title: Activation of signaling pathways following localized delivery of systemically administered neurotrophic factors across the blood-brain barrier using focused ultrasound and microbubbles.
abstract: The brain-derived neurotrophic factor (BDNF) has been shown to have broad neuroprotective effects in addition to its therapeutic role in neurodegenerative disease. In this study, the efficacy of delivering exogenous BDNF to the left hippocampus is demonstrated in wild-type mice (n = 7) through the noninvasively disrupted blood-brain barrier (BBB) using focused ultrasound (FUS). The BDNF bioactivity was found to be preserved following delivery as assessed quantitatively by immunohistochemical detection of the pTrkB receptor and activated pAkt, pMAPK, and pCREB in the hippocampal neurons. It was therefore shown for the first time that systemically administered neurotrophic factors can cross the noninvasively disrupted BBB and trigger neuronal downstream signaling effects in a highly localized region in the brain. This is the first time that the administered molecule is tracked through the BBB and localized in the neuron triggering molecular effects. Additional preliminary findings are shown in wild-type mice with two additional neurotrophic factors such as the glia-derived neurotrophic factor (n = 12) and neurturin (n = 2). This further demonstrates the impact of FUS for the early treatment of CNS diseases at the cellular and molecular level and strengthens its premise for FUS-assisted drug delivery and efficacy.
authors.affiliation: Department of Biomedical Engineering, Columbia University, New York, NY, USA.
authors.forename: Babak
authors.initials: B
authors.lastname: Baseri
authors.forename: James J
authors.initials: JJ
authors.lastname: Choi
authors.forename: Thomas
authors.initials: T
authors.lastname: Deffieux
authors.forename: Gesthimani
authors.initials: G
authors.lastname: Samiotaki
authors.forename: Yao-Sheng
authors.initials: YS
authors.lastname: Tung
authors.forename: Oluyemi
authors.initials: O
authors.lastname: Olumolade
authors.forename: Scott A
authors.initials: SA
authors.lastname: Small
authors.forename: Barclay
authors.initials: B
authors.lastname: Morrison
authors.forename: Elisa E
authors.initials: EE
authors.lastname: Konofagou
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods*; D005240:Feasibility Studies; D006624:Hippocampus / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D045423:Microbubbles; D009414:Nerve Growth Factors / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D014465:Ultrasonics / Q000379:methods*
chemical_list: D009414:Nerve Growth Factors