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

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.