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PubMed2003

Stereotactic radiosurgery (SRS) for multiple metastatic brain tumors: effects of the number of target tumors on exposure dose in normal brain tissues.

BACKGROUND: This study was carried out to clarify the practical limit of the number of stereotactic radiosurgery (SRS)-targeted tumors based on the irradiation dose of normal brain tissues. METHODS: Twenty-five patients with multiple brain metastases who received SRS from October 1998 to May 2002 were enrolled in the study. In each patient, the treatment options were thoroughly studied before deciding upon a course of treatment. The number of irradiated targets was increased one by one until all of the targets were included in a treatment plan. Given a surface dose of 25 Gy, we calculated the dose volume histogram (DVH) for the entire brain in each treatment plan and compared it with those of other treatment plans. Ultimately, only 5 of the 25 patients received irradiation for all of their tumors; the others received selective irradiation targeting only those tumors that were causing symptoms. RESULTS: When the number of targets increased, the DVH curve shifted to the right. The volume of the brain irradiated at a dose of 5 Gy or higher was 25.7% or less for 4 or fewer targets, 45.7% for 5-6 targets, 81.0% for 7-8 targets and 100% for 9-11 targets. When the number of the targets exceeded 8, more than 50% of the entire brain was irradiated at levels of at least 8.7 Gy. The dose distribution became very complex as the number of targets increased. Although the survival time of the group in which tumors were selectively targeted was longer than that in the group in which all tumors were irradiated, the difference between the two groups was not statistically significant ( P = 0.2537). CONCLUSION: In SRS for multiple brain metastases, risks of both acute and late sequelae may increase because the exposure dose to normal brain tissues increases with increased numbers of target tumors. Dose distribution becomes more complex according to the increase in the number of targets. Based on our DVH curves, we conclude that the exposure dose to normal brain tissues is acceptable when the number of targets is less than 7. Importantly, our study also reveals that it may not be necessary or desirable to irradiate all metastatic tumors.

Adult↗
PubMed1987

Demonstration and structural comparison of receptors for insulin-like growth factor-I and -II (IGF-I and -II) in brain and blood-brain barrier.

Specific receptors for insulin-like growth factors (IGF) I and II on microvessel-free rat brain cell membranes (RBCM) and in the microvessels that constitute the blood-brain barrier (BBB) were identified and characterized by means of affinity cross-linking techniques and specific anti-receptor antibodies. Two different models of BBB were examined: isolated rat brain capillaries and cultured bovine brain microvessel endothelial cells. Cross-linking with 125-I-IGF-I, followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), revealed an alpha subunit of apparent Mr = 138,000 in both BBB preparations, compared to 120,000 in RBCM. Cross-linking was inhibited by unlabeled IGF and insulin, but not by antibody directed against the IGF-II receptor. When 125-I-IGF-II was cross-linked, followed by SDS-PAGE under reducing conditions, a major band of apparent Mr = 250,000 was identified in RBCM and both BBB preparations. This band, which migrated with an approximately equivalent Mr in both brain and BBB membranes, was inhibited by unlabeled IGF and by antibody specific for the IGF-II receptor. Thus, both rat and bovine brain microvessels possess classical Type I and II IGF receptors. While the alpha subunit of the Type I receptor of brain is smaller than that of the BBB, the Type II receptor of brain and BBB appear to be structurally and immunologically identical.

Animals↗
PubMed1977

Brain protein metabolism and the acquisition of new behaviors. II. Immunological studies of the alpha, beta and gamma proteins of goldfish brain.

In a previous study, the labeling pattern of three proteins (alpha, beta and gamma) in goldfish brain was found to change after the animals successfully acquired a new pattern of behavior. In the present study, these proteins were isolated from the brain cytoplasmic fraction, purified by successive gel electrophoresis and used as antigent to immunize rabbits. Antisera containing antibodies to two of the proteins (beta and gamma) were obtained. These gave single precipitin bands when plated against the antigens and a mixture of the total cytoplasmic proteins. The distribution of beta and gamma in brain subcellular fractions and in a variety of goldfish tissues was determined by immunodiffusion methods. gamma was specific to brain. The beta protein cross-reacted but was not identical to a widely distributed substance in plasma, liver and kidney. Both beta and gamma appear to be species specific in that no cross-reactivity was obtained with mouse, chick or rat brain proteins. Immunological methods, in combination with double labeling experiments were used to establish that the beta and gamma antigens were proteins which were normally present in goldfish brain. Both the beta and gamma antisera were equally capable of specifically precipitating the proteins which were differentially labeled after training as well as purified proteins of the same molecular weight present in the brains of control animals. These results suggest that the acquisition of a new pattern of behavior can increase the demand for the synthesis of specific proteins (beta and gamma) normally present in goldfish brain.

Animals↗
PubMed1990

Effects of internal carotid administration of MPTP on rat brain and blood-brain barrier.

Unlike primates, rats are resistant to systemic 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) neurotoxicity, but direct infusion of MPTP into rat substantia nigra causes specific destruction of dopaminergic neurons. We now demonstrate that rats are resistant to MPTP neurotoxicity even when MPTP is injected directly into the brain circulation. Injection of 1-3.5 mg of MPTP into the internal carotid artery of Wistar rats causes no behavioral or motor abnormalities and small, but significant, dopamine loss in the ipsilateral striatum. MPTP caused no changes in the levels of norepinephrine or serotonin in the cerebral cortex. Higher doses of intracarotid MPTP were lethal. Pretreatment with pargyline, a monoamine oxidase inhibitor, did not alter the mortality but prevented dopamine depletion. The high uptake and retention of MPTP by rat brain, yet its failure to cause major dopaminergic toxicity suggest that MPTP is rapidly metabolized in brain capillaries to 1-methyl-4-phenylpyridinium (MPP+) and other polar metabolites that have difficulty in traversing the blood-brain barrier. Sequestration of MPTP metabolites in brain capillary endothelial cells could result in their dysfunction. However, we found no defects in the ability of the blood-brain barrier to prevent the entry of vascular aminoisobutyric acid or horseradish peroxidase into brain in spite of morphologic evidence of endothelial changes and astrocytic swelling after intracarotid MPTP injections. Our results provide further evidence that the rat's resistance to systemic MPTP neurotoxicity is probably due to its unique blood-brain barrier properties.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

Transport of iodothyronines from bloodstream to brain: contributions by blood:brain and choroid plexus:cerebrospinal fluid barriers.

Thyroid hormone entering the brain from the cerebral circulation must first cross barriers at the the blood:brain and choroid plexus:cerebrospinal fluid interfaces. The route taken after entry through those barriers might bring about selective delivery of hormone to different regions of the brain and those differences might be crucial for the ultimate functional effects of the hormone. To determine whether and how distribution of hormone in the brain might vary according to the route of entry, film autoradiograms of serially sectioned brains were prepared after delivery of a pulse of 125I-labeled thyroid hormone into either the right lateral cerebral ventricle or the femoral vein. The results after intrathecal injection, reflecting the penetration of hormone into brain after crossing the choroid plexus:cerebrospinal fluid barrier, revealed a markedly limited, essentially periventricular distribution of radioactivity at both 3 and 48 h after hormone administration. Results after i.v. administration, which allows hormone access across both barriers, revealed an initial distribution pattern (at 3 h) generally similar to that seen after administration of markers of cerebral blood flow; at 48 h there was strong resolution in selected brain regions never noted to be labeled after intrathecal hormone injection. The functional implications of the differences in results produced by the two different routes of hormone entry are not known. However, ready access to circumventricular organs would appear to be favored by hormone crossing the choroid plexus:cerebrospinal fluid barrier whereas access to the panoply of nuclear triiodothyronine receptors would be favored by hormone crossing the blood:brain barrier. Therefore both routes of barrier transport should be taken into account in assessing the kinetics and actions of thyroid hormones in the central nervous system.

Animals↗
PubMed1988

Effects of etoposide-induced blood-brain barrier disruption on brain water, intracranial pressure, and cerebral vasomotor tone.

This study investigated the effects of hypertension and water loading on etoposide-induced, reversible blood-brain barrier disruption in a rat model. Twenty-nine animals were divided into four groups: group 1--intracarotid (i.c.) injection of saline followed in 1 h by 5 ml i.c. water; group 2--i.c. etoposide followed by i.c. water; group 3--i.c. saline followed by i.v. metaraminol to increase systemic blood pressure; group 4--i.c. etoposide followed by i.v. metaraminol. Systemic blood pressure and intracranial pressure were monitored continuously. Evans blue staining of the brain was used as a monitor of blood-brain barrier disruption. Animals were killed 1 h after either aramine or water infusion, and the brains removed and inspected for the degree of disruption. After dehydration, brain water was calculated for each hemisphere. Two-thirds of the animals infused with etoposide had evidence of barrier disruption, whereas none of the control animals infused with saline were disrupted. Neither control groups 1 or 3 showed significant change in intracranial pressure after water loading or augmentation of systemic blood pressure, respectively. Group 4 animals failed to demonstrate any significant change in intracranial pressure despite marked barrier disruption and acute hypertension (within the limits of normal autoregulation). A small but statistically significant increase in intracranial pressure was noted in group 2 animals with the greatest degree of barrier disruption. A significant increase in brain water was observed ipsilateral to etoposide infusion in only those animals with the most marked barrier disruption. These results indicate that etoposide-induced blood-brain barrier disruption caused significant increases in brain water without significant alteration of cerebral vasomotor tone or increases in intracranial pressure after water loading except in the most severe disruption. The classic untoward consequences of vasogenic edema were not encountered in the present model.

Animals↗
PubMed1995

Permeability of the developing blood-brain barrier to 14C-mannitol using the rat in situ brain perfusion technique.

The brain penetration of 14C-mannitol was investigated using a bilateral in situ brain perfusion technique followed by capillary depletion analysis. This technique measures the uptake of slowly penetrating solutes in the absence of the systemic circulation, and separates accumulation in brain endothelial cells from uptake into brain parenchyma. Penetration of 14C-mannitol was linear up to 30 min in rats aged 1, 2, 3 weeks and in adults. The brain mannitol space was higher in 1-week-old neonatal rats compared with adults (P < 0.05) and was due to a greater initial volume of distribution (Vi) for mannitol in the neonates, and not due to an elevated transfer rate (K(in)). Thirty percent of mannitol in the neonatal brain was associated with the capillary containing fraction, whereas in the adult only 13% was found in this fraction. This suggests that the permeability of the blood-brain barrier to mannitol does not change significantly with development but that more mannitol is associated with endothelial cells in the neonate. An investigation of 14C-glycine uptake was also carried out, and unlike mannitol the K(in) was greater in the neonate compared to the adult suggesting an elevated rate of transfer for this amino acid into the neonatal rat brain.

Age Factors↗
PubMed1992

24R,25-dihydroxyvitamin D3 prevents aluminum-induced alteration of brain gangliosides in uremic rats by keeping the metal within perivascular astrocytes of the blood-brain barrier.

The administration of aluminum (Al) to uremic rats leads to Al accumulation in different brain regions with subsequent alteration of brain gangliosides. Addition of 24R,25-dihydroxyvitamin D3[24R,25-(OH)2D3] did not influence the brain Al content determined by plasma argon emission spectrometry, but prevented the decrease in brain gangliosides. By using electron microscopy and laser microprobe mass analysis, it was demonstrated that in rats given 24R,25-(OH)2D3 together with Al, the metal was mainly kept within perivascular astrocytes of the blood-brain barrier. On the contrary, in rats given Al only, the metal was evenly distributed throughout the brain areas causing extensive demyelination, chromatolysis of nerve cells in some brain regions (hippocampus) and brain edema. Our results could find application in the prevention of Al-induced encephalopathy in patients on hemodialysis.

24,25-Dihydroxyvitamin D 3↗
PubMed2006

Demonstration of a common artifact in immunosorbent assays of brain extracts: development of a solid-phase extraction protocol to enable measurement of amyloid-beta from wild-type rodent brain.

In the process of developing species-specific, immunosorbent assays for brain amyloid-beta (Abeta) in non-transgenic animals, we have demonstrated an artifact that impedes accurate quantitation of Abeta in this assay format. Using synthetic peptides, cerebrospinal fluid (CSF), or plasma samples, no nonspecific binding or cross-species immunoreactivity was detected in human or rodent Abeta assays. However, extracts of guinea pig brain (human Abeta sequence) or rat brain (rodent Abeta sequence) demonstrated immunoreactivity regardless of which capture antibody, detection antibody, or reporter method (colorimetric or fluorescent) was used. This immunoreactivity remained even in the absence of a capture antibody. Various blocking conditions failed to resolve the nonspecific binding of detection antibodies in the presence of brain extracts. Fractionation of DEA-extracted guinea pig brain over Sephadex G-50 demonstrated the feasibility of separating specific from nonspecific binding components in the brain extracts. Thus, a solid phase extraction method, compatible with multiple extraction buffers, has been developed to isolate and concentrate Abeta from brain extracts. This isolation method eliminates non-specific binding components from brain extracts and allows for accurate quantitation and robust detection of multiple Abeta peptides in extracts from wild-type animals.

Amyloid beta-Peptides↗
PubMed2006

Functional characterization of the brain-to-blood efflux clearance of human amyloid-beta peptide (1-40) across the rat blood-brain barrier.

The present study sought to characterize the brain-to-blood efflux transport of human amyloid-beta peptide (hAbeta)(1-40) across the blood-brain barrier (BBB) in rats. We determined the apparent brain-to-blood [(125)I]hAbeta(1-40) efflux clearance in rats and found it to be 11.0 microL/(ming brain). There were no significant gender differences in the apparent brain-to-blood [(125)I]hAbeta(1-40) efflux clearance. The brain-to-blood [(125)I]hAbeta(1-40) efflux transport was significantly inhibited by unlabeled hAbeta(1-40) and hAbeta(1-42) by 79.1% and 36.4%, respectively, but was not inhibited by hAbeta(1-43) and hAbeta(40-1), and was significantly facilitated by hAbeta(17-40) by 16.0%, which is one of the major proteolytic fragments of hAbeta(1-40) generated by the action of Abeta degradation enzymes, such as endothelin-converting enzyme. Pre-administration of human receptor-associated protein, a low-density lipoprotein receptor-related protein (LRP) antagonist, reduced the elimination of [(125)I]hAbeta(1-40) by 20.3%, while quinidine or verapamil, P-glycoprotein (P-gp) inhibitors, did not significantly affect the elimination. Western blot analysis suggested that LRP-1 is expressed in rat brain capillary endothelial cells. In conclusion, the partial contribution of LRP-1 and the minor contribution of P-gp suggest that the hAbeta(1-40) elimination from rat brain is mediated by as yet unidentified molecules.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

The involvement of the blood-brain and the blood-cerebrospinal fluid barriers in the distribution of leptin into and out of the rat brain.

Leptin is a 16 kDa hormone that is produced by adipose tissue and has a central effect on food intake and energy homeostasis. The ability of leptin to cross the blood-brain and blood-cerebrospinal fluid (CSF) barriers and reach or leave the CNS was studied by the bilateral in situ brain perfusion and isolated incubated choroid plexus techniques in the rat. Brain perfusion results indicated that [(125)I]leptin reached the CNS at higher concentrations than the vascular marker, confirming that [(125)I]leptin crossed the brain barriers. Leptin distribution varied between CNS regions and indicated that the blood-brain barrier, in contrast to the blood-CSF route, was the key pathway for [(125)I]leptin to reach the brain. Further perfusion studies revealed that [(125)I]leptin movement into the arcuate nucleus, thalamus, frontal cortex, choroid plexuses and CSF was unaffected by unlabelled human or murine leptin at a concentration that reflects the upper human and rat plasma leptin concentration (2.5 nM). In contrast, the cerebellum uptake of [(125)I]leptin was decreased by 73% with 2.5 nM human leptin. Thus, this site of dense leptin receptor expression would be sensitive to physiological changes in leptin plasma concentrations. The highest rate (K(in)) of [(125)I]leptin uptake was into the choroid plexuses (307.7+/-68.0 microl/min/g); however, this was not reflected in the CSF (8.9+/-4.1 microl/min/g) and indicates that this tissue tightly regulates leptin distribution. The multiple-time brain uptake of [(125)I]leptin was non-linear and suggested leptin could also be removed from the CNS. Studies using the incubated rat choroid plexus model found that [(125)I]leptin could cross the apical membrane of the choroid plexus to leave the CSF. However, this movement was not sensitive to unlabelled human leptin or specific transport inhibitors/modulators (including probenecid, digoxin, deltorphin II, progesterone and indomethacin).This study supports the concept of brain-barrier regulation of leptin distribution to the CNS, and highlights an important link between leptin and the cerebellum.

Animals↗
PubMed2003

Characterisation of the brain multidrug resistance protein (BMDP/ABCG2/BCRP) expressed at the blood-brain barrier.

The blood-brain barrier (BBB) plays the predominant role in controlling the passage of endogenous and xenobiotic substances between the circulating blood and the extracellular fluid environment of the brain. The transfer of compounds is strictly regulated by brain capillary endothelial cells (BCEC), which are interconnected to each other by well developed tight junctions, without fenestrations. Although hydrophobic molecules such as nicotine and ethanol readily cross the BBB by diffusion, the brain microvasculature shows a highly restrictive permeability to hydrophobic antitumor agents. So far, this multidrug resistance has been almost exclusively attributed to the most prominent member of the ATP-binding cassette (ABC) transporter family, P-glycoprotein located in the luminal membrane of brain capillary endothelial cells and to a minor extent to the multidrug resistance-associated proteins (MRPs). The brain multidrug resistance protein (BMDP) has recently been discovered at the porcine BBB and was shown to be highly homologous to the human breast cancer resistance protein (BCRP/ABCG2). Here, we demonstrate by northern blot and RT-PCR analysis that BMDP mRNA is more highly expressed in the capillary endothelial cells compared to other cell types of the brain. Immunocytochemistry of porcine BCEC showed a clear plasma membrane localisation of BMDP. Analysis of the total mRNA pool revealed that BMDP is more strongly expressed than P-glycoprotein and MRP1. Consistently, first transport studies indicate that active exclusion of the chemotherapeutic drug daunorubicin from the central nervous system is mediated mainly by this new transporter compared to P-glycoprotein or MRP1. Thus, we hypothesise that BMDP might play an important role in the exclusion of xenobiotics from the porcine brain.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2001

Brain development and generation of brain pathologies.

The timing of brain development is genetically programmed and can be profoundly altered by a number of abnormal genes that control proliferation, differentiation, migration, synapse formation, and elimination of cells and synapses. With advances in genetic techniques both the gene and gene product responsible for brain malformation are being identified which will permit a better understanding of the pathophysiology of brain malformations. In addition to genetic abnormalities, brain development can be influenced by a variety of acquired disorders. The type of brain abnormality is highly dependent on the stage of brain development during which the insult occurs. While our understanding of experience- or activity-dependent processes on brain development is limited, it is now clear that this activity can significantly alter the timing of a number of maturational events including receptor maturation and neurogenesis. The future challenge will be both to understand the biological basis of these processes and to use this information to enhance brain development.

Animals↗
PubMed1999

In vivo upregulation of the blood-brain barrier GLUT1 glucose transporter by brain-derived peptides.

Glucose is the critical metabolic fluid for the brain, and the transport of this nutrient from blood to brain is limited by the blood-brain barrier (BBB) GLUT1 glucose transporter. The expression of the BBB-GLUT1 gene is augmented in brain endothelial cultured cells incubated with brain-derived trophic factors and the brain-derived peptide preparation Cerebrolysin (C1, EBEWE, Austria). The aim of the present investigation was to determine if C1 induces similar changes in the expression of the BBB-GLUT1 gene following its administration to rats in vivo. The BBB glucose transporter activity was investigated with the intracarotid artery perfusion technique using [3H]diazepam as cerebral blood flow marker. The acute or chronic administration of C1 markedly increased the brain permeability surface area of D-[14C]glucose compared to controls (D-[14C]glucose/[3H]diazepam ratio, 1.6- to 1.9-fold increase in frontal cortex, P < 0.05). Increased activity of the BBB glucose transporter was correlated with a significant rise in the abundance of the BBB-GLUT1 protein measured by both Western blot analysis and immunocytochemistry, and with a decrease in the transcript levels of this transporter. Data presented here demonstrate that the in vivo administration of Cl increases the transport of glucose from blood to brain via BBB-GLUT1 gene expression.

Amino Acids↗
PubMed2001

Differential patterns of nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 mRNA and protein levels in developing regions of rat brain.

The present studies were undertaken to characterize the regional and temporal patterns of neurotrophin messenger RNA and protein levels for beta-nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 in the developing CNS. We have examined the levels of these neurotrophin messenger RNAs with ribonuclease protection assays and corresponding protein levels with enzyme-linked immunosorbent assays in the developing Long-Evans rat hippocampus, neocortex and cerebellum on postnatal days 1, 7, 14, 21, and 92. In addition, immunohistochemistry was used to localize the neurotrophins in these developing brain regions. Results indicated that in neocortex and hippocampus, messenger RNA for both nerve growth factor and brain-derived neurotrophic factor increased in an age-dependent manner, reaching a plateau by postnatal day 14. In the neocortex, nerve growth factor and brain-derived neurotrophic factor protein levels both peaked at postnatal day 14. In hippocampus, nerve growth factor protein peaked at postnatal day 7 while brain-derived neurotrophic factor peaked at postnatal day 14. In cerebellum, nerve growth factor messenger RNA levels were flat, while nerve growth factor protein peaked at postnatal day 7. Brain-derived neurotrophic factor messenger RNA increased in an age-dependent manner while the pattern for its protein levels was mixed. Neurotrophin-3 messeger RNA levels increased in an age-dependent manner in hippocampus, peaked at postnatal day14 in cerebellum, and no changes occurred in neocortex. Neurotrophin-3 protein was at its peak at postnatal day 1 and thereafter decreased at other postnatal days in all three brain regions. Results of neurotrophin immunohistochemistry often paralleled and complemented enzyme-linked immunosorbent assay data, demonstrating specific cell groups containing neurotrophin proteins in these regions. Within each region, patterns with regard to messenger RNA and respective protein levels for each neurotrophin were unique. No consistent relationship between patterns of neurotrophin messenger RNAs and their cognate proteins was observed between regions. The different regional patterns for neurotrophin messengerRNA and protein levels in each brain region indicate that messenger RNA studies of neurotrophin messenger RNA must be augmented by protein determination to fully characterize spatial and temporal neurotrophin distribution.

Aging↗
PubMed2003

1H-MR spectroscopy of normal brain tissue before and after postoperative radiotherapy because of primary brain tumors.

PURPOSE: Brain metabolism after surgery and postoperative radiotherapy (pRT) because of primary brain tumors was assessed by proton magnetic resonance spectroscopy ((1)H-MRS) in vivo. The study was designed to reveal the impact of pRT on normal brain tissue metabolism, which may potentially help in delineating the target volumes for reirradiated patients. METHODS AND MATERIALS: Spectra of 43 patients ages 16-63 years treated with pRT for primary glial tumors in the Center of Oncology Maria Curie Memorial Institute Branch in Gliwice were analyzed. The control group consisted of spectra acquired for 30 healthy volunteers. All patients were treated with 3D conformal techniques using 6-20 MV photons to total doses of 60 Gy. Spectra were acquired from the control region before pRT and from three uninvolved regions 9-12 months after the end of pRT. Voxels were located in the region of low (<6 Gy), medium (29-39 Gy), and high radiation dose ( approximately 60 Gy). Relative intensities of the signals relating to N-acetyl-aspartate (NAA), choline-based compounds, creatine and phosphocreatine (Cr), mio-Inositol, lactate, and lipids were obtained. RESULTS: The spectra of "normal brain" taken 9 months after pRT are significantly different from those obtained for control volunteers and from the spectra acquired before radiotherapy. The lactate and lipids signals are very strong; however, they are not correlated with absorbed dose. NAA/Cr ratios are significantly lower than before radiotherapy even for the low-dose regions. Differences increase with radiation dose: the NAA/Cr ratio is significantly lower for the regions of brain receiving a high dose of radiation than for the low-dose areas. CONCLUSION: Combined treatment of primary brain tumors (surgery + postoperative radiotherapy) causes alteration of brain metabolism, even in regions of the brain far from the postoperative tumor bed and receiving relatively low total doses of radiation. Single voxel MRS spectroscopy in vivo cannot help in delineating target volumes for secondary irradiation.

Adolescent↗
PubMed1999

Association of alcohol in brain injury, headaches, and stroke with brain-tissue and serum levels of ionized magnesium: a review of recent findings and mechanisms of action.

Although there is general agreement that chronic ingestion of alcohol poses great risks for normal cardiovascular functions and peripheral-vascular homeostasis, a direct cause and effect between the real phenomena of alcohol-induced headache and risk of brain injury and stroke is not appreciated. "Binge drinking" of alcohol is associated with an ever-growing number of strokes and sudden death. It is becoming clear that alcohol ingestion can result in profoundly different actions on the cerebral circulation (e.g., vasodilation, vasoconstriction-spasm, vessel rupture), depending upon dose and physiologic state of host. Using rats, it has been demonstrated that acute, high doses of ethanol can result in stroke-like events concomitant with alterations in brain bioenergetics. We review recent in vivo findings obtained with 31P-NMR spectroscopy, optical reflectance spectroscopy, and direct in vivo microcirculatory studies on the intact brain. Alcohol-induced hemorrhagic stroke is preceded by a rapid fall in brain intracellular free magnesium ions ([Mg2+]i) followed by cerebrovasospasm and reductions in phosphocreatine (PCr)/ATP ratio, intracellular pH, and the cytosolic phosphorylation potential (CPP) with concomitant rises in deoxyhemoglobin (DH), mitochondrial reduced cytochrome oxidase aa3 (rCOaa3), blood volume, and intracellular inorganic phosphate (Pi). Using osmotic mini-pumps implanted in the third cerebral ventricle, containing 30% ethanol, it was found that brain [Mg2+]i is reduced 30% after 14 days; brain PCr fell 15%, whereas the CPP fell 40%. Such animals became susceptible to stroke from nonlethal doses of ethanol. Human subjects with mild head injury have been found to exhibit early deficits in serum ionized Mg (IMg2+); the greater the degree of early head injury (30 min-8 h), the greater and more profound the deficit in serum IMg2+ and the greater the ionized Ca (ICa2+) to IMg2+ ratio. Patients with histories of alcohol abuse or ingestion of alcohol prior to head injury exhibited greater deficits in IMg2+ (and higher ICa2+/IMg2+ ratios) and, unlike the subjects without alcohol, did not leave the hospital for at least several days. Women, for some unknown reason, exhibit a much higher incidence of morbidity and mortality from subarachnoid hemorrhage (SAH) than men. Data on 105 men and women with different types of stroke indicate that, on the average, a 20% deficit in serum IMg2+ is seen; total Mg (TMg) or blood pH is usually near normal. Women with SAH, however, exhibit much lower IMg2+ and higher ICa2+/IMg2+ ratios; the presence of ethanol in the blood is associated with even more depression in IMg2+ in SAH in women. It is possible that prior alcohol ingestion is, in large measure, responsible for a great deal of this unexplained higher incidence of SAH in women. It has recently been reported that the cyclical changes in estrogenic hormones appear to control the serum IMg2+ level in young women. A surge in estrogenic levels prior to SAH could thus precipitate, in part, the SAH. In other human studies, it has been shown that migraines and headache, dizziness, and hangover, which accompany ethanol ingestion, are associated with rapid deficits in serum IMg2+ but not in TMg. The former, and the alcohol-associated headache, can be ameliorated with IV administration of MgSO4. Premenstrual tension-headache (PTH) and its exacerbation by alcohol in women is also accompanied by deficits in IMg2+, and elevation in serum ICa2+/IMg2+; IV MgSO4 corrects the PTH and the serum deficit in IMg2+. Animal experiments show that IV Mg2+ can prevent alcohol-induced hemorrhagic stroke and the subsequent fall in brain [Mg2+]i, [PCr], pHi, and CPP. Other recent data indicate that alcohol-induced cellular loss of [Mg2+]i is associated with cellular Ca2+ overload and generation of oxygen-derived free radicals; chronic pretreatment with vitamin E prevents alcohol-induced vascular injury and pathology in the brain. (ABSTRACT TRUNCATED)

Alcohol Drinking↗
PubMedDate not supplied

CXC chemokines generate age-related increases in neutrophil-mediated brain inflammation and blood-brain barrier breakdown.

Children are at greater risk than adults of permanent brain damage and mortality following head injury or infection [1-5]. Rodent models have demonstrated a 'window of susceptibility' in young animals during which the brain parenchyma is at greater risk of acute neutrophil-mediated breakdown of the blood-brain barrier [6-7]. The exact mechanism of this age-related susceptibility to brain inflammation has yet to be defined, but animal models have revealed that the potent pro-inflammatory cytokine interleukin-1beta (IL-1beta) initiates an intense acute neutrophil-mediated inflammatory response in the brains of young rats and mice that is not seen in adults [6]. Here, we demonstrate the rapid induction of CXC chemokines (which contain a Cys-X-Cys motif), in particular the cytokine-induced neutrophil chemoattractant CINC-1, following the intracerebral administration of IL-1beta. The CXC chemokines produced a more intense neutrophil response in young rats than in adults. The IL-1beta-induced blood-brain barrier breakdown in young rats could be attenuated by an anti-CINC-1 neutralising antibody. These results show that the immature central nervous system (CNS) is dramatically more susceptible to the chemotactic effects of CXC chemokines. Blocking the CXC chemokine activity associated with brain inflammation inhibits neutrophil-mediated blood-brain barrier damage and represents a significant therapeutic possibility.

Adult↗