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. 2018 Apr 6:12:222.
doi: 10.3389/fnins.2018.00222. eCollection 2018.

Ultrasound-Triggered Effects of the Microbubbles Coupled to GDNF Plasmid-Loaded PEGylated Liposomes in a Rat Model of Parkinson's Disease

Peijian Yue  1 , Wang Miao  2 , Lin Gao  2 , Xinyu Zhao  1 , Junfang Teng  1
Affiliations

Ultrasound-Triggered Effects of the Microbubbles Coupled to GDNF Plasmid-Loaded PEGylated Liposomes in a Rat Model of Parkinson's Disease

Peijian Yue et al. Front Neurosci. .

Abstract

Background: The purpose of this study was to investigate ultrasound-triggered effects of PEGylated liposomes-coupled microbubbles mediated gene transfer of glial cell line-derived neurotrophic factor (GDNF) plasmid (PLs-GDNF-MBs) on behavioral deficits and neuron loss in a rat model of Parkinson's disease (PD). Methods: The unloaded PLs-MBs were characterized for particle size, concentration and zeta potential. PD rat model was established by a unilateral 6-hydroxydopamine (6-OHDA) lesion. Rotational, climbing pole, and suspension tests were used to evaluate behavioral deficits. The immunohistochemical staining of tyrosine hydroxylase (TH) and dopamine transporter (DAT) was used to assess the neuron loss. The expression levels of GDNF and nuclear receptor-related factor 1 (Nurr1) were determined by western blot and qRT-PCR analysis. Results: The particle size of PLs-MBs was gradually increased, while the concentration and absolute zeta potential were gradually decreased in a time-dependent manner after injection. 6-OHDA elevated amphetamine-induced rotations and decreased the TH and DAT immunoreactivity compared to sham group. However, these effects were blocked by the PLs-GDNF-MBs. In addition, the mRNA and protein expression levels of GDNF and Nurr1 were increased after PLs-GDNF-MBs treatment. Conclusions: The delivery of PLs-GDNF-MBs into the brains using MRI-guided focused ultrasound alleviates the behavioral deficits and neuron loss in the rat model of PD.

Keywords: GDNF; PEGylated liposomes; Parkinson's disease; microbubbles; ultrasound.

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Figures

Figure 1
Figure 1
Characterization of unloaded PLs-MBs. (A) Size, (B) Concentration, and (C) zeta potential of unloaded PLs-MBs for different duration. *P < 0.05 vs. 0 h group.
Figure 2
Figure 2
The behavioral deficits and neuron loss in rats after unilateral injections of 6-OHDA into their SN. (A) The asymmetric rotational behavior induced by amphetamine after 6-OHDA injection for 1, 2, and 3 weeks. (B) Representative immunostainings of TH protein in the SN after 6-OHDA injection for 3 weeks. Scale bars = 50 μm. (C) Representative immunostainings of DAT protein in the SN after 6-OHDA injection for 3 weeks. Scale bars = 50 μm. ***P < 0.001 vs. Sham group.
Figure 3
Figure 3
Effects of PLs-GDNF-MBs on the behavioral changes and neuron loss in PD rats. (A) The asymmetric rotational behavior induced by amphetamine before and after PLs-GDNF-MBs injection for 1, 2, and 3 weeks. (B) Scores of suspension test and (C) climbing pole test before and after PLs-GDNF-MBs injection for 1, 2, and 3 weeks. (D) Representative immunostainings of TH protein in the SN of PD rats after PLs-GDNF-MBs injection for 3 weeks. Scale bars = 50 μm. (E) Representative immunostainings of DAT protein in the SN of PD rats after PLs-GDNF-MBs injection for 3 weeks. Scale bars = 50 μm. *P < 0.05 vs. PLs-MBs group, **P < 0.01 vs. PLs-MBs group.
Figure 4
Figure 4
Effects of PLs-GDNF-MBs on the mRNA and protein expression levels of GDNF and Nurr1 in PD rats. (A) QPCR analysis of GDNF and Nurr1 mRNA levels in the brain tissues of PD rats after PLs-GDNF-MBs injection for 3 weeks. (B) Western blot analysis of GDNF and Nurr1 protein levels in the brain tissues of PD rats after PLs-GDNF-MBs injection for 3 weeks. (C) Representative immunostainings of GDNF and Nurr1 proteins in the SN of PD rats after PLs-GDNF-MBs injection for 3 weeks. Scale bars = 20 μm.
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