Abstract

The activation of caspase-3 is an important hallmark in Parkinson’s disease. It could induce neuron death by apoptosis and microglia activation by inflammation. As a result, inhibition the activation of caspase-3 would exert synergistic dual effect in brain in order to prevent the progress of Parkinson’s disease. Silencing caspase-3 genes by RNA interference could inhibit the activation of caspase-3. We developed a brain-targeted gene delivery system based on non-viral gene vector, dendrigraft poly-L-lysines. A rabies virus glycoprotein peptide with 29 amino-acid linked to dendrigraft poly-L-lysines could render gene vectors the ability to get across the blood brain barrier by specific receptor mediated transcytosis. The resultant brain-targeted vector was complexed with caspase-3 short hairpin RNA coding plasmid DNA, yielding nanoparticles. In vivo imaging analysis indicated the targeted nanoparticles could accumulate in brain more efficiently than non-targeted ones. A multiple dosing regimen by weekly intravenous administration of the nanoparticles could reduce activated casapse-3 levels, significantly improve locomotor activity and rescue dopaminergic neuronal loss and in Parkinson’s disease rats’ brain. These results indicated the rabies virus glycoprotein peptide modified brain-targeted nanoparticles were promising gene delivery system for RNA interference to achieve anti-apoptotic and anti-inflammation synergistic therapeutic effects by down-regulation the expression and activation of caspase-3.

Highlights

  • Parkinson’s disease (PD) is classically characterized as loss of striatal dopaminergic neurons [1]

  • The plasmid DNA grown in E. coli was isolated with the EndoFree Plasmid Mega Kit (Qiagen GmbH, Germany)

  • The accumulation in liver increased at 1 h after administration

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Summary

Introduction

Parkinson’s disease (PD) is classically characterized as loss of striatal dopaminergic neurons [1]. The most straightforward way is to increase dopamine levels by dopamine replacement therapy or introduce key enzymes involved in dopamine metabolism [3,4]. Neurotropic factors are used to prevent the death of dopaminergic neurons [5]. Epidemiological studies suggest that environmental toxins exposure is closely associated with an increased risk of developing PD [6]. Neurotoxins such as rotenone could induce neurotoxicity via the activation of caspase-3 in both in vitro and in vivo experiments [7,8]

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