豆甾醇糖苷/聚乙二醇衍生物修饰的阳性脂质体体内分布和肝实质细胞靶向性

目的研究经豆甾醇糖苷 (sterylglucoside, SG) 修饰的以DC-Chol为阳性脂材的脂质体体内分布情况和达到小鼠肝实质细胞靶向的可能性。方法合成阳性脂材3β-［n-(n′,n′- 二甲基氨乙基) 氨基甲酰基］ 胆固醇(DC-Chol)，制备³H-胆固醇标记的阳性脂质体(caitonic liposome, CL)，SG和聚乙二醇-二硬酯酰磷酯酰乙醇胺(PEG-DSPE)修饰的阳性脂质体(SG/PEG-CL)，以及包封¹²⁵I标记的硫代反义寡核苷酸(asODN)的阳性脂质体(SG/PEG-CL-asODN)，分别测定CL,SG/PEG-CL,SG/PEG-CL-asODN和asODN溶液(asODN )在小鼠不同器官及CL,SG/PEG-CL肝内不同细胞中的分布。结果CL和SG/PEG-CL表现较高肝脏聚集性，SG/PEG-CL在肝实质细胞中浓度显著高于CL (P<0.01)， 非实质细胞中浓度明显小于CL(P<0.01)。SG/PEG-CL-asODN相对于asODN表现出明显的肝脾聚集性(P<0.01)。结论用阳性脂质体包载基因药物能改善药物的体内分布，SG的修饰则能提高脂质体肝实质细胞选择性。     

肝靶向去甲斑蝥素微乳的研究

目的考察去甲斑蝥素(NCTD)微乳的形态、粒径分布及生物安全性，研究去甲斑蝥素微乳及其注射液在小鼠体内的组织分布、药代动力学和体外药效学。方法用气相法测定小鼠体内去甲斑蝥素含量。数据用3P87处理，得到各主要药代动力学参数。采用体外细胞毒性和体内全身急性毒性试验方法，评价去甲斑蝥素微乳的抗肿瘤活性及其生物安全性。结果微乳平均粒径为(44±9) nm。血浆中成分及制剂中辅料不干扰去甲斑蝥素测定。小鼠静脉注射去甲斑蝥素微乳及其去甲斑蝥素注射液后的药-时曲线均符合二室模型。去甲斑蝥素微乳的药代动力学研究表明，在同剂量条件下，NCTD微乳可在体内较长时间保持较高浓度，即可在一定程度上延长体内循环时间；微乳及注射液的AUC，MRT，T_1/2分别为(29.7±0.9)，(9.25±0.09) mg·h·L^-1，(110±11)，(86.7±0.8)，(103±12)，(42±4) h，NCTD微乳改变NCTD注射剂在小鼠体内的药时曲线和血药浓度的高低，其消除T_1/2和MRT比其注射剂分别增加了2.48和1.27倍，AUC增加了3.21倍；NCTD微乳在肝、肾中的靶向指数分别为0.43和0.12。去甲斑蝥素微乳的生物安全性与其市售注射液比较无显著性差异。结论去甲斑蝥素微乳较去甲斑蝥素注射液增强了药物的肝靶向性，降低了肾脏分布，在一定程度上延长药物在小鼠体内的循环时间。     

盐酸他克林前体药物的研究盐酸他克林前体药物的研究

目的制备盐酸他克林(THA)的酰化前体药物以提高其透过血脑屏障(BBB)的能力。方法THA和酸酐反应制得N-酰化-THA系列前体药物;考察了前体药物在不同介质中的降解情况,并以N-单丁酰-他克林(BTHA)为模型药物,考察其在小鼠体内的分布和降解情况。结果合成的化合物经¹HNMR,MS和IR鉴定为目标化合物。前体药物在不同介质中均较稳定。与原药相比,前药的脂水分布系数增大。BTHA主要分布于脑、血浆和肝脏中(最高浓度分别为17.572 5,13.140 0和22.827 9 mg·L^-1),在肺和心中的分布浓度很低(最高浓度分别为4.947 5和4.492 5 mg·L^-1)。BTHA在脑内的降解速率较慢,给药12 h后仍有较高浓度(2.415 9 mg·L^-1)。结论N-羧酰-THA系列前体药物提高了THA透过BBB的能力,有望成为脑内定向给药的有效途径。     

反式曲马多及氧去甲基曲马多对映体跨血脑屏障转运

目的　研究反式曲马多(trans T)及其活性代谢物氧去甲基曲马多(M₁)对映体的跨血脑屏障转运。方法大鼠ip盐酸 trans T (16.7mg·kg^-1 或5.0mg·kg^-1) 1 h后取血、脑脊液和大脑皮层,高效毛细管电泳测定血清、脑脊液和大脑皮层中 trans T和M₁ 对映体的浓度。结果　trans T和M₁ 各对映体浓度以大脑皮层中最高,血清中浓度居中,脑脊液中浓度最低。在血清中,(+)-trans T的浓度明显高于(-)-trans T的浓度,M₁ 两对映体的浓度无明显区别;在脑脊液和大脑皮层中,(+)-trans T的浓度明显高于(-)-trans T的浓度,(+)-M₁ 的浓度明显低于(-)-M₁ 的浓度。结论　trans T和M₁ 的跨血脑屏障转运具有立体选择性,脑组织中分别以(+)-对映体和(-)-对映体浓度较高。     

N-乙酰基-L-谷氨酰基-泼尼松龙肾靶向前体药物研究

目的通过研究N-乙酰基-L-谷氨酰基-泼尼松龙的体内分布，考察该前体药物的肾靶向性。方法小鼠iv后，采用高效液相法，在规定时间段测定各组织脏器的泼尼松龙浓度, 并采用大鼠骨密度的测定仪确证前体药物的副作用。结果小鼠给药后15 min，前体药物组肾脏中泼尼松龙浓度为(86±8) μg·g^-1，泼尼松龙组为(57±4) μg·g^-1，60 min后前体药物组肾脏药物浓度为 (67±5) μg·g^-1；泼尼松龙组(42±4) μg·g^-1。大鼠给药30 d后，股骨的骨密度分别为(0.08±0.03) g·cm^-2 （泼尼松龙）和(0.14±0.06) g·cm^-2(前体药物组)。结论前体药物具有肾靶向性, 并能降低致骨质疏松的副作用。     

藻蓝蛋白亚基脂质体制备及其光动力学抗肿瘤作用实验

本研究建立了藻蓝蛋白亚基脂质体的制备方法，检测其对肿瘤细胞转染及光动力杀伤作用(PDT)效果。采用薄膜水合-超声分散法制备藻蓝蛋白亚基脂质体，测定其粒径大小及分布，荧光显微镜观察藻蓝蛋白亚基(PCS)及其脂质体(PCS-lip)的细胞转染率，MTT法检测藻蓝蛋白亚基及其脂质体对肿瘤细胞光动力杀伤效果。结果显示脂质体的粒径为80～160 nm，包封率为42.3%；在质量浓度为100 μg·mL^-1时，藻蓝蛋白亚基脂质体对小鼠肉瘤细胞S180转染率在2 h达到(18.5±0.8)%，4 h为(23.1±0.9)%，5～6 h转染率不再上升。肿瘤细胞光动力杀伤实验表明，在0～200 μg·mL^-1内，光照剂量为22 J·cm^-2时，随着藻蓝蛋白亚基及其脂质体浓度的增加，对胃癌细胞BGC-823和S180的光敏作用也随之增强；在200 μg·mL^-1时PCS-lip对两种细胞生存率分别降低为(45±5.2)%和(36±5.5)%，PCS-lip-PDT组与PCS-PDT组对细胞生存率影响有显著性差异(P<0.05)。研究结果表明，藻蓝蛋白亚基脂质体可很好地保持藻蓝蛋白亚基的生物活性，在相同蛋白浓度时藻蓝蛋白亚基脂质体比藻蓝蛋白亚基更快地转染进肿瘤细胞，药物作用的最佳时间为4 h。在相同浓度及光照剂量的情况下，藻蓝蛋白亚基脂质体对肿瘤细胞的光动力学作用略强于藻蓝蛋白亚基。     

丁基苯酞对蛛网膜下腔出血后脑血流的改善及血脑屏障的保护作用

侧脑室注入自体血液造成蛛网膜下腔出血模型,观察丁基苯酞(dl-NBP)对局部脑血流的改善作用及血脑屏障的保护作用。结果表明,dl-NBP5～20mg·kg^-1明显提高蛛网膜下腔出血后3h内尾状核的血流量,但无明显的剂量效应关系。0.25mg·kg^-1的尼莫地平亦明显提高脑血流。并发现dl-NBP10mg·kg^-1及尼莫地平0.25mg·kg^-1(分别于蛛网膜下腔出血后5min和3hip)均能明显降低蛛网膜下腔出血6h后皮层组织中伊文氏蓝的摄取量,提示对血脑屏障有明显的保护作用。     

人参皂苷Rb1调控MAPK通路改善小鼠脑缺血再灌注诱导血脑屏障损伤的作用研究

目的 探讨人参皂苷Rb₁对小鼠脑缺血再灌注诱导的血脑屏障（BBB）损伤的作用及机制。方法 将C57BL/6小鼠随机分为假手术组、模型组和人参皂苷Rb₁低、中、高剂量（5、10、20 mg·kg^-1）组,采用线栓法栓塞颈内动脉1 h后复灌建立脑缺血再灌注损伤模型,假手术组不栓塞,其余操作同模型小鼠。缺血1 h后ip相应药物,于再灌注24 h后处死取材。采用伊文思蓝染色法检测各组小鼠BBB损伤程度;采用实时荧光定量PCR （qRT-PCR）法检测各组小鼠脑组织中炎症因子白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）以及紧密连接蛋白1（ZO-1）、闭合蛋白（Occludin）的mRNA表达水平;同时采用Western blotting检测各组小鼠脑组织中ZO-1、Occludin蛋白,金属基质蛋白酶-2（MMP-2）、基质金属蛋白酶-9（MMP-9）以及MAPK通路相关蛋白磷酸化的表达水平。结果 与模型组相比,人参皂苷Rb₁可显著减少脑缺血再灌注小鼠脑组织中伊文思蓝的渗漏量（P<0.05）,显著降低脑组织中IL-1β、IL-6和TNF-α的mRNA转录水平（P<0.05、0.01）;显著上调ZO-1和Occludin的mRNA转录和蛋白表达水平（P<0.05、0.01）;显著降低MMP-2、MMP-9的蛋白表达水平（P<0.05、0.01）;显著抑制MAPK通路p38、JNK及ERK磷酸化蛋白的表达（P<0.05、0.01）。结论 人参皂苷Rb₁对小鼠脑缺血再灌注诱导的BBB损伤具有一定的改善作用,其作用机制可能与抑制MAPK信号通路激活,减少MMP-2、MMP-9蛋白的表达,进而减轻对ZO-1、Occludin等紧密连接蛋白的降解有关。     

白首乌C21甾体苷诱导肝癌细胞凋亡的作用及其机制

研究白首乌C₂₁甾体苷对肝癌实体瘤细胞的凋亡作用及其机制。建立肝癌实体型(Heps)小鼠移植性肿瘤模型，随机分为模型组和C₂₁甾体苷各用药组，连续灌胃，10 d后脱颈椎处死小鼠，进行抑瘤率计算，对肿瘤组织进行电镜下观察，采用免疫荧光(AO/EB)测定肿瘤细胞凋亡，免疫组化染色检测bcl-2基因的表达。C₂₁甾体苷(10，20和40 mg·kg^-1)对小鼠移植性肝癌Heps有抑制作用，3个剂量组的抑瘤率分别为34.79%，47.08%和50.23%。C₂₁甾体苷(10，20和40 mg·kg^-1)可增加肿瘤细胞的凋亡，电镜下可见凋亡的形态学改变，并出现凋亡小体；免疫组化结果显示，bcl-2基因的表达与模型组比较明显降低(p<0.01)，但不同于凋亡结果的是高剂量组的阳性面积表达比中剂量略高。降低高表达的bcl-2基因从而促进肝癌细胞的凋亡，可能是C₂₁甾体苷抗肝癌的机制之一。     

非手性与手性色谱法研究尼莫地平及其对映体在大鼠体内的药代动力学及组织分布

目的研究尼莫地平及其对映体在大鼠体内药代动力学及组织分布特性。方法生物样品在碱性条件下,经正己烷-醋酸乙酯(1∶1)提取。非手性色谱分析用ODS柱(150 mm×4.6 mm ID),以甲醇-水(70∶30)为流动相;手性色谱分析用Chiralcel OJ柱(250 mm × 4.6 mm ID),以正己烷-无水乙醇(85∶15)为流动相;检测波长为236 nm。结果尼莫地平及其对映体分别在非手性及手性色谱系统中分离良好,在血浆及组织匀浆液中线性关系、最低检测限、精密度和准确度均满足分析要求。对映体间主要药动学参数T_max,C_max,AUC和CL_s,S-(-)-尼莫地平为:(2.1±0.3) h,(197±5) μg·L^-1,(656±18) μg·h·L^-1和(0.30±0.03) mL·min^-1,r-(+)-尼莫地平为:(1.7±0.5) h,(128±4)μg·L^-1,(381±8) μg·h·L^-1和(0.53±0.03) mL·min^-1;在主要的效应器官中S-(-)-尼莫地平的浓度高于r-(+)-尼莫地平,在主要消除器官中r-(+)-尼莫地平浓度高于S-(-)-尼莫地平的浓度。结论尼莫地平对映体在大鼠体内药代动力学及组织分布存在着立体差异性。     

RMP-7及其衍生物对脂质体跨血脑屏障作用的影响

目的研究RMP-7及其衍生物对脂质体跨血脑屏障的促进作用。方法测定RMP-7与DSPE-PEG-NHS偶联的物质的量比；用血脑屏障的体外模型验证其生物活性；观察脑组织切片中伊文思蓝的荧光位置和强度，测定脑组织中伊文思蓝的浓度。结果RMP-7与DSPE-PEG-NHS偶联物质的量比为1∶1；RMP-7和DSPE-PEG-RMP-7能使过氧化合物酶跨血脑屏障体外模型的转运速率增加2～3倍，修饰脂质体后能使所包封的伊文思蓝在脑中的浓度增加。结论RMP-7与DSPE-PEG-RMP-7对脂质体跨血脑屏障均有促进作用，且后者效果更好。     

The study on brain targeting of the amphotericin B liposomes

To improve transporting drugs across the Blood Brain Barrier (BBB) into the brain, RMP-7 was conjugated to the surface of liposomes containing Amphotericin B (AmB) for cerebral inflammation, because it can selectively bound to the B2 receptors on the capillary blood vessel. First, RMP-7 was conjugated to DSPE-PEG-NHS [1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-n-[poly (ethylenegly-col)]-hydroxy succinamide, PEG M 3400] under mild condition to obtain a predominantly 1:1 conjugate (DSPE-PEG-RMP-7), as evidenced by the Matrix-Assisted Laser Desorption-Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF-MS). The second, endothelium cell was cultured on the cell insert to form an in vitro BBB model and the stereoscan microscope, electric resistance and permeation of horse-radish peroxidase (HRP) across the endothelium cell monolayer were used as indicators to evaluate the integrality of the monolayer, and then the in vitro BBB model was used to determine the bioactivity of DSPE-PEG-RMP-7 "opening" BBB. The results demonstrated the in vitro BBB model was set up, RMP-7 and DSPE-PEG-RMP-7 could improve the transporting of HRP across the BBB. The third, the liposomes containing AmB (AmB-L-PEG) was prepared by modified Film-sonication method and DSPE-PEG-RMP-7 was used to modify the AmB-L-PEG to obtain AmB-L-PEG-RMP-7. The fourth, tissue distribution of AmB in the rats of three groups was determined: Group I, AmB-L-PEG; Group II, AmB-L-PEG+RMP-7 (the physical mixture of AmB-L-PEG and RMP-7); Group III, AmB-PEG-RMP-7. The drugs were transfused into the rats through the femoral vein. The concentration of AmB in the tissue was checked using High-Performance Liquid Chromatography (HPLC) method. The rank of AmB concentration in the brain were as follows: III>II>I. The AmB concentration in the liver, spleen, lung and kidney had no significant difference. The concentration of AmB in the brain of the group III was raised several times higher than that in the other two groups, because the DSPE-PEG-RMP-7 had been inserted in the surface of AmB-L-PEG. Both the RMP-7 and AmB-L-PEG could reach BBB at the same time. When RMP-7 selectively reacted with the B2 receptor, the BBB is "opened" and AmB was transported into the brain at the same time. While in group II, the RMP-7 could improve the AmB concentration in the brain a little, because the RMP-7 and liposomes could not reach BBB at the same time. The distribution of AmB in the tissues demonstrated that the RMP-7 and its derivative had selectivity to the brain.     

The Study on Brain Targeting of the Amphotericin B Liposomes

To improve transporting drugs across the Blood Brain Barrier (BBB) into the brain, RMP-7 was conjugated to the surface of liposomes containing Amphotericin B (AmB) for cerebral inflammation, because it can selectively bound to the B2 receptors on the capillary blood vessel. First, RMP-7 was conjugated to DSPE-PEG-NHS [1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-n-[poly (ethylenegly-col)]-hydroxy succinamide, PEG M 3400] under mild condition to obtain a predominantly 1:1 conjugate (DSPE-PEG-RMP-7), as evidenced by the Matrix-Assisted Laser Desorption-Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF-MS). The second, endothelium cell was cultured on the cell insert to form an in vitro BBB model and the stereoscan microscope, electric resistance and permeation of horse-radish peroxidase (HRP) across the endothelium cell monolayer were used as indicators to evaluate the integrality of the monolayer, and then the in vitro BBB model was used to determine the bioactivity of DSPE-PEG-RMP-7 "opening" BBB. The results demonstrated the in vitro BBB model was set up, RMP-7 and DSPE-PEG-RMP-7 could improve the transporting of HRP across the BBB. The third, the liposomes containing AmB (AmB-L-PEG) was prepared by modified Film-sonication method and DSPE-PEG-RMP-7 was used to modify the AmB-L-PEG to obtain AmB-L-PEG-RMP-7. The fourth, tissue distribution of AmB in the rats of three groups was determined: Group I, AmB-L-PEG; Group II, AmB-L-PEG+RMP-7 (the physical mixture of AmB-L-PEG and RMP-7); Group III, AmB-PEG-RMP-7. The drugs were transfused into the rats through the femoral vein. The concentration of AmB in the tissue was checked using High-Performance Liquid Chromatography (HPLC) method. The rank of AmB concentration in the brain were as follows: III>II>I. The AmB concentration in the liver, spleen, lung and kidney had no significant difference. The concentration of AmB in the brain of the group III was raised several times higher than that in the other two groups, because the DSPE-PEG-RMP-7 had been inserted in the surface of AmB-L-PEG. Both the RMP-7 and AmB-L-PEG could reach BBB at the same time. When RMP-7 selectively reacted with the B2 receptor, the BBB is "opened" and AmB was transported into the brain at the same time. While in group II, the RMP-7 could improve the AmB concentration in the brain a little, because the RMP-7 and liposomes could not reach BBB at the same time. The distribution of AmB in the tissues demonstrated that the RMP-7 and its derivative had selectivity to the brain.     

The Effect of RMP-7 and its Derivative on Transporting Evens Blue Liposomes into the Brain

To investigate the effect of RMP-7 and its derivative on drug transport across blood brain barrier (BBB), RMP-7 and DSPE-PEG-NHS [1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-n-[poly(ethyleneglycol)]-hydroxy succinamide, PEG M 3400] were conjugated under mild conditions and the reaction ratio was determined using MALDI–TOF-MS (matrix-assisted laser desorption-ionization time-of-flight mass spectrometry). An endothelial cell monolayer in vitro BBB model was established and used to determine the bioactivity of RMP-7 and its derivative “opening BBB.” Horse radish peroxide (HRP), liposome (HRP-L-PEG), and Evens blue (EB) liposome (EB-L-PEG) were prepared using the reverse-phase evaporation method. HRP-L-PEG-RMP-7 and EB-L-PEG-RMP-7 were obtained by inserting DSPE-PEG-RMP-7 into the surface of liposome. The bioactivity of RMP-7 and DSPE-PEG-RMP-7 opening BBB were evaluated to determine their effect on the permeation ratio of HRP and HRP liposome across the in vitro BBB model. To evaluate the in vivo bioactivity of RMP-7 and DSPE-PEG-RMP-7 on EB transport across BBB into the brain, the indicated compounds were administered to rats. Then, brain slices were analyzed using confocal laser scanning microcopy and the EB concentration in the brain, liver, spleen, lung, and kidney was determined using the formamide–extraction–ultraviolet-spectrophotometric method. The results demonstrated that RMP-7 was conjugated with DSPE-PEG-NHS at the molecular ratio of 1:1 and the product is DSPE-PEG-RMP-7. Compared with adding HRP alone, RMP-7 and DSPE-PEG-RMP-7 improved 2- to 3-fold the transport of HRP in the in vitro BBB model. The in vivo experiments showed that DSPE-PEG-RMP-7 was better at facilitating EB transport into brain than RMP-7. The reason may be that DSPE-PEG-RMP-7 can “open BBB” as soon as the EB-L-PEG-RMP-7 reaches BBB.     

The effect of RMP-7 and its derivative on transporting Evans blue liposomes into the brain

To investigate the effect of RMP-7 and its derivative on drug transport across blood brain barrier (BBB), RMP-7 and DSPE-PEG-NHS [1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-n-[poly(ethyleneglycol)]-hydroxy succinamide, PEG M 3400] were conjugated under mild conditions and the reaction ratio was determined using MALDI-TOF-MS (matrix-assisted laser desorption-ionization time-of-flight mass spectrometry). An endothelial cell monolayer in vitro BBB model was established and used to determine the bioactivity of RMP-7 and its derivative “opening BBB.” Horse radish peroxide (HRP), liposome (HRP-L-PEG), and Evens blue (EB) liposome (EB-L-PEG) were prepared using the reverse-phase evaporation method. HRP-L-PEG-RMP-7 and EB-L-PEG-RMP-7 were obtained by inserting DSPE-PEG-RMP-7 into the surface of liposome. The bioactivity of RMP-7 and DSPE-PEG-RMP-7 opening BBB were evaluated to determine their effect on the permeation ratio of HRP and HRP liposome across the in vitro BBB model. To evaluate the in vivo bioactivity of RMP-7 and DSPE-PEG-RMP-7 on EB transport across BBB into the brain, the indicated compounds were administered to rats. Then, brain slices were analyzed using confocal laser scanning microcopy and the EB concentration in the brain, liver, spleen, lung, and kidney was determined using the formamide-extraction-ultraviolet-spectrophotometric method. The results demonstrated that RMP-7 was conjugated with DSPE-PEG-NHS at the molecular ratio of 1:1 and the product is DSPE-PEG-RMP-7. Compared with adding HRP alone, RMP-7 and DSPE-PEG-RMP-7 improved 2- to 3-fold the transport of HRP in the in vitro BBB model. The in vivo experiments showed that DSPE-PEG-RMP-7 was better at facilitating EB transport into brain than RMP-7. The reason may be that DSPE-PEG-RMP-7 can “open BBB” as soon as the EB-L-PEG-RMP-7 reaches BBB.     

神经生长因子脂质体跨血脑屏障体内外研究神经生长因子脂质体跨血脑屏障体内外研究

目的研究神经生长因子（nerve growth factor,NGF）脂质体在体外血脑屏障（blood-brain barrier,BBB）模型上的通透性以及在体内脑组织的分布，并对体内外结果进行相关性分析。方法用小鼠脑微血管内皮细胞(BMVEC)建立的BBB体外实验模型，研究NGF脂质体在体外模型上的通透率；¹²⁵I-NGF和SDS-PAGE法联合使用研究NGF脂质体在脑组织的分布。结果NGF脂质体的最高包封率为34%，平均粒径小于100 nm。脂质体能够增加NGF在BBB模型上的通透率，以NGF-SSL-T为最大。脑组织药物浓度次序为NGF-SSL-T>NGF-SSL+RMP-7>NGF-SSL。体内外结果具有良好相关性。结论脂质体能够增加NGF跨越BBB的能力，RMP-7偶联在脂质体上（NGF-SSL-T）效果好于RMP-7与脂质体的简单混合（NGF-SSL+RMP-7）。     

Cerebral open flow microperfusion: A new in vivo technique for continuous measurement of substance transport across the intact blood–brain barrier

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Catalase and alpha-tocopherol attenuate blood-brain barrier breakdown in pentylenetetrazole-induced epileptic seizures in acute hyperglycaemic rats.

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