Ultrasound-targeted microbubble destruction (UTMD) in conjunction with neurotrophic factors (NFs) gene delivery has the potential to facilitate the penetration of therapeutic genes into the brain for neuroprotective therapy against neurodegenerative diseases. We previously presented a gene delivery system that conjugates gene-carrying liposomes with microbubbles (MBs) to open the blood-brain barrier (BBB) for the delivery of genes into the brain. Since both glia cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) can protect dopaminergic neurons from neurotoxicity demonstrated in Parkinson's disease (PD) animal models, the present study seeks (1) to develop a novel gene-nanocarrier MB complex carrying BDNF or GDNF gene and (2) to protect dopaminergic neurons in a mouse model of PD via the proposed UTMD system. In the experimental design, PD animals received treatment that delivered GDNF, BDNF, or combined GDNF/BDNF in conjunction with UTMD treatment, and pathological changes in dopamine neurons were histologically examined. Rotarod assay was employed to evaluate the motor behavior. Our results demonstrate that either BDNF or GDNF gene delivery via the UTMD system provides a neuroprotective effect with evidence of improvements of behavioral deficits, decreased calcium influx, GFAP and caspase 3 expression, and rescued dopaminergic neuronal loss. Simultaneously performing GDNF/BDNF gene delivery did not show additional benefits beyond individually delivering BDNF or GDNF genes, possibly due to a hampering effect of simultaneous GDNF/BDNF competing expressions, thus dampening the overall therapeutic effect. In conclusion, these results suggest that UTMD in conjunction with delivery of GDNF or BDNF gene can synergistically serve as an effective gene therapy strategy for neurodegenerative diseases.
Keywords: BDNF; Blood-brain barrier opening; GDNF; Gene therapy; Ultrasound (US)-targeted microbubble destruction (UTMD).
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