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. 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 blood-brain barrier (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 (GDNF) (n=12) and neurturin (NTN) (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.

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

“…For this study, the pFUS+MB parameters were chosen to cause BBBD and cerebral vasculature vasospasm without causing parenchymal damage or microhemorrhages (31,34). We demonstrate that pFUS+MB initiated a cascade of molecular profile and cellular changes consistent with the induction of a sterile inflammation in the targeted brain.…”

“…Pulsed FUS+MB has been reported to increase the expression of pAkt along with the downstream signaling molecule pGSK3β at 1.5 h and 24 h, but there are conflicting reports as to whether there are changes in MAPK following sonication of the brain (34,77). In the current study, transient significant elevations (P < 0.05) in pAkt (at 6 h) and pGSK3β (at 5 and 30 min) were detected following pFUS+MB; these elevations declined to baseline levels by 12 h. However, there was no increase in p38-MAPK.…”

The Size of Blood–Brain Barrier Opening Induced by Focused Ultrasound is Dictated by the Acoustic Pressure

“…1 Unfortunately, the majority of the therapeutic agents are larger than the size limit, and thus cannot cross the BBB. Focused ultrasound (FUS) in combination with microbubbles (MBs) is an emerging technique that has been successfully used in trans-BBB delivery of therapeutic agents of various sizes, such as chemotherapeutic drugs (MW B500 Da), 2 neurotrophins (MWB20 kDa), 3 antibodies (MW B150 kDa), 4 and gene vectors (MW B4 MDa). 5 Although neurosurgical, pharmacologic, or physiologic strategies have been developed to circumvent the BBB for brain drug delivery, 1 transcranial FUS in combination with MBs is the only known technique that can induce localized and reversible BBB opening.…”

Ultrasound-Based Therapies for the Treatment of Cancer

“…However, like most large molecules, neurotrophic factors do not cross the BBB. BDNF, which shows promise as a neuroprotective agent 133 , maintains its bioactivity after FUSmediated delivery across the BBB and generates significant downstream signaling activity 134 . Neurturin (NTN), another factor that has been identified as a potential therapy for neurodegenerative diseases 133 , has also been delivered successfully 134 .…”