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Article(id=1198628601810744266, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198628599835227075, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2022-1393, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1671120000000, receivedDateStr=2022-12-16, revisedDate=1673539200000, revisedDateStr=2023-01-13, acceptedDate=null, acceptedDateStr=null, onlineDate=1763704928114, onlineDateStr=2025-11-21, pubDate=1686499200000, pubDateStr=2023-06-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763704928114, onlineIssueDateStr=2025-11-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763704928114, creator=13701087609, updateTime=1763704928114, updator=13701087609, issue=Issue{id=1198628599835227075, tenantId=1146029695717560320, journalId=1189982191388893191, year='2023', volume='58', issue='6', pageStart='0', pageEnd='1724', issueExtLink='null', onlineDate='null', pubDate='1686499200000', pubDateStr='2023-06-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1763704927643, creator='13701087609', updateTime=1766137690373, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1208832346359468483, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198628599835227075, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1208832346359468484, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198628599835227075, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=1515, endPage=1520, ext={EN=ArticleExt(id=1198628602678965202, articleId=1198628601810744266, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Non clinical pharmacodynamic evaluation system of high-altitude hypoxic brain injury, columnId=1190335348648547107, journalTitle=Acta Pharmaceutica Sinica, columnName=Reviews, runingTitle=null, highlight=null, articleAbstract=

The air at high altitude is thin and belongs to the environment of low temperature, low oxygen and low pressure. The human brain is the most sensitive to hypoxia. Hypoxia will cause dysfunction of the central nervous system, resulting in high-altitude hypoxic brain injury, including mild high altitude headache and more destructive high altitude cerebral edema (HACE). Recently, with more and more people work and live in high altitude areas, the development of high-altitude hypoxic brain injury drugs would produce great economic value and social significance. Non clinical pharmacodynamic evaluation is the basic of drug development, which plays a key role in improving the success rate of clinical transformation and reducing the risk of clinical research. This review summarizes the cell models and animal models, and the evaluation indicators usually used to explore the candidates of high-altitude hypoxic brain injury. We aim at establishing a standardized non clinical efficacy evaluation system for high altitude hypoxic encephalopathy, and provide a standardized reference for drug development in hypoxic encephalopathy at high altitude at nonclinical stage.

, authors=null, authorsList=Meng-yao LIU, Chun-yang ZHAO, Nian-ying SHANG, Qing-li WANG, Ying PENG, authorCompany=null, correspAuthors=Qing-li WANG, Ying PENG, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2023 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1198628603341665247, articleId=1198628601810744266, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=高原缺氧性脑病的非临床药效学评价体系, columnId=1190335349655180086, journalTitle=药学学报, columnName=综述, runingTitle=null, highlight=null, articleAbstract=

高原空气稀薄, 属于低温、低氧、低压环境, 人脑对缺氧最敏感, 低压低氧会引发中枢神经系统功能障碍, 出现高原缺氧性脑病, 临床上包括高原头痛和严重的高原脑水肿。随着越来越多的人工作、生活在高原地区, 开发抗高原缺氧性脑病药物具有很大的经济价值和社会意义。非临床药效学评价是药物开发的基础环节, 对提高临床转化成功率和降低临床研究风险起到了关键作用。本文总结了高原缺氧性脑病的细胞模型和动物模型, 以及用于评价药物药效的检测指标, 旨在建立起规范的抗高原缺氧性脑病的非临床药效学评价体系, 以期为广大药物研发人员提供参考, 提高创新药物的临床转化的成功率。

, authors=null, authorsList=刘梦瑶, 赵春阳, 商廿颍, 王庆利, 彭英, authorCompany=null, correspAuthors=王庆利, 彭英, authorNote=null, correspAuthorsNote=
*王庆利, Tel: 86-10-68585566, Fax: 86-10-68584189, E-mail: ;
彭英, Tel: 86-10-83165742, Fax: 86-10-63017757, E-mail:
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高原缺氧性脑病的非临床药效学评价体系
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刘梦瑶 1 , 赵春阳 2 , 商廿颍 1 , 王庆利 2, * , 彭英 1, *
药学学报 | 综述 2023,58(6): 1515-1520
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药学学报 |综述 2023 , 58 (6) : 1515 -1520
高原缺氧性脑病的非临床药效学评价体系
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刘梦瑶1, 赵春阳2, 商廿颍1, 王庆利2, * , 彭英1, *
作者信息
  • 1.中国医学科学院、北京协和医学院药物研究所, 北京 100050
  • 2.国家药品监督管理局药品审评中心, 北京 100022
通讯作者:
*王庆利, Tel: 86-10-68585566, Fax: 86-10-68584189, E-mail: ;
彭英, Tel: 86-10-83165742, Fax: 86-10-63017757, E-mail:
Non clinical pharmacodynamic evaluation system of high-altitude hypoxic brain injury
Meng-yao LIU1, Chun-yang ZHAO2, Nian-ying SHANG1, Qing-li WANG2, * , Ying PENG1, *
Affiliations
  • 1. Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
  • 2. Center for Drug Evaluation, National Medical Product Administration, Beijing 100022, China
出版时间: 2023-06-12 doi: 10.16438/j.0513-4870.2022-1393
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高原空气稀薄, 属于低温、低氧、低压环境, 人脑对缺氧最敏感, 低压低氧会引发中枢神经系统功能障碍, 出现高原缺氧性脑病, 临床上包括高原头痛和严重的高原脑水肿。随着越来越多的人工作、生活在高原地区, 开发抗高原缺氧性脑病药物具有很大的经济价值和社会意义。非临床药效学评价是药物开发的基础环节, 对提高临床转化成功率和降低临床研究风险起到了关键作用。本文总结了高原缺氧性脑病的细胞模型和动物模型, 以及用于评价药物药效的检测指标, 旨在建立起规范的抗高原缺氧性脑病的非临床药效学评价体系, 以期为广大药物研发人员提供参考, 提高创新药物的临床转化的成功率。

高原缺氧性脑病  /  非临床药效学评价  /  新药研发  /  细胞模型  /  动物模型

The air at high altitude is thin and belongs to the environment of low temperature, low oxygen and low pressure. The human brain is the most sensitive to hypoxia. Hypoxia will cause dysfunction of the central nervous system, resulting in high-altitude hypoxic brain injury, including mild high altitude headache and more destructive high altitude cerebral edema (HACE). Recently, with more and more people work and live in high altitude areas, the development of high-altitude hypoxic brain injury drugs would produce great economic value and social significance. Non clinical pharmacodynamic evaluation is the basic of drug development, which plays a key role in improving the success rate of clinical transformation and reducing the risk of clinical research. This review summarizes the cell models and animal models, and the evaluation indicators usually used to explore the candidates of high-altitude hypoxic brain injury. We aim at establishing a standardized non clinical efficacy evaluation system for high altitude hypoxic encephalopathy, and provide a standardized reference for drug development in hypoxic encephalopathy at high altitude at nonclinical stage.

high altitude hypoxic brain injury  /  non-clinical efficacy  /  drug discovery  /  cell model  /  animal model
刘梦瑶, 赵春阳, 商廿颍, 王庆利, 彭英. 高原缺氧性脑病的非临床药效学评价体系. 药学学报, 2023 , 58 (6) : 1515 -1520 . DOI: 10.16438/j.0513-4870.2022-1393
Meng-yao LIU, Chun-yang ZHAO, Nian-ying SHANG, Qing-li WANG, Ying PENG. Non clinical pharmacodynamic evaluation system of high-altitude hypoxic brain injury[J]. Acta Pharmaceutica Sinica, 2023 , 58 (6) : 1515 -1520 . DOI: 10.16438/j.0513-4870.2022-1393
正文
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高原一般是指地理学上海拔高度在1 000 m以上的地区。在医学上, 把海拔大于2000 m的地区称作高原。高原空气稀薄, 属于低温、低氧、低压环境, 对人体的机能和代谢都产生广泛影响。人体不能迅速适应高海拔环境会导致高原疾病[1, 2], 人脑对缺氧最敏感, 受低氧影响最为显著, 低压低氧会引发中枢神经系统功能障碍, 出现高原缺氧性脑病, 临床上表现为头痛、头晕、疲乏、失眠、共济失调、神经精神异常等症状。高原缺氧性脑病包括高原头痛和严重的高原脑水肿(high altitude cerebral edema, HACE)[3, 4]。高原缺氧引起低氧血症, 脑血流量增加, 血管内皮压力增加、破坏血脑屏障通透性, 导致脑水肿, 脑脊液缓冲不足, 若缺氧时间持续增加, 会发生更为严重的HACE。HACE以躯干性共济失调和意识下降为特征。HACE一般发生在急性高原病后24~36 h。当在一天内海拔上升到4 300 m后, HACE的发病率高达31%。
目前, 用于治疗或预防高原缺氧性脑病的药物非常有限, 包括乙酰唑胺和地塞米松。其中乙酰唑胺是FDA推荐的预防高原缺氧性脑病的首选药物[5]。乙酰唑胺是一种强效碳酸酐酶抑制剂, 能够通过血脑屏障、抑制脑脊液生成, 并降低水通道蛋白-4 (aquaporin-4, AQP-4) 表达, 减轻星形胶质细胞肿胀, 减少脑组织含水量。但乙酰唑胺服用后会出现尿频等不良反应, 且长期服用可造成低钾血症等电解质紊乱及急性肾功能衰竭等[6]。地塞米松可以有效地掩盖症状, 其作用机制尚不清楚。但停用地塞米松会导致疾病反跳甚至病情加重。近年来, 随着航空运输业和旅游业的快速发展, 前往高海拔地区的人逐年增多, 而我国是世界上高原面积最大的国家, 高原缺氧性脑病的发病率逐年增加, 成为危害我国高原地区的人类活动能力和生命健康的主要因素。因此, 开发用来预防和治疗急性高原病和高原脑水肿的新药迫在眉睫。
非临床药效学研究是新药研发的重要阶段, 建立规范化的评价体系将有助于提高临床转化成功率[7]。目前, 高原缺氧性脑病的细胞和动物模型种类很多, 但模型的制备和评价指标缺乏统一的标准。本文总结了国内外模拟高原缺氧性脑病的细胞和动物经典模型及其评价指标, 旨在建立起规范的高原缺氧性脑病的非临床药效学评价体系, 提高药物的转化成功率。
1 神经细胞缺氧损伤模型
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研究高原环境对神经细胞损伤的影响对预防和治疗高原缺氧性脑病具有重要意义。目前在高原缺氧研究中, 主要是通过调控细胞培养环境中氧分压或细胞利用氧的能力建立细胞缺氧性损伤模型。通常采用的细胞包括神经母细胞瘤细胞系(SK-N-SH或SH-SY-5Y) 和乳鼠原代神经细胞。缺氧神经细胞的培养可采用常压性缺氧和低压性缺氧两种培养方法。
1.1 低压性缺氧神经细胞损伤模型
为了能真实地模拟高原低压性细胞缺氧环境, 在大型低压氧舱的实验舱内建立细胞培养间, 可避免在常氧条件下处理缺氧细胞时产生的缺氧复氧损伤问题, 使测定结果更为准确可靠。具体实验流程: 将神经细胞放入大型低压氧舱的培养箱中, 将实验舱海拔上升至目标高度, 待缺氧一段时间后, 实验者进入工作舱, 并将工作舱海拔高度由正常海拔上升至与实验舱相同的高度, 实验人员在实验舱内取出缺氧细胞, 进行各项指标的测定, 实验完毕后, 再将工作舱海拔降至正常海拔。细胞在1%氧浓度、41 kPa压力条件下培养24 h可以建立低压性缺氧损伤模型。
1.2 常压性缺氧神经细胞损伤模型
1.2.1 常压缺氧培养室
可将神经细胞放入常压缺氧室中, 通过逐步降低吸入空气中的氧分压[pO2; 21.25 kPa (0 k)、16.42 kPa (2 k)、12.63 kPa (4 k) 和9.64 kPa (6 k)] 来诱导缺氧, 37 ℃缺氧培养至少24 h。
1.2.2 连二亚硫酸钠法
连二亚硫酸钠为氧清除剂, 2 mmol·L-1连二亚硫酸钠可以快速清除培养液中的氧, 使溶液氧含量降低为零, 导致细胞化学性缺氧[8]。
2 缺氧细胞模型的主要评价指标
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2.1 细胞形态改变
显微镜下观察细胞形态, 常压缺氧条件下, 细胞固缩成圆形, 轴突数量减少, 细胞膜较粗糙, 贴壁性较差。低压缺氧条件下, 细胞肿胀, 生长停滞, 死细胞增多[9]。
2.2 细胞活力检测
可采用MTT法、CCK-8法检测缺氧环境下受试物对神经细胞活性的影响。
2.3 细胞培养液中乳酸脱氢酶(lactate dehydrogenase, LDH) 活性测定
当缺氧引起细胞膜受损时, LDH被迅速释放进入细胞培养液中。神经细胞加入受试物后, 分别在正常环境和缺氧环境下培养24 h, 测定细胞培养液中LDH活性。
2.4 流式细胞术检测神经细胞凋亡和细胞周期
应用流式细胞仪, 将细胞悬液加入FITC-Annexin V和碘化丙啶(propidium iodide, PI) 染液混匀检测, 观察细胞凋亡情况并计算凋亡率。Annexin V+/PI-为早期凋亡细胞, Annexin V+/PI+为坏死或晚期凋亡细胞。相比正常组细胞, 缺氧可以诱导神经细胞发生凋亡, 缺氧模型组的G0/G1期细胞比例显著升高。
2.5 缺氧诱导因子(hypoxia-inducible factors, HIF) 及相关细胞因子的检测
HIF-1在常氧下很快被降解, 只有在缺氧条件下HIF-1才可稳定表达。缺氧会促进红细胞生成素(erythropoietin, EPO) 和血红素氧合酶1 (heme oxygenase-1, HO-1) 的表达。采用Real-time PCR和ELISA法检测HIF-1、EPO、HO-1的基因含量变化。
3 动物缺氧模型
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根据文献报道, 模拟高原缺氧性脑病的动物模型有很多种, 动物种属一般选择大鼠和小鼠, 也可以选择与人类遗传背景更为相似的灵长类动物如食蟹猴。主要分为低压缺氧模型和常压缺氧模型。
3.1 低压缺氧模型
在低氧低气压和低氧常气压环境下均可发生缺氧性脑病, 但在低氧低气压环境下发病最快且更严重。模拟高原环境是最为接近真实高原缺氧性脑病的动物模型建立方法。研究者可以直接将动物输送到高海拔地区, 构建高原缺氧动物模型。但这一方法不适用于远离高原的地区, 因此, 很多研究者采用低压氧舱来模拟高原低压缺氧的状况。
3.1.1 急性低压缺氧模型
低压氧舱通过强大的真空泵将室内空气抽离, 同时让新鲜空气循环, 保持室内空气流量在0.9 L·min-1, 以补充消耗的氧气和去除产生的二氧化碳, 结合精确监测温度和相对湿度, 以此模拟缺氧环境。实验组动物分别在海拔3 000和4 500 m的地方以5 m·s-1的速度进行30 min实验, 然后在海拔9 000 m进行23 h的模拟实验。实验室内的温度为15~17 ℃, 相对湿度为55%~60%。低压暴露24 h后, 立即以5 m·s-1的速度降低海拔。与此同时, 对照组在舱外海拔约600 m处进行类似条件的实验, 以模拟空气循环正常的低空环境, 而非缺氧、低气压的纯高空环境[10]。
3.1.2 急性低压缺氧结合力竭运动模型
缺氧是高原疾病的主要原因, 但交感神经系统的其他压力源, 如劳累, 也会加速疾病的发生和进展。动物在急性低压缺氧联合力竭运动条件下, 脑含水量和血脑屏障通透性增加, 进而导致脑水肿形成[11]。
在缺氧暴露前, 实验动物在动物跑步机上进行2天以上的跑步运动(8.5 h; 坡度0°; 速度12 m·min-1)。运动时间为15 min, 休息20 min后, 重复此计划, 每日共计6个运动时段, 即90 min的运动。然后将实验组封闭在模拟舱中, 模拟海拔高度从300 m提高到4 000 m, 提升速度为5 m·s-1。在此模拟高度下, 舱内研究人员将实验动物放置在跑步机上, 每只动物进行力竭运动(跑步机参数: 坡度10°; 速度12 m·min-1), 并使用电刺激来维持动物的运动。连续运动4 h后, 关笼休息15~20 min。在此期间, 动物可以自由进食饮水。休息后, 动物再次被放在跑步机上进行疲劳运动。这个实验重复2天(11个运动周期; 总运动时间2 640 min)。2天实验结束后, 舱内研究人员将实验送入实验舱缺氧3天(舱室环境参数为: 模拟海拔8 000 m; 舱压35.9 kPa; 氧分压7.5 kPa; 温度18 ℃)。对照组暴露于海平面大气环境3天(海拔300 m; 温度18 ℃), 可自由进食饮水, 进行12 h的光-暗循环。
3.1.3 急性低压缺氧结合冷刺激模型
寒冷也加重高原缺氧, 对72例HACE患者的临床观察表明, 冬季比夏季更易发生HACE。此外, 冷应激已被报道可诱导脑损伤[12], 严重的冷损伤被广泛用来建立脑水肿的模型。
实验动物置于大型低压缺氧动物实验室内, 以10 m·min-1的速度模拟海拔6 000 m (9.9 kPa, 9.8% O2), 72 h。实验室内环境温度在12 ℃ (8:00~20:00)~2 ℃ (次日20:00~8:00) 之间周期性波动, 模拟昼夜温差。冷刺激在增强缺氧暴露诱导的脑损伤中起到辅助作用, 是研究高原缺氧性脑病的可靠实验动物模型。
3.1.4 急性低压缺氧结合脂多糖(lipopolysaccharide, LPS) 处理模型
高海拔暴露已报道与炎症和感染风险增加相关[13]。当志愿者所处海拔上升到3 860 m时, 血浆肿瘤坏死因子α (tumor necrosis factor-α, TNF-α)、白细胞介素(interleukin, IL)-1β和IL-6水平显著升高。LPS诱导的系统性炎症反应通过破坏血脑屏障完整性和激活小胶质细胞, 促进AQP-4积累增加水的渗透性, 在急性低压缺氧暴露时迅速加重脑水肿, 最终导致认知和运动功能受损。缺氧也可增强LPS诱导的炎症反应, 进一步诱导高原脑水肿的发生和发展。
实验组动物首先腹腔注射给予LPS (0.5 mg·kg-1), 30 min后, 动物置于减压室, 在高度为6 000 m (9.9 kPa, 9.8% O2) 的低气压缺氧环境中放置6 h后, 以50 m·s-1的速度降低至正常海拔[14]。
3.1.5 食蟹猴急性低压缺氧模型
低压缺氧诱导脑损伤的病理和分子研究主要集中在小鼠和大鼠等小型哺乳动物[15]。但与人类相比, 这些啮齿动物表现出明显的缺氧耐受性。食蟹猴的遗传背景与人类更为相似, 适合建立用于低压缺氧研究的非人类灵长动物模型。
采用雄性食蟹猴, 年龄6.0~6.5岁。低压舱的模拟高度以3 m·s-1的速度从320 m增加到6 000 m, 以2 m·s-1的速度从6 000 m增加到7 500 m。高度模拟在320 m (A阶段) 开始, 然后分别在3 000 m (B阶段)、4 500 m (C阶段) 和6 000 m (D阶段) 暂停50 min, 最后在7 500 m保持最初24 h (E阶段), 然后再保持24 h (F阶段), 共48 h。在每个阶段, 猴子在相应的高度保持低压缺氧条件30 min。然后在20 min内进行血样采集和给药。出于实验者的安全考虑, 在30 min内, 高度从7 500 m下降到6 000 m, 用于E阶段的采血和给药。在整个低压缺氧实验暴露过程中, 舱内的温度、相对湿度和气流速度分别保持在22 ℃、60%和5 L·min-1。
猴子到达模拟海拔7 500 m, 2 h后进行行为监测。观察其在接下来30 min内的活动, 并采用改进的量表方法评估骨骼肌协调能力, 得分越高表明行为状态受损越严重[16]。
3.2 常压缺氧模型
临床研究表明, 常压缺氧能够导致与高原缺氧性脑病相一致的症状: 脑容量升高和颅内高压。在相同的环境pO2下, 低压和常压缺氧的AMS严重程度没有显著差异。
3.2.1 缺氧室法
将实验动物置于尺寸为65 × 105 × 50 cm的缺氧室中, 室中的气体混合物为氮气中含10%氧气[17]。在对动物进行操作的过程中, 特殊设备防止了环境空气的渗透, 从而使室内的氧气浓度稳定在10% ± 0.5%。
3.2.2 低张性模型
高原缺氧是由于血液中氧饱和度低而导致氧气暴露减少, 可采用低张性模型模拟血氧饱和度降低的情况: ①家兔急性缺氧模型: 家兔气管插管, 通过呼吸机吸入10% O2+ 90% N2 (流量0.5 L·min-1), 持续30~60 min建立急性缺氧模型[18]。1) 观察到兔耳、唇发绀明显, 心率加快。2) 血气分析显示动脉血氧分压、氧含量和氧饱和度均下降。②密闭缺氧模型: 将小鼠放入装有钠石灰的广口瓶内, 用凡士林密闭瓶盖, 由于其消耗O2而呼出的CO2又被钠石灰吸收, 密闭容器内氧分压下降, 导致缺氧[19]。小鼠活动由正常逐渐减少, 呼吸逐渐变得急促, 口唇逐渐变紫, 临终前反跳, 最后死亡。
4 动物缺氧模型的药效评价指标
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4.1 缺氧后存活时间
实验动物缺氧存活时间和缺氧延长率[缺氧延长率= (治疗组存活时间-模型组存活时间)/模型组存活时间] 可以用于评价药物抗缺氧活性。
4.2 动物行为表现
与正常对照组相比, 缺氧的动物活动频率增加, 呼吸频率增加, 头、颈部伸直, 后腿伸直。此外, 随着缺氧时间延长, 自主活动也逐渐减少。
4.3 运动协调能力
为评估动物的运动协调能力, 在缺氧暴露后1 h进行转棒实验。记录动物落下转棒的潜伏期。
4.4 学习记忆功能
通常采用新物体识别实验、T迷宫实验、Y迷宫实验、八臂迷宫实验和Morris水迷宫实验评价学习记忆功能[8]。
4.5 神经炎症指标
4.5.1 炎症因子指标
缺氧后, 全身炎症通过破坏血脑屏障的通透性、激活小胶质细胞及增强AQP-4的表达, 加重缺氧后的脑损伤[14]。可检测HIF、核因子-κB (NF-κB) 和细胞因子IL-6、IL-1β和TNF-α的表达水平, 如图 1所示。
4.5.2 小胶质细胞活化
可采用小胶质细胞的标志物离子钙结合衔接分子1 (ionic calcium-binding adapter molecule 1, Iba-1) 抗体进行脑切片免疫荧光染色。缺氧后Iba-1阳性的小胶质细胞呈阿米巴样激活形状, 体圆形, 树突稀少; 而对照组的小胶质细胞呈分支状态, 树突细长[20]。
4.5.3 星形胶质细胞活化
脑组织缺氧后, 胶质纤维状酸性蛋白(glial fibrillary acidic protein, GFAP) 阳性星形胶质细胞增加, GFAP染色增强、细胞胞体增大, 树突显著增多、增粗、增长。应用Image J软件, 以不同半径同心圆与树突交点的数目衡量所测细胞的复杂程度, 缺氧后星形胶质细胞的复杂程度增加[21]。
4.6 氧化应激指标
急性和长期暴露于低气压缺氧环境中可导致线粒体电子传递链中还原当量的积累, 进一步增加活性氧(reactive oxygen species, ROS) 的产生, 导致氧化应激损伤。ROS参与并可能在高原脑水肿中起致病作用[22]。因此, 氧化应激指标可以在一定程度上反映疾病的严重程度, 如图 2所示。可采用试剂盒或Western blot的方法检测脑组织中的MDA、PC、8-OHdG、SOD、谷胱甘肽过氧化物酶和过氧化氢酶含量。
4.7 线粒体功能评估
细胞中氧气主要在线粒体消耗, 线粒体对氧气供应减少非常敏感。可采用以下指标对线粒体的功能进行评估。如线粒体ATP生成率(MAPR)、线粒体膜电位、线粒体通透性转换孔的开放程度。也可采用Seahorse细胞检测仪测量细胞的氧消耗速率。
4.8 脑水含量
大脑含水量的百分比计算如下: 含水量(%) = (湿重-干重)/湿重×100%。
4.9 血脑屏障通透性
① Evans蓝染色: 动物尾静脉注射Evans Blue溶液后, 取脑组织与二甲基甲酰胺50 ℃水浴48 h, 测量Evans蓝渗漏量。②荧光示踪剂: 尾静脉注射具有从小到大不同分子尺寸的荧光示踪剂[23], 包括生物素三甲基罗丹明[24]、伊文思蓝或TMR葡聚糖。这些荧光示踪剂通常只在细胞旁渗透性增强时才穿过血脑屏障[25], 通过荧光共聚焦显微镜获取图像。
4.10 神经元形态学变化
① Nissl染色: 可用于检测神经元的组织形态学变化, 使用Image-Pro Plus软件分析Nissl小体数量。② TUNEL染色能反映神经元凋亡的典型形态特征, 使用Image-Pro Plus软件分析TUNEL阳性凋亡细胞率。
5 抗高原缺氧性脑病药物非临床研究的合理化建议
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目前, 大量文献已报道了多种高原缺氧性脑病的细胞模型和动物模型。细胞在培养过程中具有易获得、研究条件人为可控、研究样本均一、有利于观察单一因素等优势[26]。目前, 用于研究高原缺氧性脑病的细胞模型主要是通过调控细胞培养环境中的氧分压或细胞利用氧的能力而建立神经细胞缺氧性损伤模型。与常压缺氧细胞模型相比, 低压性缺氧细胞模型可模拟由于高原环境低气压下氧分压降低造成的高原缺氧, 更接近真实的高原环境, 是用于抗高原缺氧性脑病药物的初步筛选和作用机制研究的首选细胞模型。
低压和常压的缺氧动物模型各有其优势和劣势, 选择合适的模型是实验成功的一项关键因素。缺氧环境是引发高原缺氧性脑病的主要原因, 低气压也是引发高原缺氧性脑病的重要原因之一, 有研究表明暴露于非缺氧低气压可能导致大脑皮质下白质疏松症[27]。另外, 高原缺氧性脑病在低气压缺氧下比在常压缺氧下更严重。低压缺氧模型在理论上更贴近真实的高原缺氧情况, 但低压缺氧模型建立的难度较大, 需要真实的高海拔环境或者低压氧舱设备。研究者需结合实验室的情况及需求, 选择合适的模型。在非临床药效学研究中, 如果能够同时构建不同类型的高原缺氧模型, 那么实验结果会更加客观、全面。
6 中国抗高原性缺氧药物研发现状
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目前, 我国处于临床阶段的高原缺氧药物较少, 其中天士力医药集团股份有限公司正在进行复方丹参滴丸预防和治疗高原病的临床Ⅲ期试验。此外, 褪黑素(ChiCTR2200059896)、罗沙司他(ChiCTR2000039934)、曲美他嗪(ChiCTR-TRC-13003298)、布地奈德(ChiCTR-PRC-13003296) 也处于临床试验阶段。近年来的研究表明, 很多藏药在治疗高原缺氧性脑病方面有较大潜力, 如红景天、藏紫苑、唐古特青兰、三味檀香散等藏药, 都被证实可以改善机体的缺氧状态, 缓解由于高原缺氧对机体所造成的不适症状[28], 但治疗效果尚需要经过大规模的临床研究进行验证。
随着中国抗高原缺氧性脑病药物研究的增多, 研究者们急需采用一个非临床药效学评价标准进行系统、规范的药效学评价。本文梳理了模拟高原缺氧性脑病的细胞及动物模型, 并总结了常用的药效学评价指标, 旨在建立起规范的抗高原缺氧性脑病的非临床药效学评价体系, 以期为广大药物研发人员提供参考, 提高创新药物的临床转化成功率。
作者贡献: 刘梦瑶完成了论文的撰写; 赵春阳和商廿颍协助完成了本论文的文献收集和修改; 通讯作者王庆利和彭英确定了写作思路, 并对本论文进行了修改和指导。
利益冲突: 本文不涉及任何利益冲突。
基金
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  • 国家自然科学基金资助项目(81802877)
  • 中国医学科学院医学与健康科技创新工程(2021-I2M-1-054)
  • 中国医学科学院医学与健康科技创新工程(2021-I2M-1-028)
文献
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参考文献 引证文献
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2023年第58卷第6期
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doi: 10.16438/j.0513-4870.2022-1393
  • 接收时间：2022-12-16
  • 首发时间：2025-11-21
  • 出版时间：2023-06-12
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  • 收稿日期：2022-12-16
  • 修回日期：2023-01-13
基金
国家自然科学基金资助项目(81802877)
中国医学科学院医学与健康科技创新工程(2021-I2M-1-054)
中国医学科学院医学与健康科技创新工程(2021-I2M-1-028)
作者信息
    1.中国医学科学院、北京协和医学院药物研究所, 北京 100050
    2.国家药品监督管理局药品审评中心, 北京 100022

通讯作者:

*王庆利, Tel: 86-10-68585566, Fax: 86-10-68584189, E-mail: ;
彭英, Tel: 86-10-83165742, Fax: 86-10-63017757, E-mail:
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https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2022-1393
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2种不同金属材料的力学参数
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Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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