Selective Blood-brain Barrier Research Articles

Nanoparticles for imaging and treating brain cancer.

Brain cancer tumors cause disruption of the selective properties of vascular endothelia, even causing disruptions in the very selective blood-brain barrier, which are collectively referred to as the blood-brain-tumor barrier. Nanoparticles (NPs) have previously shown great promise in taking advantage of this increased vascular permeability in other cancers, which results in increased accumulation in these cancers over time due to the accompanying loss of an effective lymph system. NPs have therefore attracted increased attention for treating brain cancer. While this research is just beginning, there have been many successes demonstrated thus far in both the laboratory and clinical setting. This review serves to present the reader with an overview of NPs for treating brain cancer and to provide an outlook on what may come in the future. For NPs, just like the blood-brain-tumor barrier, the future is wide open.

Noninvasive, Transient and Selective Blood-Brain Barrier Opening in Non-Human Primates In Vivo

The blood-brain barrier (BBB) is a specialized vascular system that impedes entry of all large and the vast majority of small molecules including the most potent central nervous system (CNS) disease therapeutic agents from entering from the lumen into the brain parenchyma. Microbubble-enhanced, focused ultrasound (ME-FUS) has been previously shown to disrupt noninvasively, selectively, and transiently the BBB in small animals in vivo. For the first time, the feasibility of transcranial ME-FUS BBB opening in non-human primates is demonstrated with subsequent BBB recovery. Sonications were combined with two different types of microbubbles (customized 4–5 µm and Definity®). 3T MRI was used to confirm the BBB disruption and to assess brain damage.

Tumor Necrosis Factor α and Endothelin-1 Increase P-Glycoprotein Expression and Transport Activity at the Blood-Brain Barrier

The ATP-driven drug efflux pump, P-glycoprotein, is a critical and selective element of the blood-brain barrier and a primary impediment to pharmacotherapy of central nervous system (CNS) disorders. Thus, an understanding of how P-glycoprotein function is regulated has the potential to improve CNS therapy. We recently demonstrated rapid (minutes) and reversible inactivation of P-glycoprotein in rat brain capillaries signaled through tumor necrosis factor-alpha (TNF-alpha) and endothelin-1 (ET-1), components of the brain's innate immune response. In this study, we examined the longer-term consequences of continuous exposure of rat brain capillaries to low levels of TNF-alpha and ET-1. Exposing brain capillaries to TNF-alpha or ET-1 caused a rapid decrease in P-glycoprotein transport activity with no change in transporter protein expression. This was followed by a 2- to 3-h plateau at the low activity level and then by a sharp increase in both transport activity and protein expression. After 6 h, transport activity and transporter protein expression was double that of control samples. TNF-alpha signaled through TNF-R1, which in turn caused ET release and action through ETA and ETB receptors, nitric-oxide synthase, protein kinase C and nuclear factor-kappaB (NF-kappaB) and finally increased P-glycoprotein expression and transport activity. Assuming similar effects occur in vivo, the present results imply a tightening of the selective blood-brain barrier with chronic inflammation and thus reduced efficacy of CNS-acting drugs that are P-glycoprotein substrates. Moreover, involvement of NF-kappaB raises the possibility that other effectors acting through this transcription factor may have similar effects on this key blood-brain barrier transporter.

Time‐dependent tumor necrosis factor (TNF)‐α signaling to P‐glycoprotein (P‐gp) in rat brain capillaries

The ATP-driven drug efflux pump, P-gp, is a critical, selective element of the blood-brain barrier and a primary impediment to CNS pharmacotherapy. We recently demonstrated rapid and reversible inactivation of P-gp in rat brain capillaries signaled through the brain’s innate immune response (LPS and TNF-α) and the endothelin (ET) B-type receptor (Hartz et al, Mol Pharm 66:387, 2004, and in press). Neither tight junctional permeability nor p-gp expression were altered. Here we show here that P-gp activity and expression changed in a complex manner in capillaries exposed continuously to low levels of TNF-α or ET-1. The initial reduction in transport activity with unaltered expression was followed by a 2-3 h plateau and then by increased activity and expression; after 6 h, both had increased to twice control levels. Signaling involved the following sequence:1) TNF-α binding to TNF-R1, 2) big-ET release and cleavage, 3) ET binding to ETA and ETB receptors, 4) NOS activation, 5) PKC activation, 6) NF-κB activation and translocation from cytoplasm to nucleus, and 7) increased P-gp expression and function. These results imply a tightening of the selective blood-brain barrier with chronic, low level inflammation. Moreover, by implicating NF-κB, they raise the possibility that other effectors acting through this transcription factor may also similarly induce the selective component of the barrier.

Determination of atropisomeric and planar polychlorinated biphenyls, their enantiomeric fractions and tissue distribution in grey seals using comprehensive 2D gas chromatography

High prevalence of uterine occlusions and sterility is found among Baltic ringed and grey seal. Polychlorinated biphenyls (CBs) are suspected to be the main cause. The CB concentrations are higher in affected than in healthy animals, but the natural variation is considerable. Thus, it might be possible to assess the health status of seals by CB analysis. The ratios of chiral compounds (enantiomeric fractions (EFs)) such as atropisomeric CBs are of particular interest, since these may reflect differences in metabolic rates. An analytical procedure was developed and used to determine the levels of atropisomeric CBs, planar-CBs (WHO-PCBs) and total CBs in seals of different health status. Comprehensive 2D gas chromatography (GC×GC) was used to separate the target analytes from other CBs and interferences and a micro electron-capture detector (μECD) was used for detection. EFs of the atropisomeric CBs were difficult to determine as the levels were low and the interferences many. Two column combinations had to be used to avoid biased results—both had a chiral column as first-dimension column. The second-dimension column was coated with either a high-polarity cyanopropyl or a liquid crystal phase. EFs were determined for five atropisomeric CBs, i.e. CBs 91, 95, 132, 149 and 174. The results were verified by GC×GC–time-of-flight mass spectrometry (TOF-MS). Some atropisomeric CBs had EFs that deviated strongly from the racemic-mixture value. The deviations were larger in liver than blubber, which indicates enantioselective metabolism. However, there was no selective passage of the studied atropisomeric CBs across placenta and no selective blood–brain barrier. Similarly, no correlation between EFs and health status was observed, although there was a correlation between the total CB levels and health status.

Olfactory Absorption of Insulin to the Brain

A vast number of potent neuropharmaceuticals, many of which are peptides, are excluded from entry into the brain because of the highly selective blood-brain barrier. The fact that a number of drugs have been shown to be transported directly to the central nervous system following application to the olfactory region of the nose is therefore of major interest. In the present study, the feasibility of delivering peptides to the brain via the olfactory route was assessed using insulin as a model peptide. Systemic hyperinsulinemia induced by subcutaneous injection did not significantly reduce the amount of 125I-insulin transported from the nose to the brain in vivo, which suggests that the impact of systemic absorption on drug transport is minimal. A linear relationship was seen between insulin accumulation in the brain and the dose applied, without any relevant saturation. Contrary to what was expected, both systemic and olfactory absorption of insulin was enhanced when the pH of the medium was near the isoelectric point. The amount absorbed to the brain was found to be linearly related to the net charge of the molecule (r = -0.61; n = 20). It was concluded that insulin gains access to the central nervous system from the olfactory region of the nose by a nonspecific pathway. The olfactory route may therefore become an important means to deliver peptides to the brain.

Passage of amino acids and glucose across the blood-brain barrier in patients with hepatic encephalopathy

We repeatedly measured blood-brain barrier passage of phenylalanine, leucine, glucose and GABA in nine patients with hepatic encephalopathy using the intravenous double-indicator technique. Controls were four patients without liver disease and two of the patients who had recovered completely from their hepatic encephalopathy. The corrected cerebral venous output curves were fitted by use of a three-compartment model with four parameters. In the patients with hepatic encephalopathy, the permeability-surface area products for phenylalanine and leucine from the blood to the brain and from the brain interstitial fluid to the intracellular compartment, the unidirectional extraction and the brain amino acid influx were similar in the two groups. The permeability from the brain back to blood for phenylalanine was decreased by 72% in patients with hepatic encephalopathy compared with that in the control group (p < 0.05), whereas no difference was seen for leucine. The permeability from the brain back to the blood for phenylalanine decreased with coma grade and normalized in the two patients who recovered. Correspondingly, the calculated brain interstitial fluid concentration of phenylalanine was increased in the patients with hepatic encephalopathy. The transfer variables for blood-brain barrier passage of glucose were similar in the two groups. The permeability from the blood to the brain for GABA was very low in both the patients with hepatic encephalopathy and the control group. We conclude that in hepatic encephalopathy the permeability from brain to blood for phenylalanine decreases with coma grade. The decrease is caused by an increased interstitial fluid concentration of the amino acid. No evidence was found of general or selective blood-brain barrier disturbance in hepatic encephalopathy.

Passage of amino acids and glucose across the blood-brain barrier in patients with hepatic encephalopathy

We repeatedly measured blood-brain barrier passage of phenylalanine, leucine, glucose and GABA in nine patients with hepatic encephalopathy using the intravenous double-indicator technique. Controls were four patients without liver disease and two of the patients who had recovered completely from their hepatic encephalopathy. The corrected cerebral venous output curves were fitted by use of a three-compartment model with four parameters. In the patients with hepatic encephalopathy, the permeability-surface area products for phenylalanine and leucine from the blood to the brain and from the brain interstitial fluid to the intracellular compartment, the unidirectional extraction and the brain amino acid influx were similar in the two groups. The permeability from the brain back to blood for phenylalanine was decreased by 72% in patients with hepatic encephalopathy compared with that in the control group (p < 0.05), whereas no difference was seen for leucine. The permeability from the brain back to the blood for phenylalanine decreased with coma grade and normalized in the two patients who recovered. Correspondingly, the calculated brain interstitial fluid concentration of phenylalanine was increased in the patients with hepatic encephalopathy. The transfer variables for bloodbrain barrier passage of glucose were similar in the two groups. The permeability from the blood to the brain for GABA was very low in both the patients with hepatic encephalopathy and the control group. We conclude that in hepatic encephalopathy the permeability from brain to blood for phenylalanine decreases with coma grade. The decrease is caused by an increased interstitial fluid concentration of the amino acid. No evidence was found of general or selective blood-brain barrier disturbance in hepatic encephalopathy. (HEPATOLOGY 1993;17:987–992.)