FOCUSED ULTRASOUND USING NEUROTROPHIC FACTORS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASE

Abstract

Focused Ultrasound (FUS) in conjunction with microbubbles has been shown to induce a safe, transient and localized opening of the blood-brain barrier (BBB). In this study, neurotrophic delivery through the opened BBB was studied in mice undergoing neurodegeneration. Wild-type mice received a sub-acute MPTP regimen, and the lesions were allowed to stabilize for 4 weeks. Mice then received sonication (FUS+) or not (FUS-), and NTN (NTN+) or saline (NTN-) IV injection, they were divided into 3 groups (FUS+/NTN+, FUS+/NTN-, FUS-/NTN-), and they were allowed to survive for 4 weeks. The caudate and the putamen were targeted using FUS (center frequency: 1.5 MHz, PRF: 10 Hz, acoustic pressure: 0.45 MPa; pulse length: 10,000 cycles;sonication duration: 60 s) immediately after the IV administration of monodisperse bubbles (diameter: 4-5 μm, 2.5*108#/kg). The mice were survived for 28 days before sacrifice for TH staining. Immunohistochemistry revealed statistically significant (p<.05) neurorestoration of the dopaminergic neurons only in the (FUS+/NTN+) group and only in the ipsilateral (FUS+) substantia nigra and caudate putamen. Since the MPTP lesions and the DA neuronal apoptosis preceded NTN delivery by 4 weeks, neuroregeneration was concluded for this group. Neurorestoration was shown to be feasible using neurotrophic factors through the induced BBB opening using focused ultrasound in a neurodegenerative mouse model.