Neuroprotection and neurorestoration through the opened blood-brain barrier using focused ultrasound and microbubbles

Abstract

After cancer and heart disease, neurodegenerative diseases, such as Alzheimer's, Parkinson's, multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS), take more lives each year than any other illness. Although some effective treatments are available, most of those diseases remain undertreated. The blood-brain barrier (BBB) has been proclaimed as the “bottleneck“ of brain drug delivery. Focused ultrasound (FUS) in conjunction with microbubbles is currently the only technique that can open the BBB locally, transiently, and noninvasively. Our group has demonstrated that pharmacological compounds of variable sizes can not only traverse the BBB but also induce therapeutic effects in the presence of neurodegenerative disease. In this paper, the trans-BBB neurotherapeutic delivery with FUS is shown to (1) be safely facilitated within a specific pressure range in both mice and non-human primates through the mechanism of cavitation, (2) be controlled through the pressure amplitude and microbubble characteristics, (3) induce downstream signaling effects in the neuronal cell, (4) trigger neuroprotection and neurorestoration relevant in the treatment of neurodegeneration, (5) be localized and monitored in real time through cavitation monitoring and mapping. BBB opening is combined with systemic administration of neurotrophic molecules or adeno-associated viruses that allow for neuronal protection and growth in the BBB-opened regions.