Focused Ultrasound Promotes the Delivery of Gastrodin and Enhances the Protective Effect on Dopaminergic Neurons in a Mouse Model of Parkinson's Disease.
Authors: Wang Y, Luo K, Li J, Liao Y, Liao C, Chen WS, Chen M, Ao L
Parkinson's disease (PD) is the second most common chronic neurodegenerative disease globally; however, it lacks effective treatment at present. Focused ultrasound (FUS) combined with microbubbles could increase the efficacy of drug delivery to specific brain regions and is becoming a promising technology for the treatment of central nervous system diseases. In this study, we explored the therapeutic potential of FUS-mediated blood-brain barrier (BBB) opening of the left striatum to deliver gastrodin (GAS) in a subacute PD mouse model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The concentration of GAS in the left hemisphere was detected by ultra-high performance liquid chromatography electrospray Q-Orbitrap mass spectrometry (UHPLC/ESI Q-Orbitrap) and the distribution of tyrosine hydroxylase (TH) neurons was detected by immunohistochemical staining. The expression of TH, Dopamine transporter (DAT), cleaved-caspase-3, B-cell lymphoma 2 (Bcl-2), brain-derived neurotrophic factor (BDNF), postsynaptic density protein 95 (PSD-95), and synaptophysin (SYN) protein were detected by western blotting. Analysis showed that the concentration of GAS in the left hemisphere of PD mice increased by approximately 1.8-fold after the BBB was opened. FUS-mediated GAS delivery provided optimal neuroprotective effects and was superior to the GAS or FUS control group. In addition, FUS enhanced GAS delivery significantly increased the expression of Bcl-2, BDNF, PSD-95, and SYN protein in the left striatum (<i>P</i> < 0.05) and reduced the levels of cleaved-caspase-3 remarkably (<i>P</i> = 0.001). In conclusion, the enhanced delivery by FUS effectively strengthened the protective effect of GAS on dopaminergic neurons which may be related to the reinforcement of the anti-apoptotic activity and the expression of synaptic-related proteins in the striatum. Data suggests that FUS-enhanced GAS delivery may represent a new strategy for PD treatment.
Introduction
Purpose
Drug delivery with BBB opening
Study Objective
To determine whether focused ultrasound–mediated opening of the blood–brain barrier in the striatum enhances delivery of gastrodin and improves neuroprotective effects in an MPTP-induced Parkinson’s disease mouse model.
Animal model / Human subject
Mouse (Mus musculus); strain: not specified; age: not specified; sex: not specified
Disease model
Parkinson's disease (MPTP-induced subacute mouse model)
Targeted brain region(s)
Striatum
Cargo name and characteristics
Gastrodin (GAS), small molecule (plant-derived phenolic glycoside) neuroprotective agent
Outcomes and Safety
Summary of Outcomes
FUS-mediated BBB opening (optimal parameter: 150 mV with microbubbles, repeated every 3 days for six sessions) increased gastrodin uptake ~1.8-fold and enhanced neuroprotection in MPTP PD mice — preserving TH+ dopaminergic neurons and DAT, increasing Bcl-2, BDNF, PSD-95 and synaptophysin, and reducing cleaved-caspase-3; 100 mV produced only superficial (cortical) BBB opening and 200 mV caused erythrocyte exudation/hemorrhage.
Safety-related matter
FUS at 200 mV produced obvious erythrocyte exudation/bleeding, so 150 mV was chosen as optimal; with six repeated BBB openings at this setting there was no hemorrhage or histological abnormality, Nissl staining was normal, and there was no significant change in body weight, indicating the repeated procedure was safe and feasible.
Brain Region
Ultrasound Parameters
Focal Characteristics
focal depth: None; focal length: None; aperture size: None
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