Intracerebral administration of ultrasound-induced dissolution of lipid-coated GDNF microbubbles provides neuroprotection in a rat model of Parkinson's disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disease characterized by loss of dopaminergic neurons in the substantia nigra. Neurotrophic factors, such as glial cell derived neurotrophic factor (GDNF), have been shown to provide a neuroprotective effect in PD rats. We have previously reported that ultrasound-induced lipid-coated GDNF microspheres, which release GDNF in a sustained manner after low frequency ultrasound stimulation, can reduce hypoxic-ischemic injury in neonatal rats. In the present study, we investigated whether lipid-coated GDNF microspheres can provide a neuroprotective effect in a rat model of PD. After a rat model of PD was produced by 6-hydroxydompamine (6-OHDA) injections, lipid-coated GDNF microspheres (1.5mg/kg) were injected into the striatum of PD rats. We found that GDNF levels were increased in the striatum of PD rats after lipid-coated GDNF microspheres administration following low frequency ultrasound stimulation (20kHz, 5min per day, daily for 4 weeks). Moreover, GDNF microspheres reduced apomorphine-induced rotations, and increased striatal dopamine and nigral tyrosine hydroxylase (TH) levels in PD rats. Additionally, GDNF microspheres reduced caspase-3, tumor necrosis factor-alpha, matrix metalloproteinase 9 (MMP-9) and OX-6 levels induced by 6-OHDA injections in PD rats. These data indicated that lipid-coated GDNF microspheres can provide a neuroprotective effect in PD rats.

Keywords: Caspase-3; GDNF-containing microbubbles; MMP-9; OX-6; Parkinson's disease; Tumor necrosis factor-alpha.