The effect of cationic albumin-conjugated PEGylated tanshinone IIA nanoparticles on neuronal signal pathways and neuroprotection in cerebral ischemia

被引：100
作者：
Liu, Xin [1 ]
Ye, Ming [2 ]
An, Chiying [3 ]
Pan, Liqiang [1 ]
Ji, Litong [4 ]
机构：
[1] Zhejiang Univ, Coll Pharmaceut Sci, Hangzhou 310058, Zhejiang, Peoples R China
[2] Harbin Med Univ, Affiliated Hosp 2, Harbin 150086, Peoples R China
[3] Harbin Med Univ, Affiliated Hosp 1, Harbin 150001, Peoples R China
[4] Harbin Med Univ, Affiliated Hosp 4, Harbin 150001, Peoples R China
来源：
BIOMATERIALS | 2013年 / 34卷 / 28期
基金：
中国国家自然科学基金;
关键词：
Tanshinone IIA; Cationic bovine serum albumin-conjugated; PEGylated nanoparticles; Cerebral ischemia; Neuroprotection; MAPK signal pathways; ACTIVATED PROTEIN-KINASES; DRUG CARRIER; BRAIN-INJURY; EXPRESSION; INFLAMMATION; INHIBITION; STROKE; P38; APOPTOSIS; ERK;
D O I：
10.1016/j.biomaterials.2013.05.021
中图分类号：
R318 [生物医学工程];
学科分类号：
0831 ;
摘要：
Targeted treatment of ischemic stroke remains problem due to the complex pathogenesis of this disease and the difficulty in drug delivery across the blood brain barrier (BBB). In the present study, the delivery efficiency of cationic bovine serum albumin-conjugated tanshinone IIA PEGylated nanoparticles (CBSA-PEG-TIIA-NPs) in rat brain was investigated. We further explored whether the protective mechanism of CBSA-PEG-TIIA-NPs in cerebral ischemia was associated with modulating neuronal signaling pathways. The experimental cerebral ischemia model was established to evaluate the treatment efficacy of CBSA-PEG-TIIA-NPs. The pharmacokinetics demonstrated that CBSA-PEG-TIIA-NPs could obviously prolong circulation time and increase plasma concentration compared with intravenously administrated TIIA solution. The biodistribution and brain uptake study confirmed that CBSA-PEG-TIIA-NPs possessed better brain delivery efficacy with a high drug accumulation and fluorescence quantitative level in brain. CBSA-PEG-THA-NPs effectively reduced infarction volume, neurological dysfunctions, neutrophils infiltration and neuronal apoptosis. Moreover, CBSA-PEG-THA-NPs significantly suppressed the expression of pro-inflammatory cytokines TNF-alpha and IL-8; upregulated the expression of anti-inflammatory cytokines IL-10 and increase TGF-beta 1 level in the ischemic brain. In addition, treatment with CBSA-PEG-THA-NPs markedly inhibited the mRNA expressions of GFAP, MMP-9, COX-2, p38MAPK, ERK1/2 and JNK, down-regulated the protein levels of GFAP, MMP-9 and COX-2, as well as decreased the phosphorylation of ERK1/2, p38MAPK and JNK. These results demonstrated that CBSA-PEG-TIIA-NPs displayed remarkable neuroprotective effects on ischemic stroke through modulation of MAPK signal pathways involved in the cascades of neuroinflammation. Crown Copyright (C) 2013 Published by Elsevier Ltd. All rights reserved.
引用
收藏
页码：6893 / 6905
页数：13
相关论文
共 58 条
[1]   Cytokines and acute neurodegeneration [J].
Allan, SM ;
Rothwell, NJ .
NATURE REVIEWS NEUROSCIENCE, 2001, 2 (10) :734-744
[2]   STEALTH ME.PEG-PLA NANOPARTICLES AVOID UPTAKE BY THE MONONUCLEAR PHAGOCYTES SYSTEM [J].
BAZILE, D ;
PRUDHOMME, C ;
BASSOULLET, MT ;
MARLARD, M ;
SPENLEHAUER, G ;
VEILLARD, M .
JOURNAL OF PHARMACEUTICAL SCIENCES, 1995, 84 (04) :493-498
[3]   Protective effects of indomethacin-loaded nanocapsules against oxygen-glucose deprivation in organotypic hippocampal slice cultures: Involvement of neuroinflammation [J].
Bernardi, Andressa ;
Frozza, Rudimar L. ;
Horn, Ana Paula ;
Campos, Maria Martha ;
Calixto, Joao B. ;
Salbego, Christianne ;
Pohlmann, Adriana R. ;
Guterres, Silvia S. ;
Battastini, Ana Maria O. .
NEUROCHEMISTRY INTERNATIONAL, 2010, 57 (06) :629-636
[4]  
Bhuiyan Mohammad Iqbal Hossain, 2010, Int Neurourol J, V14, P203, DOI 10.5213/inj.2010.14.4.203
[5]  
Borsello T, 2007, CURR PHARM DESIGN, V13, P1875
[6]   Tracking the inflammatory response in stroke in vivo by sensing the enzyme myeloperoxidase [J].
Breckwoldt, Michael O. ;
Chen, John W. ;
Stangenberg, Lars ;
Aikawa, Elena ;
Rodriguez, Elisenda ;
Qiu, Shumei ;
Moskowitz, Michael A. ;
Weissleder, Ralph .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (47) :18584-18589
[7]   Long-circulating PEGylated polycyanoacrylate nanoparticles as new drug carrier for brain delivery [J].
Calvo, P ;
Gouritin, B ;
Chacun, H ;
Desmaële, D ;
D'Angelo, J ;
Noel, JP ;
Georgin, D ;
Fattal, E ;
Andreux, JP ;
Couvreur, P .
PHARMACEUTICAL RESEARCH, 2001, 18 (08) :1157-1166
[8]   Neuroprotective effect of osthole against acute ischemic stroke on middle cerebral ischemia occlusion in rats [J].
Chao, Xiaodong ;
Zhou, Jun ;
Chen, Tao ;
Liu, Wenbo ;
Dong, Wenpeng ;
Qu, Yan ;
Jiang, Xiaofan ;
Ji, Xituan ;
Zhen, Haining ;
Fei, Zhou .
BRAIN RESEARCH, 2010, 1363 :206-211
[9]   GluR6-Containing KA Receptor Mediates the Activation of p38 MAP Kinase in Rat Hippocampal CA1 Region During Brain Ischemia Injury [J].
Chen, Juan ;
Li, Chong ;
Pei, Dong-Sheng ;
Han, Dong ;
Liu, Xiao-Mei ;
Jiang, Hai-Xia ;
Wang, Xiao-Tian ;
Guan, Qiu-Hua ;
Wen, Xiang-Ru ;
Hou, Xiao-Yu ;
Zhang, Guang-Yi .
HIPPOCAMPUS, 2009, 19 (01) :79-89
[10]   Role of P-glycoprotein in restricting the brain penetration of tanshinone IIA, a major active constituent from the root of Salvia miltiorrhiza Bunge, across the blood-brain barrier [J].
Chen, X. ;
Zhou, Z.-W. ;
Xue, C. C. ;
Li, X. X. ;
Zhou, S.-F. .
XENOBIOTICA, 2007, 37 (06) :635-678
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