Strategies to advance translational research into brain barriers

Neuwelt, Edward A.; Abbott, N. Joan; Abrey, Lauren E.; Banks, William A.; Blakley, Brian W.; Davis, Thomas P.; Engelhardt, Britta; Grammas, Paula; Nutt, John G.; Pardridge, William M.; Rosenberg, Gary A.; Smith, Quentin R.; Drewes, Lester R.

doi:10.1016/s1474-4422(07)70326-5

Cited by 438 publications

(317 citation statements)

References 72 publications

Supporting

Mentioning

314

Contrasting

Unclassified

Order By: Relevance

“…These findings are significant given that the best method for delivering higher concentrations of intracerebral anticancer drugs remains elusive. 2,15 In addition, aside from being highly potent modulators of BBB/BTB, single molecules exhibiting mixed B1R/B2R agonist activity, such as the heterodimer described here, may provide a number of advantages over combination therapy with individual agonists. These include a single pharmacokinetic profile, a uniform ratio of activities at the cellular level and simpler in vivo preclinical testing in animal models.…”

Section: Acknowledgmentsmentioning

confidence: 99%

Dual kinin B1 and B2 receptor activation provides enhanced blood–brain barrier permeability and anticancer drug delivery into brain tumors

Côté

Savard

Neugebauer

et al. 2013

Cancer Biology & Therapy

View full text Add to dashboard Cite

Section: Acknowledgmentsmentioning

confidence: 99%

Dual kinin B1 and B2 receptor activation provides enhanced blood–brain barrier permeability and anticancer drug delivery into brain tumors

Côté

Savard

Neugebauer

et al. 2013

Cancer Biology & Therapy

View full text Add to dashboard Cite

“…1 Endothelial dysfunction is the earliest event in the initiation of vascular injury caused by inflammation due to ischemia, amyloid deposition, trauma, or brain infection. 2 Chronic inflammation in the brain is a consequence of immune activation of glia (microglia, macrophages, and astrocytes), oxidative stress, and BBB injury mediated by inflammatory factors produced by immune cells in the brain or blood. Due to their neuroprotective properties, inhibitors of glycogen synthase kinase (GSK) 3β were recently shown as beneficial drugs in preclinical trials in stroke, Huntington's and Parkinson's diseases, amyotrophic lateral sclerosis, spinal cord injury, and other conditions, as well as in clinical trials for Alzheimer's disease.…”

Section: Introductionmentioning

confidence: 99%

miR-98 and let-7g* Protect the Blood-Brain Barrier Under Neuroinflammatory Conditions

Rom

Dykstra

Zuluaga-Ramirez

et al. 2015

J Cereb Blood Flow Metab

106

110

View full text Add to dashboard Cite

Pathologic conditions in the central nervous system, regardless of the underlying injury mechanism, show a certain level of blood-brain barrier (BBB) impairment. Endothelial dysfunction is the earliest event in the initiation of vascular damage caused by inflammation due to stroke, atherosclerosis, trauma, or brain infections. Recently, microRNAs (miRNAs) have emerged as a class of gene expression regulators. The relationship between neuroinflammation and miRNA expression in brain endothelium remains unexplored. Previously, we showed the BBB-protective and anti-inflammatory effects of glycogen synthase kinase (GSK) 3β inhibition in brain endothelium in in vitro and in vivo models of neuroinflammation. Using microarray screening, we identified miRNAs induced in primary human brain microvascular endothelial cells after exposure to the pro-inflammatory cytokine, tumor necrosis factor-α, with/out GSK3β inhibition. Among the highly modified miRNAs, let-7 and miR-98 were predicted to target the inflammatory molecules, CCL2 and CCL5. Overexpression of let-7 and miR-98 in vitro and in vivo resulted in reduced leukocyte adhesion to and migration across endothelium, diminished expression of pro-inflammatory cytokines, and increased BBB tightness, attenuating barrier 'leakiness' in neuroinflammation conditions. For the first time, we showed that miRNAs could be used as a therapeutic tool to prevent the BBB dysfunction in neuroinflammation.

show abstract

“…Various methods have been developed for transient BBBD to enhance the delivery of chemotherapeutic agents, antibodies, genes, and nanoparticles to the parenchyma (20)(21)(22)(23)(24)(25)(26)(27). Invasive and noninvasive approaches have been used for drug and gene delivery into the parenchyma with or without altering BBB homeostasis.…”

mentioning

confidence: 99%

“…Invasive and noninvasive approaches have been used for drug and gene delivery into the parenchyma with or without altering BBB homeostasis. The BBB can be bypassed by direct injection or convectionenhanced delivery of drugs or viruses, but these means require surgical intervention, and the infiltration of agents into the parenchyma may be limited by diffusion (24)(25)(26). The injection of hypertonic mannitol, i.v.…”

mentioning

confidence: 99%

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

Kovács

Kim

Jikaria

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

371

388

View full text Add to dashboard Cite

MRI-guided pulsed focused ultrasound (pFUS) combined with systemic infusion of ultrasound contrast agent microbubbles (MB) causes localized blood-brain barrier (BBB) disruption that is currently being advocated for increasing drug or gene delivery in neurological diseases. The mechanical acoustic cavitation effects of opening the BBB by low-intensity pFUS+MB, as evidenced by contrast-enhanced MRI, resulted in an immediate damage-associated molecular pattern (DAMP) response including elevations in heat-shock protein 70, IL-1, IL-18, and TNFα indicative of a sterile inflammatory response (SIR) in the parenchyma. Concurrent with DAMP presentation, significant elevations in proinflammatory, antiinflammatory, and trophic factors along with neurotrophic and neurogenesis factors were detected; these elevations lasted 24 h. Transcriptomic analysis of sonicated brain supported the proteomic findings and indicated that the SIR was facilitated through the induction of the NFκB pathway. Histological evaluation demonstrated increased albumin in the parenchyma that cleared by 24 h along with TUNEL + neurons, activated astrocytes, microglia, and increased cell adhesion molecules in the vasculature. Infusion of fluorescent beads 3 d before pFUS+MB revealed the infiltration of CD68 + macrophages at 6 d postsonication, as is consistent with an innate immune response. pFUS+MB is being considered as part of a noninvasive adjuvant treatment for malignancy or neurodegenerative diseases. These results demonstrate that pFUS+MB induces an SIR compatible with ischemia or mild traumatic brain injury. Further investigation will be required before this approach can be widely implemented in clinical trials.pulsed focused ultrasound | microbubbles | blood-brain barrier | sterile inflammation | magnetic resonance imaging T he temporal proteomic profile in response to blood-brain barrier disruption (BBBD) consists of molecular features that are common across noninfectious insults such as ischemia, trauma, or autoimmune diseases (1-7). The main purpose of the bloodbrain barrier (BBB) is to maintain homeostasis, preventing the passive crossing of cells and molecules that could induce inflammation or damage to cells. The BBB consists of specialized endothelial cells connected through various tight junction proteins (TJP), astrocyte endplates, and a basement membrane. These components form part of the neurovascular unit (NVU) that is comprised of vessels, pericytes, microglia, astrocytes, and neurons along with the extracellular matrix (1,3,4,8). BBBD secondary to ischemia or trauma leads to increases in endothelial caveolae and down-regulation of TJP, transcytosis of plasma proteins (i.e., albumin), and vasogenic edema (1,6,(8)(9)(10)(11). The presence of albumin in the parenchyma following BBBD can activate astrocytes and microglia and induce the production of cytokines, chemokines, and trophic factors (CCTFs) and cell adhesion molecules (CAMs) as observed with a sterile inflammatory response (SIR) to injury (12-15). The release of CCTFs and inte...

show abstract

Strategies to advance translational research into brain barriers

Cited by 438 publications

References 72 publications

Dual kinin B1 and B2 receptor activation provides enhanced blood–brain barrier permeability and anticancer drug delivery into brain tumors

Dual kinin B1 and B2 receptor activation provides enhanced blood–brain barrier permeability and anticancer drug delivery into brain tumors

miR-98 and let-7g* Protect the Blood-Brain Barrier Under Neuroinflammatory Conditions

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

Contact Info

Product

Resources

About