Focused Ultrasound Enhanced Intranasal Delivery of Neurotrophic Factors Exhibit Neurorestorative Effects in Parkinson's Disease Mouse Model

Abstract

Focused ultrasound enhanced intranasal (IN+FUS) delivery is a unique, noninvasive approach that utilizes the olfactory pathway to administer drugs directly to the brain. Our group has shown that IN+FUS delivery of model drugs provide a more homogenous distribution of delivery when compared to IN delivery alone, and similar delivery efficiency to intravenous delivery after FUS induced BBB opening. The aim of this study was to investigate the delivery efficacy and therapeutic effects that IN+FUS administered brain-derived neurotrophic factor (BDNF) has on an early-stage Parkinsonian mouse model in order to provide an alternate and more direct administration route to the brain. Wild-type mice were given a sub-acute dose of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxin daily for 5 days, causing bilateral degeneration of the nigrostriatal dopaminergic pathway. After a stabilizing period, the mice were split into a treated group and a control group (N=7 /group). The treated group was dosed with IN+FUS of BDNF weekly for 3 weeks. Each week, 0.4 mg of BDNF was intranasally delivered followed by BBB opening in the left substantia nigra (SN) and caudate putamen (CP) using FUS and sized isolated microbubbles. The mice were then survived for 2 months to allow for any neurorestorative effects to occur. Behavioral testing through amphetamine-induced rotations was then conducted. Staining of tyrosine hydroxylase positive (TH+) neurons in the SN and terminals in the CP were used to assess the nigrostriatal dopaminergic pathway integrity. TH+ staining in the SN and CP indicated moderate neuronal survival in the ipsilateral side in treated mice while staining in untreated mice was similar bilaterally. Significant ipsilateral rotation in treated mice corroborated the immunohistochemistry findings, further validating improved ipsilateral nigrostriatal dopaminergic pathway. These findings indicate a modest neurorestorative effect of IN+FUS BDNF on MPTP mice, demonstrating the potential of an alternative and efficient drug delivery route for brain treatment with FUS. Additional immunohistochemistry assays and quantification in the SN and CP are ongoing to confirm these initial findings.