title: Enhanced delivery and bioactivity of the neurturin neurotrophic factor through focused ultrasound-mediated blood--brain barrier opening in vivo.
abstract: The blood-brain barrier (BBB) constitutes a major obstacle in brain drug delivery. Focused ultrasound (FUS) in conjunction with microbubbles has been shown to open the BBB noninvasively, locally, and transiently to allow large molecules diffusion. Neurturin (NTN), a member of the glial-derived neurotrophic factor (GDNF) family, has been demonstrated to have neuroprotective and regenerative effects on dopaminergic neurons in vivo using invasive drug delivery methods. The brain's ascending nigrostriatal pathway is severely damaged in Parkinson's disease (PD), and therefore the substantia nigra (SN) and striatal caudoputamen (CP) were selected as the target areas. The objective of the study was to investigate whether safe and efficient NTN delivery can be achieved through FUS-induced BBB opening via intravenous administration, and thus trigger the neuroregeneration cascade in the nigrostriatal pathway. After the optimization of FUS parameters and target locations in the murine brain, NTN bioavailability and downstream signaling were detected and characterized through immunostaining. FUS significantly enhanced the delivery of NTN compared with the direct injection technique, whereas triggering of the signaling cascade was detected downstream to the neuronal nuclei. These findings thus indicate the potential of the FUS method to mediate transport of proteins through the blood-brain barrier in a PD animal model.
authors.affiliation: Department of Biomedical Engineering, Columbia University, New York, New York, USA.
authors.forename: Gesthimani
authors.initials: G
authors.lastname: Samiotaki
authors.affiliation: Department of Biomedical Engineering, Columbia University, New York, New York, USA.
authors.forename: Camilo
authors.initials: C
authors.lastname: Acosta
authors.affiliation: Department of Radiology, Columbia University, New York, New York, USA.
authors.forename: Shutao
authors.initials: S
authors.lastname: Wang
authors.affiliation: 1] Department of Biomedical Engineering, Columbia University, New York, New York, USA [2] Department of Radiology, Columbia University, New York, New York, USA.
authors.forename: Elisa E
authors.initials: EE
authors.lastname: Konofagou
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D016503:Drug Delivery Systems / Q000295:instrumentation*; D004867:Equipment Design; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D051101:Neurturin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013010:Sonication / Q000295:instrumentation*
chemical_list: D018696:Neuroprotective Agents; D051101:Neurturin