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PubMed1992

Melphalan penetration of the blood-brain barrier via the neutral amino acid transporter in tumor-bearing brain.

Melphalan, a nitrogen mustard derivative of the neutral amino acid L-phenylalanine, was transported across the rat blood-brain barrier by the large (L-system) neutral amino acid transporter in tumor-bearing brain, but no evidence for blood-brain barrier transport by the alanine-serine-cysteine system carrier was obtained in the present study. The ability of melphalan to inhibit phenylalanine uptake was compared in rats implanted with two experimental CNS tumors: the C-6 glioma (a model of primary brain tumors) and Walker carcinoma (a model of metastatic brain tumors). The melphalan concentration which caused 50% inhibition of blood-brain barrier (BBB) phenylalanine uptake (Ki) was 0.49 +/- 0.18 mM in the Walker tumor, compared with 0.46 +/- 0.19 mM in the contralateral control brain. In the ipsilateral hemisphere (Ki = 0.59 +/- 0.25 mM) and contralateral hemisphere (Ki = 0.45 +/- 0.19 mM), drug entry was also via the neutral amino acid transporter. In C-6 gliomas (Ki = 0.77 +/- 0.20 mM) and contralateral control brain (Ki = 0.84 +/- 0.29 mM), melphalan also inhibited BBB phenylalanine transport. A major finding was that, at melphalan concentrations greater than 1.0 mM, BBB permeability of radiolabeled indium (chelated to EDTA) increased in proportion to melphalan concentration. In the contralateral hemisphere of rats implanted with C-6 gliomas, brain extractions of indium-EDTA measured 3 to 4% in the absence of drug, 5 to 6% at 2.5 mM melphalan, and 9 to 10% at 5 mM melphalan. A similar phenomenon was observed in the nontumoral brain regions of rats implanted with Walker carcinoma cells. In normal (nonimplanted) rats, melphalan's inhibition (Ki = 0.29 mM) of phenylalanine and tryptophan (Ki = 0.20 mM) uptake was confirmed, and brain extraction of sucrose (a nonspecific marker which does not penetrate the intact BBB) was observed to increase in proportion to melphalan concentration. We conclude that melphalan not only enters the brain via the neutral amino acid transporter, but at higher concentrations (greater than 1 mM) may open the blood-brain barrier in a nonspecific manner.

Amino Acid Transport Systems↗
PubMed1986

Phenylalanine transport at the human blood-brain barrier. Studies with isolated human brain capillaries.

The exquisite sensitivity of brain amino acid availability to changes in plasma amino acid composition arises from the uniquely high affinity (low Km) of blood-brain barrier transport sites as compared to cell membrane transport systems in nonbrain tissues. The extension of this paradigm from rats to man assumes that the Km of blood-brain barrier amino acid transport in the human is low as in the rat. This hypothesis is tested in the present studies wherein isolated human brain capillaries are used as a model system for the human blood-brain barrier. Capillaries were obtained from autopsy brain between 20 and 45 h after death and were isolated in high yield and free of adjoining brain tissue. [3H]Phenylalanine transport into the isolated human, rabbit, or rat brain capillary was characterized by two saturable transport systems and a nonsaturable component. The Km values of phenylalanine transport into brain capillaries via the two saturable systems averaged 0.26 +/- 0.08 and 22.3 +/- 7.1 microM for five human subjects. These studies provide the first evidence for a very high affinity (Km = 0.26 microM) neutral amino acid transport system at the blood-brain barrier, and it is hypothesized that this system is selectively localized to the brain side of the blood-brain barrier. The results also show that the transport Km values for phenylalanine transport are virtually identical at both the rat and human blood-brain barrier.

Adult↗
PubMed1994

Catfish express two forms of insulin-like growth factor-I (IGF-I) in the brain. Ubiquitous IGF-I and brain-specific IGF-I.

Insulin-like growth factor-I (IGF-I) is expressed not only in liver, but also in brain and other tissues. This ubiquitous IGF-I has a complex pattern of expression due to multiple transcription start sites, polyadenylation sites and exon skipping. We have isolated a cDNA encoding a brain-specific IGF-I from a catfish brain cDNA library. Also, a fragment encoding ubiquitous IGF-I was amplified from brain and liver mRNA and the deduced protein shown to be distinct (66% sequence identity) from brain-specific IGF-I. Consistent with other IGF-I prepropeptides, the brain-specific IGF-I has a 43-residue signal peptide followed by B, C, A, D, and E domains. Retained in the catfish brain-specific IGF-I peptide are residues predicted to be involved with the correct tertiary folding, disulfide linkages, and receptor binding. Northern blot analysis of poly(A+)-rich mRNA from brain indicated a single 1600-base pair transcript; a band was not detected from mRNA of liver, stomach, pancreas, pituitary, blood, herring brain, or brain poly(A-) RNA. A sensitive reverse transcriptase/polymerase chain reaction assay also showed that brain-specific IGF-I mRNA was expressed solely in the Thai catfish brain but not liver, stomach, pancreas, pituitary, ovary, and African catfish brain.

Amino Acid Sequence↗
PubMed1996

Immunohistochemical localization of brain-derived neurotrophic factor in adult rat brain.

To investigate the role of brain-derived neurotrophic factor in the central nervous system, we produced an anti-peptide antibody that specifically recognized brain-derived neurotrophic factor and performed immunohistochemistry for brain-derived neurotrophic factor-like immunoreactivity in normal adult rat brain. A synthetic peptide (EKVPVSKGQL), derived from mature brain-derived neurotrophic factor, was conjugated to bovine thyroglobulin at a ratio of 1:3 and used as an immunogen to produce a high-titre anti-brain-derived neurotrophic factor polyclonal antibody in Japanese white rabbits. Dot blotting demonstrated that the antiserum could detect 3.91 pmol of synthetic peptide, and Western blotting showed that the antiserum recognized one band with a molecular weight consistent with that of brain-derived neurotrophic factor. In immunohistochemistry, brain-derived neurotrophic factor-like immunoreactivity was widespread in adult rat brain, including cerebral cortex, hippocampus, basal forebrain, striatum, hypothalamus, brainstem and cerebellum. Not only neuronal somata but also nerve fibres showed positive staining. Our data suggest that brain-derived neurotrophic factor is transported through axons in a subpopulation of neurons in adult rat brain, and that brain-derived neurotrophic factor influences a great variety of neurons and acts as a neurotrophic factor in the central nervous system.

Animals↗
PubMed1999

Regulation of pituitary adenylate cyclase activating polypeptide and its receptor type 1 after traumatic brain injury: comparison with brain-derived neurotrophic factor and the induction of neuronal cell death.

Neurotrophic factors are known to promote neuronal survival during development and after acute brain injury. Recent data suggest that some neuropeptides also exhibit neurotrophic activities, as shown for the pituitary adenylate cyclase activating polypeptide, which increases the survival of various neuronal populations in culture. Employing in situ hybridization techniques, we have studied the regulation of messenger RNA for pituitary adenylate cyclase activating polypeptide and its receptor type 1 after a moderate traumatic brain injury to rat brain cortex. We have further compared their messenger RNA expression to that of brain-derived neurotrophic factor and to the amount of cell death occurring in the brain at various times after the brain injury. Levels of brain-derived neurotrophic factor messenger RNA increased rapidly within 2 h after trauma in cortex and hippocampus, and returned to control levels thereafter. The levels of messenger RNA for pituitary adenylate cyclase activating polypeptide also increased with time in the injured brains and reached maximal expression at 72 h, i.e. the end of the observation period. The alterations in pituitary adenylate cyclase activating polypeptide messenger RNA levels were particularly pronounced in the perifocal region and in the ipsilateral dentate gyrus of the brain injury. In contrast, the messenger RNA levels encoding pituitary adenylate cyclase activating polypeptide receptor type 1 first decreased after trauma and were then normalized in the dentate gyrus. There was a large increase in the number of cells labelled for DNA breaks at 12 h post-trauma, indicative of enhanced cell death. The number of labelled cells, however, decreased at later stages concomitant with an increase in the expression of pituitary adenylate cyclase activating polypeptide messenger RNA. Pituitary adenylate cyclase activating polypeptide rescued cortical neurons in cultures against ionomycin-induced cell death, supporting the concept of a neuroprotective effect for the peptide. These results demonstrate a differential regulation of messenger RNA for brain-derived neurotrophic factor and the pituitary adenylate cyclase activating polypeptide and its receptor after brain trauma. The data also suggest that pituitary adenylate cyclase activating polypeptide might have a beneficial effect in brain injury by counteracting neuronal cell death.

Animals↗
PubMed2003

Intraoperative monitoring of brain tissue oxygen and carbon dioxide pressures reveals low oxygenation in peritumoral brain edema.

Brain edema and swelling often complicate surgery for brain tumors. Its pathophysiology is unclear, as is the relationship with brain tissue oxygenation. Our hypothesis was that brain edema around tumor is cytotoxic type caused by impaired local tissue oxygenation due to increased local tissue pressure. Therefore, we monitored brain tissue oxygen pressure (p(ti)O2) and carbon dioxide pressure (p(ti)CO2) in 19 patients undergoing craniotomy for removal of a brain tumor and specifically studied the effect of decompression by dura opening and by tumor removal with respect to the presence of brain swelling. Before craniotomy, multiparameter sensors were inserted into the peritumoral brain tissue guided by MRI-based stereotaxy. In eight patients who had severe brain swelling upon opening of the dura mater, p(ti)O2 immediately rose from 7 +/- 8 mm Hg to 24 +/- 15 mm Hg ( < 0.05), whereas in patients who did not have swelling, p(ti)O2 went from 16 +/- 9 to 18 +/- 10 mm Hg after opening of the dura. The mean p(ti)O2 of all patients at the start of resection of the tumor was 18 +/- 11 mm Hg, and increased to 30 +/- 15 mm Hg after resection was completed ( < 0.05). The effect on p(ti)O2 of raising the FiO2 to 1.0 was limited in this group of patients, as an increase greater than 50% was found in only six of twelve patients. Notably, in six patients, sensor malfunctions or associated hardware problems occurred, prohibiting useful data acquisition. We conclude that brain tissue oxygenation is reduced in the peritumoral area and improves after local tissue pressure relief, especially in patients with brain swelling. Thus, ischemic processes may contribute to brain edema around tumors. Intraoperative p(ti)O2 monitoring may enhance the safety of neuroanesthesia, but the high incidence of failures with this type of sensor remains a matter of concern.

Adult↗
PubMed1986

Disruption of the blood-brain barrier in cerebrum and brain stem during acute hypertension.

The purpose of this study was to examine hemodynamic mechanisms of protection of the blood-brain barrier in the brain stem during acute hypertension. We used a new method to examine the microcirculation of the brain stem. Intravital fluorescent microscopy and fluorescein-labeled dextran were used to evaluate disruption of the blood-brain barrier during acute hypertension in rats. During control conditions, pressure (servo null) in arterioles (60 microns in diameter) was 50 +/- 2% (mean +/- SE) of systemic arterial pressure in the cerebrum and 67 +/- 1% of systemic arterial pressure in the brain stem (P less than 0.05 vs. cerebrum). In the cerebrum, pial venous pressure increased from 7 +/- 1 to 25 +/- 2 mmHg during acute hypertension, and there was marked disruption of the blood-brain barrier in venules (26 +/- 2 leaky sites). In contrast, in the brain stem, pial venous pressure increased from 4 +/- 1 to only 8 +/- 1 mmHg (P less than 0.05 vs. cerebrum), and there was minimal disruption of the blood-brain barrier in venules (1.5 +/- 0.6 leaky sites, P less than 0.05 vs. cerebrum). During acute hypertension, increases in blood flow (microspheres) were less in brain stem than in cerebrum. The findings suggest distribution of vascular resistance differs in the brain stem and cerebrum under control conditions, whereas large arteries account for a greater fraction of resistance in cerebrum; pial venous pressure increases less in brain stem than cerebrum during acute hypertension, so that the blood-brain barrier is protected.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1984

The kallikrein-kinin system as mediator in vasogenic brain edema. Part 2: Studies on kinin formation in focal and perifocal brain tissue.

Vasogenic edema was induced in mongrel cats by cold injury to study uptake and activation of the plasma-kallikrein-kinin system in central nervous system (CNS) tissue. A method was developed for quantitative assessment of kinin formation in affected brain tissue areas. Gross disruption of the blood-brain barrier by focal trauma causes marked penetration of plasma kininogens into necrotic and edematous brain tissue. Moreover, the kallikrein-kinin (KK) system was activated in both necrotic and perifocal edematous areas, and was markedly enhanced by additional cerebral ischemia. Formation of kinins in necrotic brain tissue led to consumption of approximately 60% to 80% of the amount of kininogens being taken up. In perifocal edematous tissue, formation of kinins was less pronounced, or even absent. However, if cerebral ischemia evolved after severe intracranial hypertension, kinins were also formed in the perifocal edematous brain. The intravascular origin of kininogens found in pathological tissue areas secondary to injury was deduced from the observation that cerebral tissue of the contralateral hemisphere with an intact blood-brain barrier had no measurable quantities of kininogens. Consumption of plasma kininogens or formation of kinins were assessed as the difference of the total amount of plasma kininogens taken up into the tissue minus the amount of kininogens found in the brain at postmortem examination. The data indicate that uptake and activation of the plasma-KK system might occur under all pathological conditions in which blood-brain barrier damage permits cerebral penetration of plasma proteins, such as with cerebral contusion, focal ischemia, and tumors. The potent pathophysiological mechanisms induced by kinins in CNS tissue, such as formation of brain edema, microcirculatory dysfunction, and enhancement of blood-brain barrier permeability, together with their formation in focal and perifocal pathological brain tissue, provide further support for a mediator function of the KK system. Methods that specifically interfere with the formation of kinins in damaged brain should therefore be expected to attenuate vasogenic edema.

Animals↗
PubMed1998

Changes in brain barbiturate concentration in brain-dead rabbits.

Pentobarbital concentration was evaluated in the brain tissues of brain-dead rabbits. Pentobarbital was infused into the vein of Japanese white male rabbits at 60 mg/kg/h until an isoelectric EEG of the cortex was reached. Brain death was induced by inflation of a balloon catheter placed in the subdural space. The diagnosis of brain death was confirmed by a flat line ABR wave. A significant increase in heart rate, intracranial pressure, and mean arterial pressure, was observed following brain death induction. These parameters returned to below basal values within 60 mm. Immediately after, and at 6 h and 24 h after brain death, each group of rabbits was sacrificed by phenobarbital overdose, and brains were then removed for determination of pentobarbital concentration in the brain tissue. Blood pentobarbital disappeared about 18 h after brain death was induced. Although the brain pentobarbital concentration slightly decreased over time, a high concentration of pentobarbital remained in the brain 24 h after brain death was induced.

Animals↗
PubMed1999

Characteristics of brain injury-derived neurotrophic peptide-binding sites on rat brain synaptosomes and neurons in culture.

Brain injury-derived neurotrophic peptide is the fragmental 13-mer peptide of the novel neurotrophic factor which was extracted and purified from Sponge Gelform made of gelatin implanted at the mechanically-induced injury site in neonatal rat brains. Brain injury-derived neurotrophic peptide supports survival of septal cholinergic and mesencephalic dopaminergic neurons in culture, and rescues hippocampal neurons in culture from glutamate neurotoxicity. Here we studied the binding characteristics of brain injury-derived neurotrophic peptide to synaptosomes from normal adult rat brains and neurons in culture from neonatal rat brains. [125I]Asp-[Tyr11]-brain injury-derived neurotrophic peptide binding to rat brain synaptosomes was specific and saturable. Equilibrium binding studies revealed that [125I]Asp-[Tyr11]-brain injury-derived neurotrophic peptide bound to 1.1 pmol/mg protein with a Kd (dissociation constant) of 0.17 microM in hippocampal synaptosomes and to 2.0 pmol/mg protein with a Kd of 0.38 microM in septal synaptosomes. [125I]Asp-[Tyr11]-brain injury-derived neurotrophic peptide could bind to a subpopulation of hippocampal neurons in culture from embryonic rat brains. Affinity cross-linking with the carboxyl-reactive cross-linking reagent 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-HCl and [125I]Asp-[Tyr11]-brain injury-derived neurotrophic peptide produced radiolabeled bands corresponding to 100,000, 50,000 and 40,000 mol. wt molecules on hippocampal neurons in culture. These results suggest that the 13-mer sequence of brain injury-derived neurotrophic peptide plays a crucial role in expressing the neurotrophic properties of the factor.

Animals↗
PubMed2000

Calcium channel blockers for acute traumatic brain injury.

BACKGROUND: Acute traumatic brain injury is a major cause of death and disability. Calcium channel blockers have been used in an attempt to prevent cerebral vasospasm after injury, maintain blood flow to the brain and so prevent further damage. OBJECTIVES: To estimate the effects of calcium channel blockers in patients with acute traumatic brain injury and in a subgroup of brain injury patients with traumatic subarachnoid haemorrhage. SEARCH STRATEGY: Hand searching and electronic searching for randomized controlled trials available by October 1997. SELECTION CRITERIA: Randomized controlled trials in patients with all levels of severity of clinically diagnosed acute traumatic brain injury. DATA COLLECTION AND ANALYSIS: Two reviewers (JL and CG) independently assessed the identified studies for eligibility and extracted data from each study. Summary odds ratios were calculated using the Mantel-Haenszel method. MAIN RESULTS: Four RCTs were identified as eligible for inclusion in the systematic review. The effect of calcium channel blockers on the risk of death was reported in all RCTs. The pooled odds ratio for the four studies was 0.91 (95% confidence interval 0. 70 to 1.17). For the three RCTs that reported death and severe disability the pooled odds ratio was 0.85 (95% CI 0.68 to 1.07). In the two RCTs which reported the risk of death in a sub group of traumatic subarachnoid haemorrhage patients, the pooled odds ratio was 0.59 (95% CI 0.37 to 0.94). Three RCTs reported death and severe disability as an outcome in this subgroup, and the pooled odds ratio was 0.67 (95% CI 0.46 to 0.98). REVIEWER'S CONCLUSIONS: This systematic review of randomized controlled trials of calcium channel blockers in acute traumatic head injury patients shows that considerable uncertainty remains over their effects. The effect of nimodipine in a subgroup of brain injury patients with subarachnoid haemorrhage shows a beneficial effect, though the increase in adverse reactions suffered by the intervention group may mean that the drug is harmful for some patients.

Brain Injuries↗
PubMed1990

The brain-type glucose transporter mRNA is specifically expressed at the blood-brain barrier.

The brain-type glucose transporter (bGT) is assumed to be distributed among neurons and glial cells, but to be particularly enriched in brain microvascular endothelium, which makes up the blood-brain barrier (BBB) in vivo. However, in the course of the present studies it was found that the bGT is specifically expressed at the BBB in brain. The relative abundance of bGT and actin (used as a control) mRNAs were measured in bovine brain, brain capillaries, and capillary-depleted brain. Northern blot analysis showed that the bGT 2.9 Kb mRNA was increased 21-fold in brain capillaries as compared to total brain, and it was not detected in capillary-depleted brain even after overexposure of the film. This study demonstrates that i) the bGT is specifically expressed at the BBB in brain, ii) the bGT transcript in total brain represents only dilution of the capillary or BBB glucose transporter transcript, and iii) as yet unidentified glucose transporters are likely expressed in neurons and in glial cells.

Actins↗
PubMed1998

Correlations between brain tissue oxygen tension, carbon dioxide tension, pH, and cerebral blood flow--a better way of monitoring the severely injured brain?

BACKGROUND: The ideal method for monitoring the acutely injured brain would measure substrate delivery and brain function continuously, quantitatively, and sensitively. We have tested the hypothesis that brain PO2, pCO2, and pH, which can now be measured continuously using a single sensor, are valid indicators of regional cerebral blood flow (CBF) and oxidative metabolism, by measuring its product, brain pCO2. METHODS: Twenty-five patients (Glasgow Coma Score < or = 8) were studied. A Clark electrode, combined with a fiber optic system (Paratrend 7, Biomedical Sensors, Malvern, PA) was used to measure intraparenchymal brain PO2, pCO2, and pH. Data were averaged over a 1-h period before and after CBF studies. Regional CBF was measured around the probe, using stable xenon computed tomography. Regression analyses and Spearman Rank tests were used for data analysis. RESULTS: Regional CBF and mean brain PO2 were strongly correlated (r=0.74, p=0.0001). CBF values < 18 mL/100 g/min were all accompanied by brain PO2 < or = 26 mm Hg. The four patients with a brain PO2 < 18 mm Hg died. Brain pCO2 and pH, however, were not correlated with CBF (r=0.36, p=0.24 and r=0.30, p=0.43, respectively). CONCLUSIONS: Until recently, substrate supply to the severely injured brain could only be intermittently estimated by measuring CBF. The excellent intra-regional correlation between CBF and brain pO2, suggests that this method does allow continuous monitoring of true substrate delivery, and offers the prospect that measures to increase O2 delivery (e.g., increasing CBF, CPP, perfluorocarbons etc.) can be reliably tested by brain PO2 monitoring.

Blood Flow Velocity↗
PubMed1997

Ethanol alters brain phospholipid levels which correlate with altered brain morphology.

The effects of embryonic exposure on brain phospholipid levels were studied by injecting various concentrations of ethanol into fertile chicken eggs at 0 days of development. At 18 days of development, the levels of total phospholipids and various phospholipid classes were assayed in brain tissue and correlated to neuron densities within the cerebral hemispheres and the optic lobes. Although ethanol concentrations ranging from 0 to 3700 microns/Kg egg wt. failed to influence either total brain weight or total brain phospholipid levels, ethanol-induced changes in the levels of individual phospholipid classes were observed. When injected with 7 microns of ethanol/Kg egg wt., a 2- to 3-fold increase in brain phosphatidylethanolamine (PE) levels were observed with reduced levels of brain phosphatidylcholine (PC) and brain sphingomyelin (SP). When injected with 74 microns of ethanol/Kg egg wt., ethanol-induced increases in brain phosphatidylserine (PS) and PE were observed with ethanol-induced decreases in brain PC and SP. Cell fractionation studies demonstrated ethanol-induced increases in brain PE and PS and ethanol-induced decreases in brain PC and SP in nuclear, mitochondrial, and microsomal membranes. These ethanol-induced alterations in brain phospholipid profiles correlated with ethanol-induced reductions in neuron densities within the cerebral hemispheres and optic lobes.

Animals↗
PubMed2000

Brain-derived neurotrophic factor administration after traumatic brain injury in the rat does not protect against behavioral or histological deficits.

Brain-derived neurotrophic factor has been shown to be neuroprotective in models of excitotoxicity, axotomy and cerebral ischemia. The present study evaluated the therapeutic potential of brain-derived neurotrophic factor following traumatic brain injury in the rat. Male Sprague-Dawley rats (N=99) were anesthetized and subjected to lateral fluid percussion brain injury of moderate severity (2.4-2.8 atm) or sham injury. Four hours after injury, the animals were reanesthetized, an indwelling, intraparenchymal cannula was implanted, and infusion of brain-derived neurotrophic factor or phosphate-buffered saline vehicle was initiated from a mini-osmotic pump and continued for two weeks. In Study 1 (N=48), vehicle or 12 microg/day of brain-derived neurotrophic factor was infused into the dorsal hippocampus. In Study 2 (N=51), vehicle or brain-derived neurotrophic factor at a high (12 microg/day) or low dose (1.2 microg/day) was infused into the injured parietal cortex. All animals were evaluated for neurological motor function at two days, one week and two weeks post-injury. Cognitive function (learning and memory) was assessed at two weeks post-injury using a Morris Water Maze. At two weeks post-injury, neuronal loss in the hippocampal CA3 and dentate hilus and in the injured cortex was evaluated. In Study 2, neuronal loss was also quantified in the thalamic medial geniculate nucleus. All of the above outcome measures demonstrated significant deleterious effects of brain injury (P<0.05 compared to sham). However, post-traumatic brain-derived neurotrophic factor infusion did not significantly affect neuromotor function, learning, memory or neuronal loss in the hippocampus, cortex or thalamus when compared to vehicle infusion in brain-injured animals, regardless of the infusion site or infusion dose (P>0.05 for each). In contrast to previous studies of axotomy, ischemia and excitotoxicity, our data indicate that brain-derived neurotrophic factor is not protective against behavioral or histological deficits caused by experimental traumatic brain injury using the delayed, post-traumatic infusion protocol examined in these studies.

Animals↗
PubMed1999

Barrier mechanisms in the brain, I. Adult brain.

1. The adult brain functions within a well-controlled (internal) environment that is separate from that of the internal environment of the rest of the body as a whole. 2. The underlying mechanism of control of the brain's internal environment lies in the presence of tight junctions between the cerebral endothelial cells at the blood-brain interface (blood-brain barrier) and between choroid plexus epithelial cells (blood-cerebrospinal fluid (CSF) barrier). 3. The effect of tight junctions at the blood-brain and blood-CSF barriers is to convert the properties of the individual endothelial and epithelial cells into properties of these interfaces as a whole. 4. Superimposed on the diffusion restriction provided by the tight junctions in the blood-brain and blood-CSF barriers is a series of transport mechanisms into and out of the brain and CSF that determine and control the internal environment of the brain with respect to a wide range of molecules, such as electrolytes, amino acids, glucose, vitamins and peptides. 5. The physical characteristics of drugs, together with their interaction with the properties of the barriers between blood, brain and CSF, determine the extent to which drugs penetrate into the brain. 6. Drugs can be targeted to the brain by making use of knowledge of this interaction between the physical properties of a drug (which can be modified by manipulation of the structure of the molecule in predictable ways) and the influx/efflux mechanisms present in the blood-CSF and blood-brain interfaces.

Adult↗
PubMed1996

Lack of the DNA repair protein O6-methylguanine-DNA methyltransferase in histologically normal brain adjacent to primary human brain tumors.

Exposure to exogenous alkylating agents, particularly N-nitroso compounds, has been associated with increased incidence of primary human brain tumors, while intrinsic risk factors are currently unknown. The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is a major defense against the carcinogenicity of N-nitroso compounds and other alkylators. We report here that in 55% (64/117) of cases, histologically normal brain tissue adjacent to primary human brain tumors lacked detectable MGMT activity [methyl excision repair-defective (Mer-) status]. The incidence of Mer- status in normal brain tissue from brain tumor patients was age-dependent, increasing from 21% in children 0.25-19 years of age to 75% in adults over 50. In contrast, Mer- status was found in 12% (5/43) of normal brain specimens from patients operated for conditions other than primary brain tumors and was not age-dependent. The 4.6-fold elevation in incidence of Mer- status in brain tumor patients is highly significant (chi2 = 24; p < or = 0.001). MGMT activity was independent of age in the lymphocytes of brain tumor patients and was present in lymphocytes from six of nine tumor patients whose normal brain specimen was Mer-. DNA polymerase beta, apurinic/apyrimidinic endonuclease, and lactate dehydrogenase activities were present in all specimens tested, including Mer- specimens from brain tumor patients. Our data are consistent with a model of carcinogenesis in human brain in which epigenetically regulated lack of MGMT is a predisposing factor and alkylation-related mutagenesis is a driving force.

Adolescent↗
PubMed2005

Differences between brain and rectal temperatures during routine critical care of patients with severe traumatic brain injury.

Theoretical models suggest that small differences only exist between brain and body temperature in health. Once the brain is injured, brain temperature is generally regarded to rise above body temperature. However, since reports of the magnitude of the temperature gradient between brain and body vary, it is still not clear whether conventional body temperature monitoring accurately predicts brain temperature at all times. In this prospective, descriptive study, 20 adults with severe primary brain trauma were studied during their stay in the neurointensive care unit. Brain temperature ranged from 33.4 to 39.9 degrees C. Comparisons between paired brain and rectal temperature measurements revealed no evidence of a systematic difference [mean difference -0.04 degrees C (range -0.13 to 0.05 degrees C, 95% CI), p = 0.39]. Contrary to popular belief, brain temperature did not exceed systemic temperature in this relatively homogeneous patient series. The mean values masked inconsistent and unpredictable individual brain-rectal temperature differences (range 1.8 to -2.9 degrees C) and reversal of the brain-body temperature gradient occurred in some patients. Brain temperature could not be predicted from body temperature at all times.

Abbreviated Injury Scale↗