【作者】 李超；

【导师】 张丹参；

【作者基本信息】 河北北方学院 ， 药理学， 2011， 硕士

【摘要】 脑血管疾病（Cerebrovascular disease，CVD）是严重危害人类健康的疾病，其中以缺血性脑血管病（Ischemia cerebrovascular disease，ICVD）最为多见，是中老年人的常见病，具有高发病率、高患病率、高复发率、高致残率及高死亡率等特点，也是国内外重点防治的疾病之一。但由于其病因及发病机制尚未阐明，目前缺乏有效的治疗手段。因此，研究脑血管疾病的病因及发病机制、寻找有效的预防和治疗药物是国内外医药学领域的研究热点。近年来，国内外学者对应用天然药物有效成分治疗脑血管疾病进行了大量研究，但都未取得突破性进展。大黄酚（Chrysophanol，Chry）是大黄中提取的蒽醌类化合物，我们前期的研究工作证实，大黄酚具有显著的抗衰老作用。但由于大黄酚单体在水中的溶解度低、性质不稳定、直接用药对胃肠有刺激作用等缺点，限制了其进一步的临床应用。前期的研究表明，配制大黄酚的溶剂主要是10 % N，N-二甲基甲酰胺（N，N-Dimethylformamide，DMF），但由于其为有机溶剂，具有一定毒性，只能低浓度、少量应用于动物实验研究，不能应用于临床。因此，为寻找适合临床应用的剂型，我们进行了大黄酚的临床用药剂型筛选研究。目前，本研究室已经完成了大黄酚聚氰基丙烯酸丁酯纳米囊、大黄酚羟丙基-β-环糊精包合物和大黄酚脂质体三种剂型制备工艺的研究，并分别进行了初步药效学和药代动力学考察。为进一步比较大黄酚三种剂型各自的特点，设立本课题。欲通过建立小鼠脑缺血再灌注损伤模型，分别给予大黄酚三种剂型药物，比较三种剂型不同剂量组的药效学作用及其组织分布特点，以期进一步完善三种制剂的药理学研究，同时筛选出最佳剂型应用于临床。昆明种雄性小鼠285只，随机分为19组，分别为：①对照组：正常对照组、假手术组、脑缺血再灌注损伤模型组、DMF溶剂对照组、纳米囊对照组、包合物对照组、脂质体对照组；②大黄酚DMF（10 %DMF溶解）10.0，1.0，0.1 mg·kg-1三个剂量组；③大黄酚纳米囊10.0，1.0，0.1 mg·kg-1三个剂量组；④大黄酚包合物10.0，1.0，0.1 mg·kg-1三个剂量组；⑤大黄酚脂质体10.0，1.0，0.1 mg·kg-1三个剂量组。除正常对照组和假手术组外，其余各组小鼠进行脑缺血再灌注操作，假手术组小鼠进行手术但不进行脑缺血再灌注操作。手术后，正常对照组、假手术组和模型对照组腹腔注射生理盐水，其余各组给予相应溶剂或药物，每天一次，连续给药18 d。给药d 8~d 9进行避暗实验，给药d 11~d 12进行跳台实验，给药d 14~d 15进行探索实验，给药d 17~d 18进行穿梭实验，通过实验观察比较三种大黄酚制剂对脑缺血再灌注损伤模型小鼠记忆障碍的改善作用。通过测定脑、肝、血清过氧化氢酶（Catalase，CAT）、谷胱甘肽过氧化物酶（Glutathioneperoxidase，GSH-Px）和超氧物歧化酶（Superoxide dismutase，SOD）、一氧化氮（Nitric oxide，NO）、一氧化氮合酶（Nitric oxide synthase，NOS）、单胺氧化酶-B（Monoamine oxidase-B，MAO-B）的活性；测定脑及肝丙二醛（Malondialdehyde，MDA）、脑及心脏组织脂褐素（Lipofuscin，LF）的含量；观察比较三种大黄酚制剂对脑缺血再灌注损伤模型小鼠上述各氧化相关酶活性和代谢产物含量的影响。通过测定脑组织乙酰胆碱酯酶（Acetylcholinesterase，AChE）的活性，观察比较三种大黄酚制剂对脑缺血再灌注损伤模型小鼠AChE活性的影响。通过测定脑组织氨基酸（Amino acid，AA）的含量，观察比较三种大黄酚制剂对脑缺血再灌注损伤模型小鼠脑内氨基酸的影响。通过观察小鼠断头耐缺氧生存时间、张口呼吸次数和脑指数，比较三种大黄酚制剂对脑缺血再灌注损伤模型小鼠耐缺氧能力的影响。进行脑、肝组织2，3，5-三苯基氯化四氮唑（2，3，5-Triphenyltetrazolium chloride，TTC）染色和苏木精-伊红（Hematoxylin and eosin，HE）染色，观察比较三种大黄酚制剂对脑缺血再灌注损伤模型小鼠脑梗死面积和病理形态学的影响。连续腹腔给药18 d后将小鼠断头处死，取血并迅速留取各组织器官（心、脑、肝、脾、肺、肾），通过高效液相色谱法（Highperformance liquid chromatography，HPLC）测定各组织中大黄酚含量，观察不同剂型大黄酚的组织分布差异。1三种大黄酚剂型的药效学实验1.1三种大黄酚剂型对学习记忆的影响结果显示，脑缺血再灌注损伤可引起小鼠明显的记忆功能障碍（p<0.05~p<0.01）。与各对应的模型组比较，大黄酚DMF及三种不同剂型的10.0，1.0 mg·kg-1剂量组均可不同程度地改善脑缺血再灌注损伤所致记忆功能障碍（p<0.05~p<0.01），且呈剂量依赖性：在避暗实验中，小鼠进入暗室的潜伏期延长，错误次数明显减少（p<0.05~p<0.01）；在跳台实验中，小鼠在平台上的潜伏期和错误次数减少（p<0.05~p<0.01）；在探索实验中，小鼠进入暗室潜伏期明显延长、爬高时间和到达明室时间均明显提前，爬高次数显著增多（p<0.05~p<0.01）；在穿梭实验中，小鼠被电击次数和电击时间明显较少，主动逃避时间延长（p<0.05）。而大黄酚DMF及三种不同剂型的0.1 mg·kg-1剂量组对上述各项指标无显著改善作用（p>0.05）。各剂型之间药效作用比较，大黄酚纳米囊和包合物这两种剂型改善记忆障碍作用与大黄酚DMF组相比，无显著性差异（p>0.05）；而大黄酚脂质体10.0 mg·kg-1剂量组改善作用差异显著（p<0.01）。结果表明，大黄酚各剂型均具有改善脑缺血再灌注损伤作用，其中大黄酚脂质体作用最佳。1.2三种大黄酚剂型对组织氧化相关酶活性和代谢产物含量的影响结果显示，脑缺血再灌注损伤可引起脑、肝、血清CAT、GSH-Px、SOD活性降低（p<0.05~p<0.01），使NO、NOS和MAO-B活性升高（p<0.05~p<0.01）；使脑及肝组织MDA含量升高（p<0.01）、脑及心脏组织LF含量增高（p<0.01）。与各对应的模型组比较，大黄酚DMF及三种不同剂型的10.0，1.0 mg·kg-1剂量组可不同程度改善脑缺血再灌注损伤引起的氧化相关酶活性和代谢产物含量的变化（p<0.05~p<0.01），呈剂量依赖性；而大黄酚DMF及三种不同剂型的0.1 mg·kg-1剂量组对上述各项指标无显著改善作用（p>0.05）。各剂型之间药效作用比较，大黄酚纳米囊和包合物这两种剂型与大黄酚DMF组相比作用相似，无显著性差异（p>0.05）；而大黄酚脂质体的作用较好，大黄酚脂质体10.0 mg·kg-1剂量组改善作用较显著（p<0.01）。结果表明，大黄酚各剂型均具有改善脑缺血再灌注损伤，缓解损伤对氧化相关酶活性和代谢产物含量的影响，其中大黄酚脂质体作用最佳。1.3三种大黄酚剂型对脑组织乙酰胆碱酯酶活性的影响结果显示，脑缺血再灌注损伤可引起脑组织AChE活性升高（p<0.01）。与各对应的模型组比较，大黄酚DMF及三种不同剂型的10.0，1.0 mg·kg-1剂量组均可不同程度抑制脑组织中AChE的活性（p<0.05~p<0.01），且呈剂量相关性；而大黄酚DMF及三种不同剂型的0.1 mg·kg-1剂量组对上述各项指标无显著改善作用（p>0.05）。各剂型之间药效作用比较，大黄酚纳米囊和包合物两种剂型对AChE活性的影响与大黄酚DMF组无显著性差异（p>0.05）；而大黄酚脂质体对AChE的作用较好，其中以大黄酚脂质体10.0 mg·kg-1剂量组改善作用较显著（p<0.01）。结果表明，大黄酚各剂型均可抑制组织中AChE活性，其中大黄酚脂质体作用最佳。1.4三种大黄酚剂型对脑内氨基酸含量的影响结果显示，脑缺血再灌注损伤可引起脑组织AA含量显著降低（p<0.05）。与各对应的模型组比较，大黄酚DMF及三种不同剂型的10.0，1.0 mg·kg-1剂量组可明显增加AA的含量（p<0.05~p<0.01），且呈剂量依赖性；而大黄酚DMF及三种不同剂型的0.1 mg·kg-1剂量组对上述各项指标无显著改善作用（p>0.05）。各剂型之间药效作用比较，大黄酚纳米囊和包合物两种剂型对脑内氨基酸含量的影响与大黄酚DMF组无显著性差异（p>0.05）；而大黄酚脂质体对脑内氨基酸的作用较好，其中以大黄酚脂质体10.0mg·kg-1剂量组改善作用较显著（p<0.01）。结果表明，大黄酚各剂型均可不同程度影响脑内氨基酸水平，其中大黄酚脂质体作用最佳。1.5三种大黄酚剂型的耐缺氧能力的影响结果显示，脑缺血再灌注损伤可引起小鼠断头耐缺氧生存时间和张口呼吸次数明显减少（p<0.05），脑指数减小（p<0.05）。与各对应的模型组比较，大黄酚DMF及三种不同剂型的10.0，1.0 mg·kg-1剂量组小鼠断头耐缺氧生存时间明显延长、张口呼吸次数明显增加（p<0.05），脑指数增大（p<0.05），且呈剂量依赖性；而大黄酚DMF及三种不同剂型的0.1 mg·kg-1剂量组对上述各项指标无改善作用（p>0.05）。各剂型之间药效作用比较，大黄酚纳米囊和包合物两种剂型对耐缺氧能力的影响与大黄酚DMF组无显著性差异（p>0.05）；而大黄酚脂质体对耐缺氧的作用较好，其中以大黄酚脂质体10.0 mg·kg-1剂量组改善作用较显著（p<0.05）。结果表明，大黄酚各剂型均可不同程度增强脑耐缺氧能力，其中大黄酚脂质体作用最佳。1.6三种大黄酚剂型对脑、肝组织病理形态的影响结果显示，脑缺血再灌注损伤可引起脑、肝组织病理形态的改变。与各对应的模型组比较，大黄酚DMF及三种不同剂型的10.0，1.0mg·kg-1剂量组脑梗死体积减小，具有显著性差异（p<0.01）；海马区出现神经元密集，结构正常，神经细胞间隙变小，神经细胞数量增多，神经元间质界限清晰；肝小叶结构完整，肝细胞排列规则，数目增多，且呈剂量依赖性；而大黄酚DMF及三种不同剂型的0.1 mg·kg-1剂量组对上述各项指标无明显改善作用（p>0.05）。各剂型之间药效作用比较，大黄酚纳米囊和包合物两种剂型对脑缺血再灌注损伤所致脑、肝组织形态的病理变化无改善作用（p>0.05）；而大黄酚脂质体对脑缺血再灌注损伤的作用较好，其中以大黄酚脂质体10.0 mg·kg-1剂量组改善作用较显著（p<0.01）。结果表明，大黄酚各剂型均可不同程度缓解脑缺血再灌注损伤小鼠的病理形态改变，其中大黄酚脂质体作用最佳。2三种大黄酚剂型的组织分布结果显示，大黄酚在小鼠体内的组织分布含量依次为：血>脑>肾>肝>心>脾>肺，大黄酚三种制剂10.0，1.0，0.1 mg·kg-1剂量组与大黄酚DMF组比较，血、肝及脑组织中的大黄酚含量均高于大黄酚组DMF组，有显著性差异（p<0.05~p<0.01），且呈剂量依赖性。各剂型之间组织分布情况比较，相同剂量的大黄酚纳米囊和包合物两种剂型在组织中的分布与大黄酚组比较，无显著性差异（p>0.05）；而大黄酚脂质体在各组织中含量较高，其中大黄酚脂质体10.0 mg·kg-1剂量组测得各组织含量最高（p<0.01）。结果表明，大黄酚DMF及三种剂型均可使大黄酚分布于各组织器官，且组织含量有明显差异，以血和脑组织分布较多；剂型中以大黄酚脂质体分布含量较高。上述研究结果表明，脑缺血再灌注损伤可建立血管性痴呆动物模型，通过学习记忆行为学实验、氧化相关酶活性及代谢产物含量测定、断头耐缺氧实验以及脑梗死面积和病理形态学观察等实验进行了药效学研究。结果证实，三种大黄酚剂型具有改善脑缺血再灌注损伤的作用，通过降低组织中MDA、LF含量及NO、NOS和MAO-B活性，提高CAT、GSH-Px、SOD活性，进而组织的抗氧化能力增强；抑制组织中AChE活性，进而使胆碱能神经功能增强；调节脑内氨基酸水平，从而减轻神经元的损伤；增强脑组织的耐缺氧能力，改善脑缺血再灌注的损伤作用。大黄酚聚氰基丙烯酸丁酯纳米囊、大黄酚羟丙基-β-环糊精包合物、大黄酚脂质体剂型之间的组织分布相比较，以大黄酚脂质体在各组织的分布较好，药效作用也最为显著。大黄酚脂质体有望成为大黄酚临床应用的新剂型，特别是各种途径注射给药的剂型，应用于临床治疗缺血性脑血管疾病。更多还原

【Abstract】 Cerebral vascular diseases are harmful to human life and heath.Ischemia cerebrovascular disease (ICVD) is a common disease inmiddle-aged and elderly people. Its characteristic includes high diseaseincidence rate，high prevalence rate，high recurrence rate，high cripplingrate and high mortality rate. ICVD is one of key diseases that have beenprevented or treated at home and abroad. So a lot of human and materialresources have been put into the basic and clinical study. Up to now theprimary pathological mechanisms and causes of ICVD have not beendefinite. As the lack of effective diagnostic and therapeutic methods，it isvery important and urgent to study the drug for ICVD. In recent years，inorder to find better ways and better drugs，domestic and foreignresearchers have done a lot of researches in treating ICVD with the activeingredients of natural medicines，but there is no satisfactory therapy forICVD.Chrysophanol is the compound from rhubarb anthraquinones. Theprevious study confirms that it has an evident anti-aging effect. As thesolubility of chrysophanol in water is low，its nature is unstable and thestimulating effect on gastrointestinal is obvious when used directly，itsfurther clinical application is limited. In previous studies，chrysophanol’ssolvent is mainly 10 % N, N-dimethylformamide (DMF). Because it isorganic solvent and has harmful effect，it can’t be used in clinicaladministration. But it can be used in the experiment at low concentrationand small dosage. In order to find new and suitable dosage forms forclinical application，we conducted screening study on clinical pharmacology research of chrysophanol formulations. Currently，chrysophanol was made into nanocapsules loading with chrysophanol bypolybutylcyanoacrylate，chrysophanol hydroxypropyl-β-cyclodextrininclusion complex and chrysophanol liposomes by the best preparationmethod and technics，and their preliminary pharmacokinetic studies werecompleted. In order to screen out the best formulation for clinicalapplications，we compared the differences of organization distribution andpharmacodynamics effects in three chrysophanol formulations by adoptingto cerebral ischemia reperfusion.285 male mice were divided into nineteen groups randomly：Group 1were normal control group，sham-operated group，cerebral ischemiareperfusion model control group，and the solvent control group of DMF，nanocapsules，inclusion complex and liposomes；Group 2 werechrysophanol (10 % DMF dissolved) 10.0，1.0，0.1 mg·kg-1 dose group；Group 3 were nanocapsules loading with chrysophanol by polybutylcyanoacrylate10.0，1.0，0.1 mg·kg-1 dose group；Group 4 were chrysophanolhydroxypropyl-β-cyclodextrin inclusion complex 10.0，1.0，0.1 mg·kg-1dose group；Group 5 were chrysophanol liposomes 10.0，1.0，0.1 mg·kg-1dose group.In various groups，cerebral ischemia reperfusion were administeredexcept normal control and sham-operated group. Sham group wasoperated on but not executed cerebral ischemia reperfusion. Aftermodeling，corresponding drugs were administered for every groups andnormal saline (NS) for normal group，sham-operated group，cerebralischemia reperfusion model control group，once a day for eighteen days inthe same way. The ethological experiments，about learning and memory，such as passive avoidance test (d 8~d 9)，exploratory movement test (d11~d 12)，step-through and step-down test (d 14~d 15) and shuttle test (d17~d 18) etc，were observed the improving effects of chrysophanolformulations on memory impairment cerebral ischemia reperfusion-induced. Through determination of the activities of CAT，GSH-Px，SOD，NO，NOS，MAO-B in brain，liver and blood tissues，the contents of MDA in brain and liver tissues，the contents of LF in brainand heart tissues，we observed the effects on oxidative related enzymes’activity and metabolites’content of chrysophanol formulations. Throughdetermination of activity of AChE in brain tissue，we observed thepharmacodynamic effects of chrysophanol formulations. Throughdetermination of contents of amino acid(AA) in brain tissue，we observedthe pharmacodynamic effects of chrysophanol formulations. Throughdetermination of survival time in beheaded hypoxia mice and brain index，we observed the pharmacodynamic effects of chrysophanol formulations.Through the TTC and HE dying experiment in brain and liver tissues，weobserved the brain’s infarction area and pathomorphological changes ofchrysophanol formulations. Through determination of chrysophanolcontent in tissues by High Performance Liquid Chromatography(HPLC)，we observed tissue distribution’s differences of chrysophanolformulations.1 Pharmacodynamicharmacodynamics experiments of three chrysophanol formulations1.1 Effect of three chrysophanol formulations on learning andmemoryResults showed that cerebral ischemia could cause significantmemory impairment in mice (p<0.05~p<0.01). Compared with thecorresponding model group，chrysophanol DMF and chrysophanolformulations (10.0，1.0 mg·kg-1 dose groups) could improve theimpairments of memory with cerebral ischemia reperfusion：instep-through test，the latency had an extended tendency，and the number ofentry times was significantly reduced (p<0.05~p<0.01)；In exploratorymovement test，the time of climbing darkroom was extended，height andbright room was evidently brought forward and the number of climbingheight was evidently increased (p<0.05~p<0.01)；In platform test，the latency and the number of error times were significantly decreased(p<0.05~p<0.01)；In shuttle test，the number and time of electric shockwas significantly decreased，the time of initiative avoiding was evidentlyprolonged (p<0.05). Chrysophanol DMF and chrysophanol formulations(0.1 mg·kg-1 dose group) had no significant improvements in the aboveindicators (p>0.05).Compared with chrysophanol group，the two groups of nanocapsulesand inclusion complex had no significant difference in improving memoryimpairment；However，chrysophanol liposome was better in this respect，particularly in 10.0 mg·kg-1 dose group (p<0.01).These results demonstrated that chrysophanol DMF andchrysophanol formulations had different levels in improving theimpairments of memory with cerebral ischemia reperfusion and the bestformulation was chrysophanol liposomes.1.2 Effect of three chrysophanol formulations on oxidative relatedenzymes’activity and metabolites’content in tissuesResults showed that cerebral ischemia-reperfusion injury could lowerthe levels of CAT，GSH-Px，SOD in brain，liver and blood tissues(p<0.05~p<0.01)，improve the levels of NO，NOS and MAO-B in brain，liver and blood tissues (p<0.05~p<0.01)，increase the contents of MDA inbrain and liver tissues (p<0.01) and the contents of LF in brain and hearttissues (p<0.01). Compared with the corresponding model group，chrysophanol DMF and chrysophanol formulations (10.0，1.0 mg·kg-1dose groups) could improve the levels of oxidative related enzymes’activity and metabolites’content (p<0.05~p<0.01)，which could improvethe cerebral ischemia-reperfusion injury，and these results were related tothe dose. Chrysophanol DMF and chrysophanol formulations (0.1 mg·kg-1dose group) had no significant improvements to the above indicators.Compared with chrysophanol DMF group，the nanocapsules and inclusioncomplex groups had no significant difference (p>0.05)；However， chrysophanol liposome was better in this respect，particularly in 10.0mg·kg-1 dose group (p<0.01).These results demonstrated that chrysophanol DMF andchrysophanol formulations had different levels in improving the levels ofoxidative related enzymes’activity and metabolites’content and the bestformulation was chrysophanol liposomes.1.3 Effect of three chrysophanol formulations on AChE in brain tissueResults showed that，cerebral ischemia-reperfusion injury couldimprove the activity of AChE in brain tissue (p<0.01). Compared with thecorresponding model group，chrysophanol DMF and chrysophanolformulations (10.0，1.0 mg·kg-1 dose groups) could lower the activity ofAChE (p<0.05~p<0.01)，and the results were related to the dose；Compared with chrysophanol DMF group，the two groups of nanocapsulesand inclusion complex had no significant difference in the activity ofAChE (p>0.05)；However，chrysophanol liposome was better in thisrespect，particularly in 10.0 mg·kg-1 dose group (p<0.01).These results demonstrated that chrysophanol DMF andchrysophanol formulations had different levels in improving the activity ofAChE and the best formulation was chrysophanol liposomes.1.4 Effect of three chrysophanol formulations on amino acid in braintissueResults showed that，cerebral ischemia-reperfusion injury couldlower the contents of AA in brain tissue (p<0.05). Compared with thecorresponding model group，chrysophanol DMF and chrysophanolformulations (10.0，1.0 mg·kg-1 dose groups) could improve the contentsof AA in brain tissue (p<0.05~p<0.01)，and the results were related to thedose；Compared with chrysophanol DMF group，the two groups ofnanocapsules and inclusion complex had no significant difference in thecontents of AA (p>0.05)；However，chrysophanol liposome was better inthis respect，particularly in 10.0 mg·kg-1 dose group (p<0.01). These results demonstrated that chrysophanol DMF andchrysophanol formulations had different levels in influencing the contentsof AA in brain tissue and the best formulation was chrysophanolliposomes.1.5 Effect of three chrysophanol formulations on hypoxia toleranceResults showed that，cerebral ischemia-reperfusion injury couldshorten the survival time of beheaded hypoxia，the number of mouth andbrain index (P<0.05). Compared with the corresponding model group，chrysophanol DMF and chrysophanol formulations (10.0，1.0 mg·kg-1dose groups) could prolong the survival time of beheaded hypoxia，thenumber of mouth and brain indexed (P<0.05)，and the result were relatedto the dose；Compared with chrysophanol DMF group，the two groups ofnanocapsules and inclusion complex had no significant difference(p>0.05)；However，chrysophanol liposome was better in this respect，particularly in 10.0 mg·kg-1 dose group (p<0.05).These results demonstrated that chrysophanol DMF andchrysophanol formulations had different levels in influencing the effects ofhypoxia tolerance and the best formulation was chrysophanol liposomes.1.6 Effect of three chrysophanol formulations on pathomorphology inbrain and liver tissuesResults were as follows，cerebral ischemia reperfusion injury haddifferent levels of pathological changes in brain and liver tissues. Incontrast to the corresponding model group，chrysophanol DMF andchrysophanol formulations (10.0，1.0 mg·kg-1 dose groups) could decreasecerebral infarction size (P<0.01)，neurons’density and neuronal structureof nerve cells in hippocampal area were normal，the interspace among thenerve cells were decreased，the number of nerve cells increased and thecircumscription between cell nucleus and membrane of some nerve cellswere clear，lobule boundary，hepatic cell structure and arrangement ofwere also normal，the number of hepatic cells increased，and the results were related to the dose；In contrast to chrysophanol DMF group，the twogroups of nanocapsules and inclusion complex had no significantdifference (p>0.05)；However，chrysophanol liposome was better in theserespects，particularly in 10.0 mg·kg-1 dose group(p<0.01).These results demonstrated that chrysophanol DMF andchrysophanol formulations had different levels in influencing the effects ofthe pathological form and the best formulation was chrysophanolliposomes.2 TissuTissue distribution of three chrysophanol formulationsResults showed that，the order of chrysophanol concentration inmice’s tissues by HPLC：blood>brain>kidney>liver>heart>spleen>lungs，compared with chrysophanol DMF，chrysophanol concentration ofchrysophanol formulations (10.0，1.0，0.1 mg·kg-1 dose groups) in brain，liver and blood tissues were a significant difference (p<0.05~p<0.01)，andthe results were related to the dose；Compared with chrysophanol DMFgroup，the two groups of nanocapsules and inclusion complex had nosignificant difference (p>0.05)；However，chrysophanol liposome wasbetter in this respect，particularly in 10.0 mg·kg-1 dose group (p<0.01).These results demonstrated that chrysophanol DMF andchrysophanol formulations had different levels in influencing the tissuedistribution，among them，the tissue distribution of blood and brain washigher and the best formulation was chrysophanol liposomes.In summary，the cerebral ischemia reperfusion could result insenescence. The learning and memory experiments，antioxidant enzymeassays，beheaded hypoxia，cerebral infarction size and pathologicalmorphous experiments had been studied. The concentrations of chry in thedifferent tissue were determined by HPLC. All the results implied thatchrysophanol formulations could lower the contents of MDA，LF and theactivities of NO，NOS，MAO-B，improve the activities of CAT，GSH-Px，SOD，inhibit the activity of AChE，affect the level amino acid in brain， enhance the effect of hypoxia tolerance，and improve the pathologyprocess of disease. Among these chrysophanol formulations，chrysophanolliposomes was best，so it might become one of new drugs of treatingICVD in the future，in particular，the injectable dosage forms can beadministered in various routes.更多还原