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.