Acute Inflammatory Response Following Increased Blood-Brain Barrier Permeability Induced by Focused Ultrasound is Dependent on Microbubble Dose

Abstract

Rationale: Focused ultrasound (FUS), in conjunction with circulating microbubbles (MBs), can be used to transiently increase the permeability of the blood-brain barrier (BBB) in a targeted manner, allowing therapeutic agents to enter the brain from systemic circulation. While promising preclinical work has paved the way for the initiation of 3 human trials, there remains concern regarding neuroinflammation following treatment. The aim of this study was to assess the magnitude of this response following sonication and explore the influence of MB dose.Methods: Differential expression of NFκB signaling pathway genes was assessed in rats at 6 h and 4 days following a FUS-mediated increase in BBB permeability. Three sonication schemes were tested: (1) a clinical imaging dose of MBs + peak negative pressure (PNP) controlled by acoustic feedback, (2) 10x clinical imaging dose of MBs + constant PNP of 0.290 MPa, and (3) 10x clinical imaging dose of MBs + PNP controlled by acoustic feedback. Follow-up magnetic resonance imaging (MRI) was performed to assess edema and hemorrhage. Hematoxylin and eosin histology was used to evaluate general tissue health.Results: MB dose has a significant impact on the expression of several key genes involved in acute inflammation and immune activation, including Tnf, Birc3, and Ccl2. At a clinical imaging dose of MBs, there were no significant changes detected in the expression of any NFκB signaling pathway genes. Conversely, a high MB dose resulted in a clear activation of the NFκB signaling pathway, accompanied by edema, neuronal degeneration, neutrophil infiltration, and microhemorrhage. Results also suggest that post-FUS gadolinium enhancement may hold predictive value in assessing the magnitude of inflammatory response.Conclusion: While a significant and damaging inflammatory response was observed at high MB doses, it was demonstrated that FUS can be used to induce increased BBB permeability without an associated upregulation of NFκB signaling pathway gene expression. This emphasizes the importance of employing optimized FUS parameters to mitigate the chances of causing injury to the brain at the targeted locations.

FGF20 protected against BBB disruption after traumatic brain injury by activating the AKT/GSK3β pathway to upregulate junction protein expression and inhibiting JNK/NFκB-dependent neuroinflammation

“…rhFGF20 was found to protect against BBB disruption through upregulating junction protein expression via the AKT/GSK3β pathway and decreasing the inflammatory response via the JNK/NFκB pathway. In our research, we found that the NFκB inhibitor Bay 11-7082 also protected against TNF-αinduced BBB injury in terms of changes to BBB permeability and endothelial resistance, which is consistent with a previous study showing that the NFκB pathway plays an important role in BBB disruption [63]. Notably, the protective effect of rhFGF20 was better than that of Bay 11-7082.…”

Focused ultrasound delivery of a selective TrkA agonist rescues cholinergic function in a mouse model of Alzheimer’s disease

“…In this study, we used the recommended clinical imaging dose of Definity microbubbles (20 l/kg) to approximate an equivalent microbubble dose between animals. Recently, McMahon and Hynynen (34) reported that Definity at 20 l/kg compared to 100 l/kg (10 times higher than the clinical imaging dose) can be used to increase BBB permeability without activation of inflammatory markers (i.e., nuclear factor B signaling pathway genes), tissue damage, or MRI evidence of edema and hemorrhage. The probability of FUS-induced BBB permeability using a clinical imaging dose of Definity and Optison is similar across a range of pressure amplitudes, as the ones achieved in our study and established previously by McDannold et al (37).…”

TNIP1‐mediated TNF‐α/NF‐κB signalling cascade sustains glioma cell proliferation

“…3 Though conventional hypothesis suggests the brain is an 'immune privilege' tissue, increasing studies indicate that brain disorders are affected by multiple immune factors, such as TNF-α and NF-κB. [4][5][6] While 'immune privilege' is the main contributor to its poor prognosis, few effective therapeutic strategies exist for glioma due to the blood-brain barrier. 7 Glioblastoma patients have a poor survival of 14-17 months in clinical investigations.…”