CN1214794C - 前列腺素a1在制备治疗脑缺血性中风疾病的药物中的用途 - Google Patents
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Abstract
本发明公开一种前列腺素A1在制备治疗脑缺血性中风疾病的药物中的用途，前列腺素A1在体内由细胞膜脂质转化而来，是内源性生物活性物质，前列腺素A1能显著地减少因缺血造成的神经元损伤，在动物实验中减少脑梗死面积40%以上，尤其是缺血后给药仍有效，是一般抗中风药达不到的，前列腺素A1毒性小、安全。
Description
技术领域
本发明涉及一种前列腺素A1的新用途。
背景技术
前列腺素是存在于体内包括中枢神经系统内的一类不饱和脂肪酸组成的具有多种生理作用的生物活性物质。前列腺素的化学本质是由一个五元环和两条20碳不饱和脂肪酸侧链组成的，前列腺素由细胞膜上的脂质经酶促法应转化而来。前列腺素在体内有多个系列，包括A，B，C，D，E，F，G，H，I等类型。各种前列腺素具有不同的生物化学特性和生物作用。前列腺素对内分泌，生殖，消化，心血管，泌尿和神经系统均有作用。其中前列腺素E1，前列腺素I2在心血管方面的研究比较多，并在临床获得应用，前列腺素Fα2在生殖方面的研究比较多，并在临床获得应用。前列腺素A系列在抗炎，抗病毒和抗肿瘤作用方面的研究比较多，但这些研究尚未在临床获得应用。前列腺素A1只是在早年试用于急性肾功能衰竭和肾性高血压危象的治疗。
前列腺素A1的化学名称为(13E，15S)-15-Hydroxy-9-Oxo-Prosta-10，13-dien-1-Oic acid，分子式为C20H32O4。
发明内容
本发明的目的是：提供一种前列腺素A1在制备治疗脑缺血性中风疾病的药物中的用途。
本发明的技术方案是：前列腺素A1虽早已不作为药物在临床使用，但由于它的作用比较广泛，作为一个工具药在科学研究中仍被广泛使用。我们在研究神经细胞调亡的分子机制时首次发现前列腺素A1在动物模型中和试管内对神经细胞有很强的保护作用。这一发现将对神经退行性疾病的研究和治疗产生重大的影响，并有临床实用价值，为前列腺素A1开辟力量了新的临床用途。
本发明的优点是：
1.前列腺素A1在体内由细胞膜脂质转化而来，是内源性生物活性物质。
2.前列腺素A1能显著地减少因缺血造成的神经元损伤，在动物实验中减少脑梗死面积40％以上，尤其是缺血后给药仍有效，是一般抗中风药达不到的。
3.从作用机制方面看，前列腺素A1能从多个环节阻断缺血对神经细胞的损伤作用，如抑制NF-κB激活，诱导热休克蛋白，抑制炎症反应等。
4.前列腺素A1毒性小、安全。
5.根据动物实验结果，前列腺素A1对其它神经退行性疾病如帕金森氏病(Parkinson’s disease)，亨迁顿舞蹈病(Huntington’s disease)，老年性痴呆(Alzheimer”s disease)等也有治疗作用。
具体实施方式
实施例：前列腺素A1在七十年代曾试用于原发性高血压，肾性高血压和急性肾功能衰蝎等的治疗。根据前列腺素A1治疗缺血性中风的动物实验结果，以及前列腺素A1可制成微脂质体制剂的情况，本发明在治疗缺血性中风等神经退行性疾病时，可采用前列腺素A1微脂质体静脉滴注。拟用剂量为1微克/分，加在生理盐水中恒速滴入。
支持前列腺素A1有保护神经细胞作用的基础研究有：
1.前列腺素A1能有效地吉抗兴奋性氨基酸受毒素引起的神经细胞损伤。
兴奋性氨基酸受体在维持大脑正常功能方面有重要作用，但是过度激活这类受体可导致神经细胞损伤甚至死亡。在大脑纹状体内注射作用于兴奋性氨基酸受体中的NMDA(N-Methyl-D-aspartate)受体激动剂喹啉酸(Quinolinic Acid)可引起纹状体内GABA投射神经细胞的死亡。这一病理特征与亨廷顿舞蹈病的神经病理极为相似。因此喹啉酸曾用来复制亨廷顿舞蹈病的动物模型。我们在研究中先在纹状体内注射不同剂量的前列腺素A1，然后再注射喹啉酸。组织形态学和生物化学的实验表明前列腺素A1能吉抗喹啉酸的神经毒性，纹状体内喹啉酸引起的神经细胞的死亡率大大降低。这一发现具有十分重要的价值，因为多种神经退行性疾病，如脑中风，帕金森氏病，老年性痴呆，亨廷顿舞蹈病，兴奋性氨基酸受体介导的兴奋性毒素在致病过程中起着重要作用。前列腺素A1吉抗兴奋性氨基酸受体引起的神经细胞毒素，提示前列腺素A1可能对某些神经退行性疾病有治疗价值。
2.前列腺素A1能有效地吉抗线粒体毒素引起的多巴胺神经元样细胞损伤。
作为保护细胞的另一证据是前列腺素A1能有效地吉抗线粒体毒素引起的多巴胺神经元样细胞损伤。SH-SY5Y细胞是一种神经纤维母细胞瘤，具有多巴胺神经细胞的许多特性。在帕金森氏病的研究中被当作多巴胺神经细胞广泛应用。Rotenone是杀虫剂中含有的一种线粒体毒素，能抑制线粒体呼吸酶，从而抑制能量的产生。给动物反复注射Rotenone可选择性地造成大脑黑质多巴胺神经细胞的死亡，从而复制帕金森氏病的病理模型。我们在体外培样的SH-SY5Y细胞内加入Rotenone诱导细胞调亡，我们在研究中发现在细胞培养液中预先加入前列腺素A1能吉抗Rotenone对SH-SY5Y细胞的毒性，减少细胞死亡。线粒体是细胞的重要细胞器，细胞活动所需的能量是全部由线粒体提供的，线粒体在细胞调亡中起着十分重要的调节作用。在亨廷顿舞蹈病，帕金森氏病，老年性痴呆中都发现有线粒体功能障碍，前列腺素A1吉抗线粒体毒素的作用进一步提示它在治疗神经退行性疾病有应用价值。
在我们以往的研究中，兴奋性氨基酸受体激动剂喹啉酸，线粒体毒素Rotenone引起的神经细胞损伤与激活因子-kappaB(NF-κB)有关，NF-γB的激活与中风后脑神经细胞的死亡有关。前列腺素A1有NF-κB激活的作用。前列腺素A1又能诱导热休克蛋白的表达。以往的研究表明热休克蛋白的表达对神经细胞的生存有益，能减轻缺血性中风引起的脑损伤。我们的研究表明A1抑制NF-κB激活，诱导热休克蛋白70，72，27的表达可能是它保护神经细胞的分子基础。
前列腺素A1对神经细胞的保护作用是由我们首先发现的。这些发现为开拓前列腺素A1在神经退行性病中的研究和应用奠定了理论基础。我们首次对前列腺素A1在神经退行性疾病中的作用，特别是在治疗缺血性中风中的应用作了研究。
前列腺素A1对缺血性中风的治疗作用
缺血性中风引起神经细胞死亡涉及多种分子机制，如兴奋性毒性，自由基产生，激活端粒酶，激活NF-κB，激活炎症反应等。目前中风治疗的研究主要有自由基清除剂，钙离子吉抗剂，端粒酶抑制剂和抗炎药等。但是大多数药物的临床试验因缺乏明确的治疗而失败。所以临床上目前没有理想的药物用来治疗缺血性中风。这就使前列腺素A1在治疗缺血性中风中的应用的研究成为一件极有意义的工作。
前列腺素A1在治疗缺血性中风方面有效的证据有：
1.SV-129小鼠大脑中动脉阻塞性缺血模型是研究缺血性中风常用的动物模型。SV-129小鼠在麻醉后分离出颈总动脉，沿颈内动脉插入一段涂有牙托粉的手术线至大脑中动脉造成供血不足。两个小时后取出手术线恢复血流。这一方法可造成同侧大脑脑大面积梗死。脑梗死体积用TTC染色后切成1mm厚的脑片并用CCD摄象机扫描到计算机内，脑梗死体积用专用计算机纫件测定。结果经t检验分析处理，实验结果表明缺血前30分钟在脑室内注射前列腺素A1，缺血两小时后血流恢复时再以同样方法给一次前列腺素A1，可以减少脑梗死体积43％(脑梗死面积对照组＝105±8mm3，n＝5；前列腺素A1组＝60±3mm3，n＝5，p＜0.05)，并显著地改善脑操作的症状(对照组＝2.2±0.4，n＝6；前列腺素A1组＝1.3±0.2，n＝5，p p＜0.05)。
为了使前列腺素A1治疗缺血性中风的研究更接近临床，我们选择在缺血两小时后再灌注时脑室内注射前列腺素A1一次，这种给药方法仍能减少脑梗死体积约NF-κB 23％。这些结果表明前列腺素A1对缺血性中风有显著的治疗作用。
表1.前列腺素A1缺血前边0分钟给药对中风的治疗作用
| Veh | PGA1(stock) | |||
| Infarct | NLD | Infarct | NLD | |
| 89 | 1 | 56 | 1 | |
| 93 | 2 | 96 | 2 | |
| 132 | 3 | 56 | 1 | |
| 98 | 3 | 67 | 2 | |
| 112 | 2 | 58 | 1 | |
| 69 | 1 | |||
| 53 | 1 | |||
| Mean | 105 | 2.2 | 60 | 1.3 |
| SD | 18 | 1 | 7 | 0 |
| SEM | 8 | 0.4 | 3 | 0.2 |
表2.前列腺素A1缺血后两小时给药对中风的治疗作用
| Infarct | Infarct | |
| PGA | 84 | Vehicle 84 |
| PGA | 52 | Vehicle 69 |
| PGA | 95 | Vehicle 118 |
| PGA | 74 | Vehicle 85 |
| PGA | 55 | Vehicle 114 |
| Mean | 72 | 94 |
| SD | 18 | 21 |
| SEM | 8 | 9 |
| N | 5 | 5 |
2.缺血性中风与血小板聚集，血栓形成有密切关系。血小板聚集，血栓形成能阻碍血流，造成大脑某些部位供血不足而发生中风。前列腺素A1在体外实验显示有抑制人和大鼠血小板聚集的作用。这一作用有助于阻止血栓形成，改善血液供应，对防治中风有利。
表3.PGA1对胶原诱导的人血小板聚集的作用
| Inhibition rate of platelet aggregation | |||
| 1’ | 5’ | Max | |
| PGA1 20μm | 0.0097±0.472 | 0.497±0.191 | 0.466±0.164 |
| PGA1 40μm | 0.149±0.516 | 0.524±0.183 | 0.487±0.139 |
| PGA1 80μm | 0.090±0.500 | 0.700±0.115 | 0.641±0.097* |
| Vdhicle Control | -0.0327±0.737 | 0.315±0.299 | 0.265±0.206 |
*p：＜0.05
表4.PGA1对ADP诱导的大鼠血小板聚集的作用
| Rate of platelet aggregation | |||
| 1’ | 5’ | Max | |
| PGA1 20μm | 58.82±6.86 | 70.16±10.43 | 73.12±8.76 |
| PGA1 40μm | 49.06±14.32 | 62.9±11.25 | 65.40±11.57 |
| PGA1 80μm | 38.8±6.58 | 32.2±16.20 | 47.6±7.84** |
| Vdhicle Control | 66.62±3.67 | 66.12±14.02 | 75.82±6.54 |
*p：＜0.05
基于以上实验证据，我们得出结论；前列腺素A1对中风有治疗作用。
Claims (1)
1.前列腺素A1在制备治疗脑缺血性中风疾病的药物中的用途。
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