻醉放血处死,迅速取出猴脑,切取左半脑,称取其湿重。然后将左半脑置于60℃干燥箱,每天固定时间称取脑重,直至脑重数值不再变化,记录终点脑重。含水量百分比=(左半脑湿重-左半脑干重)/左半脑湿重×100%。
4.3 大脑额叶皮层组织的透射电镜分析
实验猴大脑额叶皮层组织取出后切出1 mm3脑块,固定于2.5%戊二醛电镜固定液后制作超薄切片,用透射电镜观察分析以下项目:神经元的形态和血管的结构等。
4.4 大脑额叶皮层组织的HE染色分析
实验猴大脑额叶皮层组织取出后切出1 cm3的方块后固定于4%多聚甲醛中。之后按照常规HE染色步骤,进行石蜡包埋,切片,苏木素伊红染色后在显微镜下观察。
4.5 统计学处理
实验结果以均数±标准差表示,采用SigmaPlot软件进行统计分析。P<0.05表示差异有统计学意义。
结果表明,5α-雄甾-3β,5,6β-三醇显著保护低压缺氧环境食蟹猴的神经功能。实验猴在低压舱模拟海拔6000米环境下停留30分钟后,行为活动明显减少,对威迫刺激的反应也有所降低。将模拟海拔提高到7500米24小时后,溶剂对照组食蟹猴出现明显的意识抑制,行为活动大为减少,且出现运动、感觉***的功能障碍,神经功能评分为31.6±4.2;与之相比,5α-雄甾-3β,5,6β-三醇处理组的动物的神经功能评分为20.5±5.7(P<0.01),显示神经功能得到有效保护(图1)。
5α-雄甾-3β,5,6β-三醇显著减少低压缺氧环境下食蟹猴脑含水量的增加。计算并分析脑含水量百分比后显示,平原对照组食蟹猴的脑含水量为76.155%,与之相比,在低压舱内模拟海拔7500米处理48小时后,溶剂对照组食蟹猴的脑含水量增加为76.714%(P<0.05)。升至7500米前给予5α-雄甾-3β,5,6β-三醇并在7500米维持24小时后再次给予5α-雄甾-3β,5,6β-三醇,食蟹猴的脑含水量降低至76.283%(P<0.05),表明给予5α-雄甾-3β,5,6β-三醇可以抑制急性高原缺氧环境下食蟹猴脑含水量的增加(表2)。
表2:5α-雄甾-3β,5,6β-三醇对低压缺氧环境下的食蟹猴脑含水量的影响
#:与平原对照组比较,P<0.05;*:与溶剂对照组比较,P<0.05。
5α-雄甾-3β,5,6β-三醇减轻低压缺氧引起的血管性水肿。在透射电镜下观察,与平原对照组比较,溶剂对照组食蟹猴大脑额叶皮层毛细血管外出现明显加宽的血管周隙(Virchow Robin Space,VRS),表明出现严重的血管性水肿渗出;而经5α-雄甾-3β,5,6β-三醇处理的食蟹猴脑组织血管周隙趋于正常,显示并未发生明显的血管性水肿(图2)。
5α-雄甾-3β,5,6β-三醇减轻低压缺氧处理引起的神经元变性损伤。经HE染色后观察,溶剂对照组大脑额叶皮层组织结构明显疏松,血管周围出现水肿液,压迫管腔;部分神经元变性,胞体皱缩、核固缩,细胞出现空泡样变性改变(箭头所示);5α-雄甾-3β,5,6β-三醇处理组的血管性水肿不明显,与平原对照组近似神经元空泡样变性损伤减轻,表明5α-雄甾-3β,5,6β-三醇对低压缺氧环境下的神经元具有保护作用(图3)。
药物组合物
本实施例中使用的是5α-雄甾-3β,5,6β-三醇注射剂与缓释混悬剂,在制备预防或治疗低压缺氧引起的高原病时的药物剂型包括但不限于注射剂、缓释混悬剂、口服胶囊(丸) 、栓剂以及皮下埋植剂及外贴膏药型制剂等。
(1)5α-雄甾-3β,5,6β-三醇(YC-6)注射剂的制备
20% HP-β-CD溶液的配制:称取20.0 g HP-β-CD,加入80 ml生理盐水,搅拌使其溶解。加生理盐水至100 ml,经0.22μm微孔滤膜精滤,分装于15 ml离心管中,密封于4℃下保存。
2 mg/ml YC-6溶液的配制:称取6.0 g HP-β-CD,加24 ml去离子水,搅拌使其溶解。称取YC-6 0.060 g,加至上述HP-β-CD溶液中,搅拌使其溶解。称取氯化钠0.270 g,加入其中,搅拌使其溶解,加去离子水至30ml。经0.22μm微孔滤膜精滤,分装于1.5 ml Eppendorf管中,密封于4℃下保存待用。使用时按10 ml/kg液量给药,换算为20 mg/kg给药量。
(2)5α-雄甾-3β,5,6β-三醇(YC-6)缓释剂的制备
缓释混悬剂的处方是:YC-6 12.5g,甘油 30ml,HP-β-CD 50g,CMC-Na 0.48g,注射用水加至250ml。
制备方法:
0.8% CMC-Na溶液的配制,称取CMC-Na消0.8g CMC-Na,分多次加到90 ml的90度的水中,边加边搅,直至全部加入并溶解。放至室温,加水至100ml,搅匀。3000r/min离心15min,取上清液,备用。
40% HP-β-CD溶液的配制:称取HP-β-CD 80 g,加到约100ml水中,搅拌溶解,加水至200ml,备用。
称取YC-6约12.5g,置乳钵中,将颗粒研细研匀。加入30 ml甘油,继续研匀,使成乳白色润滑液,成细腻糊状。取125ml的40% HP-β-CD水溶液,逐量边加入边研磨。0.8% CMC-Na,取60ml边加入边研匀,避免产生过多的气泡。转移至定量管,补注射用水至250ml,摇晃使均匀。
5α-雄甾-3β,5,6β-三醇类似物的新用途验证
将YC-6替换为上述化合物I、II、III、IV,在相同条件下重复上述食蟹猴急性低压缺氧模型的实验。结果表明,相似地,经过化合物II、III、IV处理的食蟹猴的神经功能得到有效保护,脑含水量的增加被抑制,没有发生明显的血管性水肿,并且血管性水肿不明显。可见5α-雄甾-3β,5,6β-三醇类似物特别是化合物I和具有通式A的化合物(特别是化合物II、III、IV)也能够有效预防或治疗低压缺氧引起的高原病。
参考文献
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Claims (10)
1.5α-雄甾-3β,5,6β-三醇及其类似物在制备治疗或预防低压缺氧造成的高原病的药物中的应用。
2.根据权利要求1所述的应用,其中所述类似物是胆甾烷-3β,5α,6β-三醇。
3.根据权利要求1所述的应用,其中所述类似物是具有通式A的化合物:
通式A
其中:R1=R2=R3= OH,R4为具有1至5个碳原子的烷基或末端烯基。
4.根据权利要求3所述的应用,其中:
R4为CHCH2CH3,所述类似物是17-亚丙基-雄甾-3β,5α,6β-三醇;或者
R4为CH(CH3)2,所述类似物是17-异丙基-雄甾-3β,5α,6β-三醇;或者
R4为CH(CH2)3CH3,所述类似物是17-丁基-雄甾-3β,5α,6β-三醇。
5.根据权利要求1所述的应用,其中所述高原病为急性高原病。
6.根据权利要求1所述的应用,其中所述高原病为高原脑水肿。
7.根据权利要求1所述的应用,其中所述高原病为神经元损伤。
8.根据权利要求7所述的应用,其中所述高原病为由高原性急性低压缺氧引起的神经元损伤。
9.根据权利要求7所述的应用,其中所述高原病为由高原性慢性低压缺氧引起的神经元损伤。
10.根据权利要求1所述的应用,所述药物包含额外的用于治疗或预防低压缺氧造成的高原病的活性成分。
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CN201711306184.4A CN108125965B (zh) | 2014-04-25 | 2014-04-25 | 5α-雄甾-3β,5,6β-三醇及其类似物在高原病中的应用 |
CN201410170263.7A CN105012313B (zh) | 2014-04-25 | 2014-04-25 | 5α‑雄甾‑3β,5,6β‑三醇及其类似物在预防或治疗低压缺氧引起的高原病中的应用 |
LTEP15783742.8T LT3135288T (lt) | 2014-04-25 | 2015-04-14 | Neuroprotektorius ir jo indikacijos |
SG11201608829SA SG11201608829SA (en) | 2014-04-25 | 2015-04-14 | Neuro-protective agents and uses thereof |
DK15783742.8T DK3135288T3 (en) | 2014-04-25 | 2015-04-14 | Neuroprotector and indication therefore |
TR2019/01516T TR201901516T4 (tr) | 2014-04-25 | 2015-04-14 | Nöroprotektif ajanlar ve bunların kullanımları. |
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US15/306,437 US10357500B2 (en) | 2014-04-25 | 2015-04-14 | Neuro-protective agents and uses thereof |
AU2015251359A AU2015251359B2 (en) | 2014-04-25 | 2015-04-14 | Neuroprotectant and indication thereof |
PCT/CN2015/076528 WO2015161747A1 (zh) | 2014-04-25 | 2015-04-14 | 神经保护剂及其适应症 |
KR1020167032304A KR101873791B1 (ko) | 2014-04-25 | 2015-04-14 | 신경보호제 및 이의 적응증 |
SI201530624T SI3135288T1 (sl) | 2014-04-25 | 2015-04-14 | Nevroprotektant in indikacije zanj |
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IL248424A IL248424B (en) | 2014-04-25 | 2016-10-20 | Neuroprotective substances and their uses |
CY20191100322T CY1121566T1 (el) | 2014-04-25 | 2019-03-18 | Νευροπροστατευτικο και ενδειξη αυτου |
US16/363,007 US10835539B2 (en) | 2011-11-17 | 2019-03-25 | Neuro-protective agents and uses thereof |
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