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Download Neurorestoration of the nigrostriatal pathway through multiple
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Neurorestoration of the nigrostriatal pathway through multiple treatments with FUS-facilitated brain drug delivery Elisa E. Konofagou1,2 ¹Department of Biomedical Engineering, Columbia University, New York, NY ²Department of Radiology, Columbia University, New York, NY [email protected] Current treatments of neurological and neurodegenerative diseases are limited due to the lack of a truly noninvasive, transient, and regionally selective brain drug delivery method. The brain is particularly difficult to deliver drugs to because of the blood-brain barrier (BBB). The impermeability of the BBB is due to the tight junctions connecting adjacent endothelial cells and highly regulatory transport systems of the endothelial cell membranes. The main function of the BBB is ion and volume regulation to ensure conditions necessary for proper synaptic and axonal signaling. However, the same permeability properties that keep the brain healthy also constitute the cause of the tremendous obstacles posed in its pharmacological treatment. The BBB prevents most neurologically active drugs from entering the brain and, as a result, has been isolated as the rate-limiting factor in brain drug delivery. Until a solution to the trans-BBB delivery problem is found, treatments of neurological diseases will remain impeded. In this presentation, neuroprotection and neurorestoration of the dopaminergic pathway will be shown in a Parkinsonian mouse model. We have found that FUS-induced BBB opening allows the delivery of neurotrophic factors and adeno-associated viruses that express those factors as well as protection (before the MPTP toxin is administered) and restoration (after the toxin is administered) of the dopaminergic neurons. Gene delivery induced neuroprotection in the dopaminergic pathway. In protein delivery, comparable findings in dendritic density in the substantia nigra region of the mouse brain was found between a single and a triple delivery regimen. However, in the caudate putamen region, the triple regimen was found to significantly increase the terminal density which indicated restoration of the neuronal processes through collateral sprouting. This finding is in accordance with prior reports on neurotrophic proteins restoring impaired neurons. These findings indicate the therapeutic effect that FUS could induce in dopaminergic neurons through the enhanced drug delivery dose. Keywords- blood-brain barrier, drug delivery, focused ultrasound, mechanism,microbubble Neuronal GFP expression using gene delivery through the blood-brain barrier
