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.
Highlights
Parkinson’s disease (PD) is a common neurodegenerative disease, which is characterized by the loss of dopaminergic (DA) neurons in the substantia nigra (SN) (Proft et al, 2011)
The lipid film was hydrated for 8 h using 2.4 ml sterile phosphate-buffered solution (PBS) containing pDC315-GDNF plasmid (5 μg) which was constructed by inserting GDNF cDNA of rat into pDC315 vector (Microbix Biosystems Inc., Toronto, Canada)
GDNF and Nurr1 immunostaining was observed in the PLsGDNF-MBs group compared to the PLs-MBs group (Figure 4C). These results suggest that Ultrasound-triggered PLs-GDNF-MBs promote both GDNF and Nurr1 expression in the protection against DA neuron loss
Summary
Parkinson’s disease (PD) is a common neurodegenerative disease, which is characterized by the loss of dopaminergic (DA) neurons in the substantia nigra (SN) (Proft et al, 2011). Ultrasound-Triggered Effects of the GDNF-PLs-GDNF-MBs in Parkinson’s Disease. Glial cell line-derived neurotrophic factor (GDNF) is considered as an essential neuroprotective ligand for midbrain DA neurons (Nitta et al, 2004). It is expressed throughout the central nervous system (CNS) during development (Nosrat et al, 1996). Many studies on animal models of PD have reported beneficial effects of GDNF on DA neuron survival (Patel et al, 2013; Quintino et al, 2013). 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)
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