title: The effect of cationic albumin-conjugated PEGylated tanshinone IIA nanoparticles on neuronal signal pathways and neuroprotection in cerebral ischemia.
abstract: 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-TIIA-NPs effectively reduced infarction volume, neurological dysfunctions, neutrophils infiltration and neuronal apoptosis. Moreover, CBSA-PEG-TIIA-NPs significantly suppressed the expression of pro-inflammatory cytokines TNF-α and IL-8; upregulated the expression of anti-inflammatory cytokines IL-10 and increase TGF-β1 level in the ischemic brain. In addition, treatment with CBSA-PEG-TIIA-NPs markedly inhibited the mRNA expressions of GFAP, MMP-9, COX-2, p38MAPK, ERK1/2 and JNK, downregulated 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.
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, 310058 Hangzhou, China. xinliu98@126.com
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Ming
authors.initials: M
authors.lastname: Ye
authors.forename: Chiying
authors.initials: C
authors.lastname: An
authors.forename: Liqiang
authors.initials: L
authors.lastname: Pan
authors.forename: Litong
authors.initials: L
authors.lastname: Ji
mesh_terms: D045784:Abietanes / Q000737:chemistry*; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy*; D002417:Cattle; D008297:Male; D053758:Nanoparticles / Q000737:chemistry* / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012710:Serum Albumin, Bovine / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D045784:Abietanes; D018696:Neuroprotective Agents; C021751:tanshinone; D012710:Serum Albumin, Bovine; D011092:Polyethylene Glycols