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PubMed1985

The effects of brain blood flow on brain bilirubin deposition in newborn piglets.

Since kernicteric lesions are usually found in the subcortical regions of the brain and these areas also receive the highest blood flow during asphyxia and hypercapnia, we hypothesized that increases in brain bilirubin deposition may be related to increases in brain blood flow. Fourteen piglets underwent a 3-h infusion of bilirubin to maintain total serum bilirubin at approximately 8 mg/dl, during which time blood gases, hemodynamic variables, and brain blood flow were determined. After sacrificing the animals, regional brain bilirubin content was determined. Ten piglets underwent the same protocol; in addition, hypercapnia was induced during the last hour of study (PaCO2 approximately 70 mm Hg). The regional brain blood flow and bilirubin deposition were significantly increased over control values (p less than 0.05) following hypercapnia in the subcortical region and significantly so in the midbrain and cerebellum. In separate groups of control (n = 6) and hypercapnia (n = 6) piglets, 125I-labeled albumin was infused and demonstrated that hypercapnia was not associated with increased regional brain albumin content. We conclude that hypercapnia-induced augmentation in regional brain blood flow is associated with increased deposition brain blood flow is associated with increased deposition of unbound bilirubin. Although the causal relationship between these two observations has not been firmly established, the findings deserve future investigation to clarify the role of brain blood flow, brain bilirubin deposition, and the production of kernicterus in high risk infants.

Albumins↗
PubMed1999

Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Multiple Sclerosis Collaborative Research Group.

BACKGROUND: Episodic inflammation in the CNS during the early stages of MS results in progressive disability years later, presumably due to myelin and axonal injury. MRI demonstrates ongoing disease activity during the early disease stage, even in some patients who are stable clinically. The optimal MRI measure for the destructive pathologic process is uncertain, however. METHODS: In this post-hoc study, MRI scans were analyzed from patients with relapsing MS participating in a placebo-controlled trial of interferon beta-1a. The brain parenchymal fraction, defined as the ratio of brain parenchymal volume to the total volume within the brain surface contour, was used to measure whole brain atrophy. The relationship between disease features and brain atrophy and effect of interferon beta-1a were determined. RESULTS: MS patients had significant brain atrophy that worsened during each of 2 years of observation. In many patients, brain atrophy worsened without clinical disease activity. Baseline clinical and MRI abnormalities were not strongly related to the rate of brain atrophy during the subsequent 2 years. Treatment with interferon beta-1a resulted in a reduction in brain atrophy progression during the second year of the clinical trial. CONCLUSIONS: Patients with relapsing-remitting MS have measurable amounts of whole brain atrophy that worsens yearly, in most cases without clinical manifestations. The brain parenchymal fraction is a marker for destructive pathologic processes ongoing in relapsing MS patients, and appears useful in demonstrating treatment effects in controlled clinical trials.

Adjuvants, Immunologic↗
PubMed2000

Nonuniform transmission in brain SPECT using 201Tl, 153Gd, and 99mTc static line sources: anthropomorphic dosimetry studies and influence on brain quantification.

UNLABELLED: Nonuniform attenuation correction in brain SPECT can be done routinely by means of additional gamma transmission CT (TCT) measurements, using different commercially available line-source isotopes, 201Tl, 153Gd, and 99mTc are among the most commonly used isotopes, depending on practical and cost-effectiveness issues. We have measured additional radiation burden from static uncollimated brain SPECT transmission sources for these isotopes. The influence of the transmission isotope on brain quantification was also measured and compared with uniform attenuation correction for phantom and human data. Full iterative transmission and emission reconstruction were compared with filtered backprojection techniques. METHODS: Rod sources with 201Tl, 153Gd, and 99mTc were used on a triple-head gamma camera. Dosimetry was performed using LiF TLD-100 pellets and an anthropomorphic RANDO phantom. Effective dose equivalents were calculated on the basis of measured and extrapolated absorbed doses. For brain activity measurements, a Hoffman phantom was used. Images were corrected for scatter (triple-energy window) and were reconstructed by Chang attenuation correction and filtered backprojection as well as full iterative reconstruction (ordered-subsets expectation maximization [OSEM]). To study the effect of inhomogeneous bone attenuation, realistic measurements were performed on 10 young, healthy volunteers with 153Gd TCT. After stereotactic image realignment, a volume-of-interest analysis normalized to total counts was performed. RESULTS: Brain SPECT-TCT using 201Tl, 153Gd, and 99mTc produced total effective dose-rate equivalents of 50.3 +/- 11.2, 32.0 +/- 2.7, and 71.1 +/- 7.1 microSv/GBq x h, respectively, representing dose equivalents of 18.6, 11.9, and 26.3 microSv for a typical 20-min brain SPECT scan at maximal used source strength. Standardized quantification resulted in insignificant differences between the isotopes and methods (Chang versus OSEM) used for nonuniform correction. Iterative reconstruction enhanced image contrast and provided more accurate gray-to-white matter ratios. Between nonuniform and uniform attenuation with an optimized attenuation coefficient, slight central discrepancies were found for volunteer studies. Significantly lower intersubject variation was found for nonuniform corrected values in infratentorial and posterior brain regions. CONCLUSION: Brain transmission scanning using 201Tl, 153Gd, or 99mTc results in limited effective radiation dose equivalents compared with the typical radiation burden. Relative brain perfusion quantification is not significantly different for the various nonuniform TCT isotopes. Iterative reconstruction improves gray-to-white contrasts but has no significant influence on brain perfusion semiquantification. Nonuniform attenuation correction decreases intersubject variability in the posterior brain regions that were compared, which may lead to improved sensitivity toward clinical applications.

Adult↗
PubMed2003

Congenital and acquired brain injury. 1. Brain injury: epidemiology and pathophysiology.

UNLABELLED: This self-directed learning module highlights recent advances in the understanding of brain injury pathophysiology, epidemiology. severity scales, and treatment interventions to minimize brain injury in adults and children. It is part of the chapter on congenital and acquired brain injury in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. In this article, brain injury epidemiology is summarized, and differences in between brain injury in pediatric and elderly persons are highlighted. Underlying physiologic and chemical mechanisms for secondary brain injury are reviewed, along with strategies and research to minimize this injury. Contemporary understanding of the mechanisms and treatments of brain injury in preterm infants is also discussed. Classification of brain injury severity provides a way to stratify this heterogeneous group. OVERALL ARTICLE OBJECTIVE: (a) To summarize brain injury epidemiology and prevention strategies across the age spectrum, (b) to review the pathophysiology of pediatric and adult brain injury, and (c) to classify brain injury by severity scales.

Aged↗
PubMedDate not supplied

Alcohol intoxication results in rapid loss in free magnesium in brain and disturbances in brain bioenergetics: relation to cerebrovasospasm, alcohol-induced strokes, and barbiturate anesthesia-induced deaths.

In vivo 31P-nuclear magnetic resonance (31P-NMR) spectroscopy and ion-selective electrode measurements were undertaken to determine if administration of acute doses of alcohol (ALC, 0.2-6.6 g/kg), and lethal doses of barbiturate anesthesia, exert any influence on: (1) brain cellular bioenergetics, intracellular free Mg ([Mg2+]i) and intracellular pH (pHi), and (2) serum levels of ionized Mg (IMg2+), ionized calcium (ICa2+) and K+. Approximately 20-30 min after intraperitoneal administration of ALC to anesthetized rats, brain phosphocreatine (PCr)/ATP and PCr/inorganic phosphate (P(i)) ratios dropped from 2.5 to 1.7 and from 6.6 to 2.2, respectively, P(i) rose 20-200% (depending upon ALC dose), and free ADP and creatine rose significantly. ALC induced rapid decreases in the cytosolic phosphorylation potential (CPP) and free energy of ATP hydrolysis (-delta G/delta E). Following ALC administration, brain [Mg2+]i dropped rapidly (within 4-30 min) and significantly; the greater the dose of ALC, the greater the loss in brain [Mg2+]. Correlations were found between [Mg2+]i, PCr/ATP, CPP and delta G/delta E after ALC but not in control brains. Rats that exhibited ALC-induced strokes and death (unlike barbiturate death) exhibited huge elevations in [Mg2+]i. Although ALC administration does not alter brain pHi at least (up to 70 min), ALC- and barbiturate-induced death produces rapid brain intracellular acidosis. Concomitant with ALC-induced alterations in [Mg2+]i and brain cellular bioenergetics, we noted that ALC administration results in rapid elevations in serum IMg2+ and K+ but not ICa2+. These results suggest that ALC administration and heavy or binge-drinking of ALC (1) can result in rapid alterations in brain bioenergetics, [Mg2+]i and pHi, and (2) result in rapid elevations in serum IMg2+ and K+ in rats. In addition, ALC- and barbiturate-induced deaths do not appear to produce identical alterations in brain bioenergetics and [Mg2+]i, and lastly binge or heavy drinking of ALC may result in stroke-like events and sudden death via rapid alterations in brain cellular bioenergetics.

Alcoholic Intoxication↗
PubMed1983

[Brain death in secondary brain lesion].

The criteria of brain death established by Japanese Society of EEG in 1974, necessitates a prerequisite; be applicable only to "acute destructive, primary gross lesion of brain". Namely, because of insufficient clinical data, secondary brain lesion such as post-anoxia, intoxication, metabolic coma and some kinds of CNS infection were excluded for the object to determine brain death. The criteria published by others also describe that etiology of coma should be clarified, and that careful measures are necessary to diagnose brain death if the cause of coma is unknown. In the present study, it was investigated that whether a clinico-pathological entity of brain death could exist universally regardless of the etiology, and by what means it could be defined clinically. The patients suffering from nondestructive, secondary brain lesions and who showed "brain death-like state" were selected for the study. ("Brain death-like state" requires coma, dilated nonreactive pupis and arrest of respiration concomitantly for more than 6 hours.) And 25 patients were collected, whose underlying diseases were post-anoxia or shock, CO intoxication, Paraquat poisoning, near-drowning or suffocation, hepatic coma, accidental hypothermia and sepsis, with or without the episode of cardiac arrest. Though all the patients died from 1 to 13 days after the insult, clinical signs of brain death-like state were not always irreversible. Isoelectric EEG was obtained on that state in 11 patients and repeated EEG revealed no return on those patients. But another 5 patients showed EEG activity when brain death was strongly suspected clinically.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1984

Transplantation of embryonic brain tissue into the brain of adult rats after hypoxic hypoxia.

Brain cortex tissue of 20-day-old rat embryos ( E20 ) was transplanted into the brain parietal region of adult Wistar rats 22 days following their exposure to acute hypoxic hypoxia. 91 days after hypoxia and 69 days after transplantation the rats were killed and their brain was studied histologically. Hypoxia has been found to cause strong dystrophy, irreversible degeneration (shrunken and lysis) and the death of numerous cortex neurons. Nevertheless the transplanted E20 rat brain tissue develops in 100% of cases in the brain of recipients. Transplants have a considerably large volume (7 mm3) and establish a close morphological connection with the neughbouring nervous tissue of the host's brain. Transplants contain viable nerve and glial cells. E20 rat brain transplants improve to a certain extent the state of hypoxia-exposed dystrophic neurons of the recipient's brain. The decay products released from the transplanted E20 rat brain tissue influence the recipient's brain tissue, and neurons of the transplants establish a close morphological, probably synaptic, connection with neurons of the host's brain tissue.

Animals↗
PubMed2006

Matrix metalloproteinase-9 is associated with blood-brain barrier opening and brain edema formation after cortical contusion in rats.

Matrix metalloproteinases (MMPs) are associated with blood-brain opening and may be involved in the pathophysiology of acute brain injury. Previous research demonstrated that knockout mice deficient in MMP-9 subjected to transient focal cerebral ischemia had reduced blood-brain barrier (BBB) disruption and attenuated cerebral infarction. In this study, we examined MMP-9 up-regulation, BBB disruption, and brain edema formation after cortical impact injury in rats. Cortical contusion was induced by controlled cortical impact. Animals were sacrificed at intervals after injury. MMP up-regulation was assessed by gelatin zymography, and BBB integrity was evaluated using Evans blue dye with a spectrophotometric assay. Brain water content was measured by comparing wet and dry weights of each hemisphere as an indicator of brain edema. Zymograms showed elevated MMP-9 as early as at 3 hours after injury, reaching a maximum at 18 hours. Peak levels of BBB disruption occurred 6 hours after injury. Brain edema became progressively more severe, peaking 24 hours after injury. Compared to control group, treatment with MMP-inhibitor GM6001 significantly reduced BBB disruption 6 hours and brain water content (85.9 +/- 0.5% vs. 82.6 +/- 0.3%; p < 0.05) 24 hours after injury. These findings suggest that MMP-9 may contribute to BBB disturbance and subsequent brain edema after traumatic brain injury.

Animals↗
PubMed2003

Correlation of lesion volume and brain swelling from a focal brain trauma.

Brain edema and secondary growth of a traumatic brain tissue necrosis are important manifestations of secondary brain damage and of prognostic significance in severe head injury. Aim of the current study was to analyze the interdependency of the resulting brain swelling from the size of the focal traumatic lesion. Male Sprague-Dawley rats were intubated and mechanically ventilated. A trephination was made over the left parietal cortex for induction of a cold lesion. Different injury severities were achieved by varying the contact time of the cooled copper-cylinder and the exposed cortex. Animals were randomized into 12 experimental groups. Hemispheric brain swelling was measured in groups A1-A6 (n = 4-8) by gravimetry 24 hrs after lesions of six increasing severity levels. Correspondingly, in animals of groups B1-B6 (n = 5-7) the volume of necrosis was planimetrically assessed in histological serial sections of the brain obtained 24 hrs after trauma of different severity. In groups A1-A6. hemispheric brain swelling (increase in weight) was growing with increasing contact duration of the cold probe with the exposed cerebral cortex, i.e. from 7.7 +/- 0.4% (5 s) to a maximum of 9.9 +/- 0.5% (25 s). Longer contact periodes (30 s) were not further effective to increase hemispheric brain swelling. The contact times and extent of swelling were linearly correlated between 5 s and 25 s (r = 0.47; p < 0.01). The volume of necrosis in groups B1-B6 increased from 35.7 +/- 3.7 mm3 (5 s) to 106.3 +/- 10.3 mm3 (30 s). There was again a linear correlation between the duration of contact of the cold probe (i.e. injury severity) with the brain cortex and the volume of necrosis (r = 0.77; p < 0.01). Accordingly. the lesion volume could be increased in a reproducible manner from 35.7 up to 106.3 mm3 by extending the contact times of the cooling device and cerebral cortex. Hemispheric swelling, predominantly due to vasogenic brain edema, was expanding in relationship with the volume of necrosis.

Animals↗
PubMed1994

Simple quantitative evaluation of blood-brain barrier disruption in vasogenic brain edema.

Traumatic damage to the brain results in blood-brain barrier disruption with subsequent formation of vasogenic brain edema. The goal of this study was to evaluate a colorimetric assay of Evans blue extravasation for quantitatively studying blood-brain barrier disruption. Vasogenic brain edema was produced by a cortical freezing lesion. 52 male Wistar rats were sacrificed and cardiac perfusion was performed. A volume of dimethylformamide, twice the brain weight, was added to the brain and this was incubated for 72 hours. The supernatant was analyzed spectrophotometrically. Evans blue contents in the lesioned hemisphere was significantly increased within one hour after the lesion production relative to the normal brain and continued to increase for 24 hours (p < 0.01). This quantitative assay of Evans blue is a simple method for evaluation of blood-brain barrier disruption in vasogenic brain edema.

Animals↗
PubMed1985

The aluminum-induced increase in blood-brain barrier permeability to delta-sleep-inducing peptide occurs throughout the brain and is independent of phosphorus and acetylcholinesterase levels.

The effect of aluminum on levels of inorganic phosphorus and acetylcholinesterase in blood and brain and on permeability of the blood-brain barrier (BBB) in different regions of the brain to the neuropeptide delta-sleep-inducing peptide (DSIP) was studied in adult rats. Aluminum (100 mg/kg) significantly increased the permeability of the BBB to intracarotid 125I-N-Tyr-DSIP so that levels of radioactivity in whole brain were 45% higher than in control animals. The pattern of regional distribution of radioactivity in the brain was, however, unaffected, demonstrating that the affect of aluminum occurs throughout the BBB. Aluminum also significantly decreased inorganic phosphorus levels in the serum by 19%, but this effect did not correlate with BBB permeability to DSIP. Aluminum did not decrease brain levels of phosphorus despite the drop in blood levels of phosphorus nor affect brain or blood levels of acetylcholinesterase. Experiments with radioactive 32P reinforced the finding that blood but not brain levels of phosphorus are reliably affected by aluminum. The lack of correlation between changes in BBB permeability and decreased levels of inorganic phosphorus in the blood suggests that the effect of aluminum may not be mediated by its effects on phosphorus metabolism. Also, the change in BBB permeability after administration of aluminum does not appear to depend on changes in brain cholinergic activity but does occur throughout the brain.

Acetylcholinesterase↗
PubMed1986

Varying brain insulin concentrations differentially regulate the fetal brain insulin receptor.

We investigated the downregulating effect of varying states (physiologic and pharmacologic) of systemic and intracranial hyperinsulinism on the 28 to 30 day fetal rabbit brain insulin receptor. Alloxan-induced maternal diabetes (n = 5) produced mild fetal hyperinsulinemia (D) (plasma insulin concentrations = 59.80 +/- 8.10 microU/ml, control = 26.25 +/- 3.70; p less than 0.01), whereas systemic administration (IMI) of 1.0 U (n = 4) and 2.0 U (n = 4) of insulin to the fetus resulted in moderate (103.13 +/- 34.63 microU/ml) and severe (288.3 +/- 51 microU/ml) fetal hyperinsulinemia respectively. All three states of systemic hyperinsulinemia neither altered the fetal brain insulin content nor the brain insulin receptor number and affinity. 0.01 U (n = 4) of intracranial insulin administration (ICI) increased the brain insulin content four-fold (p less than 0.01) but did not alter the brain insulin receptor number or affinity. 0.1 (n = 5) and 2.0 U (n = 7) of intracranial insulin increased the brain insulin content to supraphysiologic concentrations (p less than 0.01) and decreased the fetal brain insulin receptor number (p less than 0.01), the affinity remaining constant. We conclude that 1) regardless of the ability of insulin to cross the blood brain barrier, the downregulation of the brain insulin receptor is insulin dose-dependent and 2) the downregulation of the fetal brain insulin receptor is not a physiologic but a pharmacologic effect of insulin.

Animals↗
PubMed1992

Histamine modulates heat stress-induced changes in blood-brain barrier permeability, cerebral blood flow, brain oedema and serotonin levels: an experimental study in conscious young rats.

The possibility that endogenous histamine plays an important role in modulating the pathophysiology of heat stress was examined in young rats using a pharmacological approach. Subjection of young animals (six to seven weeks old) to heat stress at 38 degrees C for 4 h in a biological oxygen demand incubator (relative humidity 47-50%, wind velocity 20-25 cm/s) resulted in a profound increase in blood-brain barrier permeability to Evans Blue albumin (whole brain 375%) and [131I]sodium (whole brain 478%) along with a significant reduction in the cerebral blood flow (mean 34%). The water content of the whole brain was elevated by 4.5% (about 19% volume swelling) from the control. At this time-period, the plasma and whole brain 5-hydroxytryptamine levels were elevated by 656% and 328%, respectively, from the control group. Pretreatment with cimetidine (a histamine H2 receptor antagonist) significantly thwarted the increases in the brain water content and the blood-brain barrier permeability. In cimetidine-pretreated animals, the cerebral blood flow was significantly elevated and the plasma and brain 5-hydroxytryptamine (serotonin) levels were slightly but significantly reduced as compared with the untreated stressed group. However, prior treatment with mepyramine (a histamine H1 receptor antagonist) neither attenuated the changes in water content and the blood-brain barrier permeability nor altered the cerebral blood flow and 5-hydroxytryptamine levels. In fact, there was a significantly higher permeation of the tracers across the cerebral vessels in these drug-treated animals along with a greater accumulation of the brain water content as compared with the untreated stressed group. The cerebral blood flow and 5-hydroxytryptamine levels showed only minor changes from the untreated stressed group. These results show, probably for the first time, that (i) the endogenous histamine plays an important role in the pathophysiology of heat stress, and (ii) this effect appears to be mediated via specific histamine H2 receptors.

Animals↗
PubMed2006

Differential regulation of blood-brain barrier permeability in brain trauma and pneumococcal meningitis-role of Src kinases.

Increased vascular permeability causing vasogenic brain edema is characteristic for many acute neurological diseases such as stroke, brain trauma, and meningitis. Src family kinases, especially c-Src, play an important role in regulating blood-brain barrier permeability in response to VEGF, but also mediate leukocyte function and cytokine signalling. Here we demonstrate that pharmacological inhibition of Src or c-Src deficiency does not influence cerebrospinal fluid (CSF) pleocytosis, brain edema formation, and bacterial outgrowth during experimental pneumococcal meningitis despite the increased cerebral expression of inflammatory chemokines, such as IL-6, CCL-9, CXCL-1, CXCL-2 and G-CSF as determined by protein array analysis. In contrast, inhibition of Src significantly reduced brain edema formation, lesion volume, and clinical worsening in cold-induced brain injury without decreasing cytokine/chemokine expression. While brain trauma was associated with increased cerebral VEGF formation, VEGF levels significantly declined during pneumococcal meningitis. Therefore, we conclude that in brain trauma blood-brain barrier tightness is regulated by the VEGF/Src pathway whereas c-Src does not influence brain edema formation and leukocyte function during bacterial meningitis.

Animals↗
PubMed2005

Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases.

The blood-brain barrier (BBB) serves as a protective mechanism for the brain by preventing entry of potentially harmful substances from free access to the central nervous system (CNS). Tight junctions present between the brain microvessel endothelial cells form a diffusion barrier, which selectively excludes most blood-borne substances from entering the brain. Astrocytic end-feet tightly ensheath the vessel wall and appear to be critical for the induction and maintenance of the barrier properties of the brain capillary endothelial cells. Because of these properties, the BBB only allows entry of lipophilic compounds with low molecular weights by passive diffusion. However, many lipophilic drugs show negligible brain uptake. They are substrates for drug efflux transporters such as P-glycoprotein (Pgp), multidrug resistance proteins (MRPs) or organic anion transporting polypeptides (OATPs) that are expressed at brain capillary endothelial cells and/or astrocytic end-feet and are key elements of the molecular machinery that confers the special permeability properties to the BBB. The combined action of these carrier systems results in rapid efflux of xenobiotics from the CNS. The objective of this review is to summarize transporter characteristics (cellular localization, specificity, regulation, and potential inhibition) for drug efflux transport systems identified in the BBB and blood-cerebrospinal fluid (CSF) barrier. A variety of experimental approaches available to ascertain or predict the impact of efflux transport on brain access of therapeutic drugs also are described and critically discussed. The potential impact of efflux transport on the pharmacodynamics of agents acting in the CNS is illustrated. Furthermore, the current knowledge about drug efflux transporters as a major determinant of multidrug resistance of brain diseases such as epilepsy is reviewed. Finally, we summarize strategies for modulating or by-passing drug efflux transporters at the BBB as novel therapeutic approaches to drug-resistant brain diseases.

Animals↗
PubMed2003

Alkylglycerol opening of the blood-brain barrier to small and large fluorescence markers in normal and C6 glioma-bearing rats and isolated rat brain capillaries.

1. The blood-brain barrier (BBB) represents the major impediment to successful delivery of therapeutic agents to target tissue within the central nervous system. Intracarotid alkylglycerols have been shown to increase the transfer of chemotherapeutics across the BBB. 2. We investigated the spatial distribution of intracarotid fluorescein sodium and intravenous lissamine-rhodamine B200 (RB 200)-albumin in the brain of normal and C6 glioma-bearing rats after intracarotid co-administration of 1-O-pentylglycerol (200 mm). To elucidate the mechanisms involved in the alkylglycerol-mediated BBB opening, intraluminal accumulation of fluorescein isothiocyanate (FITC)-dextran 40,000 was studied in freshly isolated rat brain capillaries using confocal microscopy during incubation with different alkylglycerols. Furthermore, 1-O-pentylglycerol-induced increase in delivery of methotrexate (MTX) to the brain was evaluated in nude mice. 3. Microscopic evaluation showed a marked 1-O-pentylglycerol-induced extravasation of fluorescein and RB 200-albumin in the ipsilateral normal brain. In glioma-bearing rats, increased tissue fluorescence was found in both tumor tissue and brain surrounding tumor. Confocal microscopy revealed a time- and concentration-dependent accumulation of FITC-dextran 40,000 within the lumina of isolated rat brain capillaries during incubation with 1-O-pentylglycerol and 2-O-hexyldiglycerol, indicating enhanced paracellular transfer via tight junctions. Intracarotid co-administration of MTX and 1-O-pentylglycerol (200 mm) in nude mice resulted in a significant increase in MTX concentrations in the ipsilateral brain as compared to controls without 1-O-pentylglycerol (P<0.005). 4. In conclusion, 1-O-pentylglycerol increases delivery of small and large compounds to normal brain and brain tumors and this effect is mediated at least in part by enhanced permeability of tight junctions.

Animals↗
PubMed2001

Interstitial brain adenosine and xanthine increase during jugular venous oxygen desaturations in humans after traumatic brain injury.

OBJECTIVE: Adenosine decreases the cerebral metabolic rate for oxygen and increases cerebral blood flow, and it may play an important role in cerebrometabolic and cerebrovascular responses to hypoperfusion after traumatic brain injury. Jugular venous oxygen saturation is monitored after traumatic brain injury to assess brain oxygen extraction, and desaturations may reflect secondary brain insults. We hypothesized that brain interstitial adenosine and related purine metabolites would be increased during jugular venous oxygen saturation desaturations (<50%) and determined associations between the purines, lactate, and glucose to assess the role of adenosine during secondary insults in humans. DESIGN: Study of critically ill adults with severe traumatic brain injury. SETTING: Adult neurointensive care unit. PATIENTS: We prospectively defined periods of normal saturation and desaturation in six patients after severe traumatic brain injury. INTERVENTIONS: During these periods, cerebral microdialysis samples of brain interstitial fluid were collected, and adenosine and purine metabolites were measured by high-pressure liquid chromatography. MEASUREMENTS AND MAIN RESULTS: Adenosine increased 3.1-fold and xanthine increased 2.5-fold during desaturation periods (both p <.05 vs. normal saturation period, signed rank). Adenosine, xanthine, hypoxanthine, and cyclic-adenosine monophosphate correlated with lactate over both study periods (r(2) =.32,.14,.31,.07, and.26, respectively, all p <.05, Pearson product moment correlation). CONCLUSION: The marked increases in interstitial brain adenosine that occur during jugular venous oxygen desaturations suggest that adenosine may play an important role during periods of secondary insults after traumatic brain injury. The correlation of these metabolites with lactate further suggests that adenosine is increased during periods of enhanced glycolytic metabolism.

Adenosine↗
PubMed1984

Chemotherapeutic agent permeability to normal brain and delivery to avian sarcoma virus-induced brain tumors in the rodent: observations on problems of drug delivery.

Four chemotherapeutic agents (cyclophosphamide, 5-fluorouracil (5-FU), methotrexate (MTX), and bleomycin) were given intravenously to rats harboring the avian sarcoma virus-induced glioma. Drug content in brain, tumor, and systemic tissue was measured. The uptake of drug and the consistency of drug levels in normal brain and tumor varied widely among these agents. [14C]Cyclophosphamide and its metabolites penetrated normal brain and, to a greater extent, brain tumor. [14C]5-FU and its metabolites also entered normal brain and brain tumor, but to lesser extent than [14C] cyclophosphamide and its metabolites. Immunoreactive MTX entry into tumor was variable, ranging from 30 to 1080 ng/g of tissue, with only minimal concentrations in normal brain. After conventional doses, immunoreactive bleomycin levels in tumor were also variable, ranging from 24 to 164 mu units/g of tissue, and little if any drug entered surrounding brain. In addition, the cerebrovascular permeability of 5-FU and MTX in normal rats was measured. Utilizing the method of Rapoport, the PA (product of permeability and capillary surface area) of 5-FU was found to be 6- to 12-fold greater than that of MTX. The PA of both drugs was increased 4- to 7-fold after osmotic blood-brain barrier opening. The variable "leakiness" of glial tumors, both experimentally and clinically, as well as the varied permeabilities of different water-soluble chemotherapeutic agents, makes the drug delivery problem in brain tumors a very complex issue.

Animals↗