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PubMed1990

Oxygen free radicals in the genesis of peritumoural brain oedema in experimental malignant brain tumours.

Disruption of blood brain barrier with increased vascular permeability is associated with genesis of peritumoural oedema. Oxygen free radicals play a role in increased vascular permeability. Recent studies have suggested that tumour cells can produce superoxide radicals and free radical scavengers such as superoxide dismutase (SOD) and catalase in tumour cells are impaired. In this study, we investigated the role of oxygen free radicals in the genesis of peritumoural brain oedema in experimental malignant brain tumours using V x 2 carcinoma cells and 9L glioma cells. In vitro data indicate that the V x 2 carcinoma cell and the 9L glioma cells produce superoxide radicals detected by nitroblue tetrazolium. Electron spin resonance spectroscopy using DMPO as a spin trap demonstrated that SOD activity was significantly lower in subcutaneous larger 9L glioma tumours than in normal brains and 9L glioma brain tumours. In the subcutaneous tumours, SOD activity was lower in the central portion of the tumour than in the peripheral portion of the tumour. In conclusion, we are not sure whether oxygen free radicals are major causative factors of peritumoural brain oedema, but the demonstration of oxygen free radicals in brain tumour cells needs further investigation.

Animals↗

PubMed1994

The effects of topical dexamethasone on experimental brain tumors and peritumoral brain edema.

To determine if topical dexamethasone administered to brain tumor beds would not only control peritumoral edema and suppress tumor growth but also prevent systemic steroid complications, we studied experimental brain tumors produced in 102 rabbits by implanted VX2 carcinoma cells. We separated 58 animals into three groups: 1) untreated rabbits (n = 15), 2) systemic dexamethasone-treated (4 mg/kg/day) rabbits (n = 18), and 3) topical dexamethasone-treated (2.5 microliters/h, osmotic pump) rabbits (n = 25). We administered systemic or topical dexamethasone from the third day or from the seventh day after tumor implantation, and sacrificed the animals on the 13th day. We compared survival in these three groups with that of another 44 rabbits, beginning treatment on the seventh day. We measured brain water content in the white matter of the sacrificed rabbits by the specific gravity method. We measured the length and width of the brain tumors of all the rabbits and estimated tumor volume. Systemic and topical dexamethasone administered from the third day produced statistically significant inhibition of tumor volume as well as a mean reduction in peritumoral brain edema in most tested sites. Systemic and topical dexamethasone treatment resulted in a statistically significant increase in survival relative to the untreated group. These results suggest that topical dexamethasone is efficacious in a brain tumor model and its administration to brain tumor beds constitutes a new therapeutic modality.

Administration, Topical↗

PubMed1995

99mTc HM-PAO brain perfusion SPECT in brain death.

Diagnosis of brain death must be certain to allow discontinuation of artificial ventilation and organ transplantation. Brain death is present when all functions of the brain stem have irreversibly ceased. Clinical and electrophysiological criteria may be misinterpreted due to drug intoxication, hypothermia or technical artefacts. Thus, if clinical assessment is suboptimal, reliable early confirmatory tests may be required for demonstrating absence of intracranial blood flow. We have easily carried out and interpreted 99mTc HM-PAO SPECT in a consecutive series of 40 comatose patients with brain damage, without discontinuing therapy. Brain death was diagnosed in 7 patients, by recognising absence of brain perfusion, as shown by no intracranial radionuclide uptake. In patients in whom perfusion was seen on brain scans, HM-PAO SPECT improved assessment of the extent of injury, which in general was larger than suggested by CT.

Adolescent↗

PubMed1994

A new therapy of post-trauma brain oedema based on haemodynamic principles for brain volume regulation.

OBJECTIVE: To evaluate a new therapy of posttraumatic brain oedema, with the main concept that opening of the blood-brain barrier upsets the normal brain volume regulation, inducing oedema formation. This means that transcapillary fluid fluxes will be controlled by hydrostatic capillary and colloid osmotic pressures, rather than by crystalloid osmotic pressure. If so, brain oedema therapy should include reduction of hydrostatic capillary pressure and preservation of normal colloid osmotic pressure. PATIENTS: 11 severely head injured comatose patients with brain swelling, raised intracranial pressure (ICP), and impaired cerebrovascular response to hyperventilation. INTERVENTIONS: To reduce capillary hydrostatic pressure the patients were given hypotensive therapy (beta 1-antagonist, metoprolol and alpha 2-agonist, clonidine) and a potential precapillary vasoconstrictor (dihydroergotamine). The latter may also decrease cerebral blood volume through venous capacitance constriction. Colloid osmotic pressure was maintained by albumin infusions. The concept implies the need of a negative fluid balance with preserved normovolaemia. RESULTS: ICP decreased significantly within a few hours of treatment with unaltered perfusion pressure in spite of lowered blood pressure. Of 11 patients 9 survived with good recovery/moderate disability, 2 died. This was compared to outcome in a historical control group with identical entry criteria, given conventional brain oedema therapy, where mortality/vegetativity/severe disability was 100%. CONCLUSION: The results indicate that the therapy should focus on extracellular rather than intracellular oedema and that ischemia is not the main triggering mechanism behind oedema formation. We suggest that our therapy is superior to conventional therapy by preventing herniation during the healing period of the blood-brain barrier.

Adolescent↗

PubMed2002

Monoclonal antibody to stage-specific fetal brain 68-kDa glycoprotein (FGP68) revealed increased FGP68 expression in human primary brain tumors.

We have produced a novel rat IgG(2a) monoclonal antibody against a stage-specific fetal brain glycoprotein of 68 kDa (FGP68), and succeeded in applying it to staining paraffin sections. To gain some insight into the pathobiological significance of this FGP68, this monoclonal antibody was used in immunohistochemical studies to compare the expression of FGP68 and Ki-67 antigen (MIB-1) in 235 primary brain tumors. Approximately half of the glioblastomas multiforme (GBMs) (44/75) and anaplastic astrocytomas (9/17) as well as some astrocytomas (5/30), medulloblastomas (2/14) and primitive neuroectodermal tumors (2/10) had tumor cells that expressed FGP68; however, pilocytic astrocytomas (0/7), oligodendrogliomas (0/15), ependymomas (0/6), schwannomas (0/21), meningiomas (0/22) and pituitary adenomas (0/18) did not express FGP68. The values of the MIB-1 labeling index were statistically higher in GBMs (0.005< P<0.01, Wilcoxon rank-sum test) and anaplastic astrocytomas (0.025< P<0.05) that expressed FGP68 than in those that did not. Normal brain tissue from 20 individuals aged 3-75 years was negative for FGP68 and MIB-1. We conclude that primary brain tumors express FGP68, one of the oncofetal proteins derived from fetal brain, and that FGP68 expression in certain brain tumor cells may depend, in part, on proliferation potential. Based on the possibility that the stage-specific FGP68 plays an important role in brain embryogenesis, some of FGP68-expressing tumor cells might phylogenetically revert to more primitive cells.

Animals↗

PubMed1994

Developmental regulation of brain-derived neurotrophic factor messenger RNAs transcribed from different promoters in the rat brain.

During the development of the nervous system many types of neurons are produced in excess and die because they fail to obtain sufficient amounts of target-derived neurotrophic factors (for review, see Refs 1, 16). Brain-derived neurotrophic factor is a protein that belongs to the nerve growth factor family of neurotrophins (for review, see Ref. 17) which promotes the survival and differentiation of distinct neuronal populations that partially overlap with those affected by the other members of the family (for review, see Ref. 11). We have recently shown that four promoters direct tissue specific expression of the rat brain-derived neurotrophic factor gene. In the present study we have quantified the levels of brain-derived neurotrophic factor messenger RNAs transcribed from different promoters during the rat brain development. Our data show that different promoters have specific regulation patterns during embryonic development but are regulated coordinately in several regions of rat brain during postnatal development, suggesting that the four transcription units have both distinct and common regulatory elements. Quantification of absolute levels of brain-derived neurotrophic factor messenger RNA revealed that it is expressed significantly higher in the rat brain than previously estimated.

Aging↗

PubMed1999

Cellular localization of brain-derived neurotrophic factor-like immunoreactivity in adult monkey brain.

Immunohistochemical localization of brain-derived neurotrophic factor (BDNF) in the monkey brain was investigated using a polyclonal anti-BDNF antibody produced in our laboratory. The antibody recognized a single band in monkey brain homogenates, and the estimated molecular weight was approximately 14 kDa, which corresponds well to the molecular weight of BDNF monomer. BDNF-like immunoreactivity was observed in the somata and processes of discrete neuronal subpopulations in the monkey brain. BDNF-positive neurons were widely distributed in various structures of the brain, including the cerebral cortex, hippocampus, basal forebrain, basal ganglia, diencephalon, brainstem and cerebellum. In addition, immunopositive glial cells were found in some brain regions. These data suggest that BDNF may exist widely in the monkey brain, and may be concerned with various types of neurons in the monkey central nervous system.

Age Factors↗

PubMed1990

Brain water content, brain blood volume, blood chemistry, and pathology in a model of cerebral edema.

STUDY OBJECTIVES: The objective was to correlate regional changes during brain water content with alterations in blood chemistry and cerebral pathology during hypo-osmotic edema. PARTICIPANTS: Sprague-Dawley male adult rats were used in these studies. DESIGN: Animals were block-randomized to receive either an intraperitoneal distilled water injection equivalent to 5% or 15% of their body weight or no injection (controls). Rats were sacrificed 15 or 60 minutes after water injection or at an equivalent time for controls. INTERVENTIONS: No interventions were performed. MEASUREMENTS AND MAIN RESULTS: Water content of cerebral cortical gray and white matter was calculated from measurements of tissue specific gravity. Blood plasma osmolality and sodium and potassium concentrations were determined at various times after water injection. An index of blood-brain barrier permeability was obtained by measuring brain red blood cell and plasma volumes. A qualitative assessment of edema was made from light and electron micrographs of the cerebral cortex. We found that water injection produced a dose-dependent decrease in plasma osmolality and sodium concentration within 15 minutes. Cortical water content was unchanged after this period. An influx of water into cerebral gray, and, less readily, into cerebral white matter occurred during the next 15 minutes. Whole blood specific gravity and brain blood content were unchanged and thus did not confound the measurement of cerebral water content. Hematocrit was increased 60 minutes after a 15% water injection. The blood-brain barrier remained intact throughout this period. Microscopy revealed astrocytic swelling with slight extracellular fluid accumulation 60 minutes after the water injection. CONCLUSIONS: Homeostatic mechanisms in the cerebral cortex can maintain constant water content for at least 15 minutes during maintained intravascular hypo-osmolality. Fluid that subsequently moves into the tissue primarily enters an intracellular compartment. This model will be useful in investigating physiological mechanisms of brain water regulation and the pathogenesis of brain edema, a common clinical entity in emergency conditions.

Animals↗

PubMed1997

Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain.

The anatomical distribution and density of cannabinoid receptors in the human brain was studied in one fetal (33 weeks gestation), two neonatal (aged three to six months) and eight adult (aged 21-81 years) human cases using quantitative receptor autoradiography following in vitro labelling of sections with the synthetic cannabinoid agonist [3H]CP55,940. Cannabinoid receptors were distributed in a heterogeneous fashion throughout the adult human brain and spinal cord. The allocortex contained very high concentrations of cannabinoid receptor binding sites in the dentate gyrus, Ammons's horn and subiculum of the hippocampal formation; high concentrations of receptors were also present in the entorhinal cortex and amygdaloid complex. Cannabinoid receptor binding sites were also present throughout all regions of the neocortex, where they showed a marked variation in density between the primary, secondary and associational cortical regions: the greatest densities of receptors were present in the associational cortical regions of the frontal and limbic lobes, with moderate densities in the secondary sensory and motor cortical regions, and with the lowest densities of receptors in the primary sensory and motor cortical regions. Relatively high concentrations of cannabinoid receptors were consistently seen in cortical regions of the left (dominant) hemisphere, known to be associated with verbal language functions. In all of the cortical regions, the pattern and density of receptor labelling followed the neocortical laminar organization, with the greatest density of receptors localized in two discrete bands--a clearly delineated narrow superficial band which coincided with lamina I and a deeper broader, conspicuous band of labelling which corresponded to laminae V and VI. Labelling in the intervening cortical laminae (II-IV) showed lower densities, with a well delineated narrow band of label in the middle of laminae IV in the associational cortical regions. The thalamus showed a distinctive heterogeneous distribution of cannabinoid receptors, with the highest concentration of receptors localized in the mediodorsal nucleus, anterior nuclear complex, and in the midline and intralaminar complex of nuclei, i.e. in thalamic nuclei which have connectional affiliations with the associational cortical areas. The basal ganglia showed a distinctive heterogeneous pattern of receptor binding, with the very highest concentrations in the globus pallidus internus, moderate concentrations in the globus pallidus externus and ventral pallidum, and moderately low levels of binding throughout the striatal complex. In the midbrain, some of the highest levels of cannabinoid receptor binding sites in the human brain were present in the substantia nigra pars reticulata, with very low levels of labelling in all other midbrain areas. The highest densities of cannabinoid receptor binding in the hindbrain were localized in the molecular layer of the cerebellar cortex and the dorsal motor nucleus of the vagus, with moderate densities of receptors in the nucleus of the solitary tract. The spinal cord showed very low levels of receptor binding. Studies on the distribution of cannabinoid receptors in the fetal and neonatal human brain showed similar patterns of receptor distribution to that observed in the adult human brain, except that the density of receptor binding was generally markedly higher, especially in the basal ganglia and substantia nigra. The pattern of cannabinoid receptor labelling in the striatum showed a striking patchy pattern of organization which was especially conspicuous in the fetal brain. These results show that cannabinoid receptor binding sites in the human brain are localized mainly in: forebrain areas associated with higher cognitive functions; forebrain, midbrain and hindbrain areas associated with the control of movement; and in hindbrain areas associated with the control of motor and sensory functions of the autonomic nervous system. (AB

Adult↗

PubMed1997

Hematogenous metastases of the human brain--characteristics of peritumoral brain changes: a review.

The brain is an important site of hematogenous metastases from malignant tumors in other organs. The effects on the brain is a combination of tissue destruction induced by invading tumor cells and reactive alterations occurring around the metastases. This review focuses on neuropathological changes around hematogenous metastases of the human brain. The peritumoral brain parenchyma shows structural and functional changes of the intracerebral microvessels and edema. The endothelial cells of peritumoral microvessels express glucose transporter protein (GLUT 1) in the same way as the normal brain. Reduction in immunostaining to GLUT 1 may occur in the microvessels located within the metastases. This would indicate abnormalities of the blood-brain barrier in tumor vessels but normal barrier function in the peritumoral region. Reactive astrocytes and activated microglial cells are both involved in the process of peritumoral gliosis. Activated glial cells produce numerous biological active compounds including endothelin-1 which after release from such cells can influence the structure and function of the peritumoral brain tissue. Lesions of oligodendrocytes and edema may be implicated in myelin degeneration. Finally, metastases will induce axonal and neuronal injuries as indicated by a recent study on expression of beta-amyloid precursor protein (beta APP) in reactive axonal swellings.

Axons↗

PubMedDate not supplied

Influence of C6 and CNS1 brain tumors on methotrexate pharmacokinetics in plasma and brain tissue.

PURPOSE: Comparison of the influence of two different brain tumors (C6 and CNS1 glioma) on methotrexate (MTX) disposition in plasma, brain, and tumor tissue extracellular fluid (ECF). METHODS: Serial collection of plasma samples and brain ECF dialysates after i.v. bolus administration of MTX (50 mg kg(-1)) for 4 h. Quantitation of MTX concentrations by HPLC-UV. RESULTS: Histological studies revealed a 3-fold higher number of blood vessels in CNS1 than in C6 tumor tissue. In vivo recoveries (reverse dialysis) were significantly different in tumor tissue (C6: 8.0 +/- 3.8%; CNS1: 4.9 +/- 2.5%), and in the contralateral hemisphere (C6: 6.0 +/- 4.0%; CNS1: 3.9 +/- 2.5%) between the two tumors. Area under the concentration-time curve (AUC) in plasma was 30% higher in CNS1 than in C6 due to a lower systemic clearance. Maximum MTX levels in brain tumor ECF were significantly higher in CNS1 than in C6, and decreased faster in CNS1 than in C6 tumor-bearing rats. Penetration in tumor ECF (AUC(ECF)/AUC(Plasma) ratio) was similar in CNS1 and C6. MTX concentrations in contralateral hemisphere were significantly lower than in tumor tissue and dependent on tumor model. CONCLUSION: C6 and CNS1 brain tumors have a distinct yet highly variable impact on MTX penetration in brain and brain tumor ECF.

Animals↗

PubMed1993

Immunolocalization of heat shock protein after fluid percussive brain injury and relationship to breakdown of the blood-brain barrier.

We have previously developed a model of mild, lateral fluid percussive head injury in the rat and demonstrated that although this injury produced minimal hemorrhage, breakdown of the blood-brain barrier was a prominent feature. The relationship between posttraumatic blood-brain barrier disruption and cellular injury is unclear. In the present study we examined the distribution and time course of expression of the stress protein HSP72 after brain injury and compared these findings with the known pattern of breakdown of the blood-brain barrier after a similar injury. Rats were subjected to a lateral fluid percussive brain injury (4.8-5.2 atm, 20 ms) and killed at 1, 3, and 6 h and 1, 3, and 7 days after injury. HSP72-like immunoreactivity was evaluated in sections of brain at the light-microscopic level. The earliest expression of HSP72 occurred at 3 h postinjury and was restricted to neurons and glia in the cortex surrounding a necrotic area at the impact site. By 6 h, light immunostaining was also noted in the pia-arachnoid adjacent to the impact site and in certain blood vessels that coursed through the area of necrosis. Maximal immunostaining was observed by 24 h postinjury, and was primarily associated with the cortex immediately adjacent to the region of necrosis at the impact site. This region consisted of darkly immunostained neurons, glia, and blood vessels. Immunostaining within the region of necrosis was restricted to blood vessels. HSP72-like immunoreactivity was also noted in a limited number of neurons and glia in other brain regions, including the parasagittal cortex, deep cortical layer VI, and CA3 in the posterior hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2003

Selenium and selenoproteins in the brain and brain diseases.

Over the past three decades, selenium has been intensively investigated as an antioxidant trace element. It is widely distributed throughout the body, but is particularly well maintained in the brain, even upon prolonged dietary selenium deficiency. Changes in selenium concentration in blood and brain have been reported in Alzheimer's disease and brain tumors. The functions of selenium are believed to be carried out by selenoproteins, in which selenium is specifically incorporated as the amino acid, selenocysteine. Several selenoproteins are expressed in brain, but many questions remain about their roles in neuronal function. Glutathione peroxidase has been localized in glial cells, and its expression is increased surrounding the damaged area in Parkinson's disease and occlusive cerebrovascular disease, consistent with its protective role against oxidative damage. Selenoprotein P has been reported to possess antioxidant activities and the ability to promote neuronal cell survival. Recent studies in cell culture and gene knockout models support a function for selenoprotein P in delivery of selenium to the brain. mRNAs for other selenoproteins, including selenoprotein W, thioredoxin reductases, 15-kDa selenoprotein and type 2 iodothyronine deiodinase, are also detected in the brain. Future research directions will surely unravel the important functions of this class of proteins in the brain.

Animals↗

PubMed1994

Brain temperature discriminates between neonates with damaged, hypoperfused, and normal brains.

Brain temperature depends on the balance of cerebral heat production and heat loss via cerebral circulation and head surface. We investigated whether brain temperature and heat loss via the head surface differed in neonates with abnormal cerebral metabolism or circulation. We measured the core temperature of the head noninvasively by the zero-gradient method, skin temperature of the head, the heat flux from the head, and esophageal and operative environmental temperature in seven healthy neonates, seven neonates with cerebral damage, and two neonates with cerebral hypoperfusion caused by an incurable congenital heart disease. Cerebral blood flow velocity in the anterior cerebral artery and systemic blood pressure were also measured. Brain temperature profile was measured in two premature infants with external ventricular drainage. Core temperature of the head, considered to represent brain temperature, was up to 1.5 degree C higher in infants with cerebral hypoperfusion than in normal neonates. The core temperature of the head was higher than the esophageal temperature in all except two infants with the most severe cerebral damage. The difference between core temperature of the head and esophageal temperature was 0.72 +/- 0.12 degree C in normal neonates, 0.16 +/- 0.4 degree C in infants with cerebral damage, and ranged from 0.9 to 1.2 degree C in infants with cerebral hypoperfusion. The relationship of core of the head to esophageal temperature discriminated between all 16 newborn infants according to their brain pathologic condition, except one infant with a mild ischemic-hypoxic encephalopathy. In conclusion, brain temperature depends on cerebral perfusion and level of brain injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Flow Velocity↗

PubMed2005

Pharmaco-thermodynamics of deuterium-induced oedema in living rat brain via 1H2O MRI: implications for boron neutron capture therapy of malignant brain tumours.

In addition to its common usage as a tracer in metabolic and physiological studies, deuterium possesses anti-tumoural activity and confers protection against gamma-irradiation. A more recent interest in deuterium emanates from the search for alternatives capable of improving neutron penetrance whilst reducing healthy tissue radiation dose deposition in boron neutron capture therapy of malignant brain tumours. Despite this potential clinical application, deuterium induces brain oedema, which is detrimental to neutron capture therapy. In this study, five adult male rats were titrated with deuterated drinking water while brain oedema was monitored via water proton magnetic resonance imaging. This report concludes that deuterium, as well as deuterium-induced brain oedema, possesses a uniform brain bio-distribution. At a steady-state blood fluid deuteration value of 16%, when the deuterium isotope fraction in drinking water was 25%, a mean oedematous volume change of 9 +/- 2% (p-value <0.001) was observed in the rat brain-this may account for neurological and behavioural abnormalities found in mammals drinking highly deuterated water. In addition to characterizing the pharmaco-thermodynamics of deuterium-induced oedema, this report also estimates the impact of oedema on thermal neutron enhancement and effective dose reduction factors using simple linear transport calculations. While body fluid deuteration enhances thermal neutron flux penetrance and reduces dose deposition, oedema has the opposite effect because it increases the volume of interest, e.g., the brain volume. Thermal neutron enhancement and effective dose reduction factors could be reduced by as much as approximately 10% in the presence of a 9% water volume increase (oedema).

Administration, Oral↗

PubMed1988

Macrophage infiltration into experimental brain metastases: occurrence through an intact blood-brain barrier.

The purpose of this study was to examine the nature of the blood-brain barrier in experimental brain metastases. Syngeneic fibrosarcoma or melanoma cells were injected into the internal carotid arteries of mice. Several weeks later, once the experimental brain metastases were established, the mice were given injections iv of sodium fluorescein. The capillaries within the metastatic foci were enlarged and irregular, but there was no leakage of sodium fluorescein, showing that the blood-brain barrier was intact. The neoplastic lesions were infiltrated by mononuclear phagocytes, which were identified by immunohistochemical localization of the macrophage-specific antigen F4/80, class II major histocompatibility complex (MHC) antigens, and the macrophage product interleukin-1 (IL-1). The metastatic foci contained numerous stellate macrophages that expressed F4/80 and MHC class II antigens, but little IL-1. Round, monocyte-like F4/80 and MHC class II-positive cells were also observed within the tumor lesions and adhering to walls of the tumor microvasculature. Mice with fibrosarcoma brain metastases also had edematous lesions at sites remote from the metastatic foci that contained numerous astrocytes expressing class II MHC but not F4/80 antigens. In conclusion, the blood-brain barrier is intact within experimental brain metastases, yet macrophages of blood monocyte origin can infiltrate the lesions.

Animals↗

PubMed2000

Role of chemokines, neuronal projections, and the blood-brain barrier in the enhancement of cerebral EAE following focal brain damage.

The role of focal brain damage as a trigger for autoimmune inflammation in multiple sclerosis (MS) is unclear. In this study we examine mechanisms by which experimental autoimmune encephalomyelitis (EAE) is enhanced by focal brain damage. EAE was produced in Lewis rats by footpad inoculation; focal brain damage, in the form of a cortical cryolesion (cryolesion-EAE), was induced 8 days post-inoculation (d.p.i.). The distribution of inflammation and chemokine production in cryolesion-EAE and EAE-only were compared. Inflammation in the brain, measured by immunocytochemistry for T lymphocytes (W3/13) and microglial activation (MHC class II -OX6), was significantly enhanced in cryolesion-EAE 11-15 d.p.i. (p < 0.01-0.05) but by 20-40 d.p.i., equated with EAE-only. Inflammation in cryolesion-EAE related to breakdown of the blood-brain barrier (BBB) at the site of the cryolesion and also to the corticospinal tracts and thalamus, reflecting the afferent and efferent neuronal connections with the cryolesioned cortex. Semiquantitative RT/PCR dot-blot hybridization assay showed a 6-fold increase in mRNA for specific chemokines in the brain in cryolesion-EAE at 9 d.p.i. (MCP-1) and 11 d.p.i. (MCP-1 and MCP-5) with no significant increase in RANTES, GRO-alpha, or MIP-1alpha. By 14 d.p.i., the levels of MCP-1 and MCP-5 mRNA equated with EAE-only animals. These results suggest that enhancement and location of autoimmune inflammation in the brain following focal cortical injury initially involve chemokines such as the macrophage chemoattractants MCP-1 and MCP-5, and the activities of afferent and efferent neuronal connections with the site of damage. By analogy, similar factors may modulate or reactivate autoimmune inflammation in MS.

Animals↗

PubMed1997

Distribution of Glut1 glucose transporters in different brain structures compared to glucose utilization and capillary density of adult rat brains.

Glut1 is a specific transporter system that mediates glucose transfer across the blood-brain barrier (BBB). Although the main location of Glut1 is in the capillary endothelium of the brain, its local distribution in different brain regions is not as well defined. In the present investigation, the local pattern of Glut1 distribution was determined in 13 brain structures using an immunoautoradiographic method developed for this purpose. A polyclonal antibody directed against the C-terminal amino acid sequence of Glut1 was applied to cryosections of rat brains. A secondary antibody was added that had been coupled to [35S]. Results show a heterogeneous distribution of Glut1 in the brain with activities of [35S] ranging from 65% below to 15% above the mean. White matter activity was lower than gray matter activity. For comparison, capillary sections were counted in corresponding cryosections by indirect immunofluorescence using fibronectin antibodies. In addition, local cerebral glucose utilization (LCGU) was analyzed in identical brain structures of conscious rats by the quantitative autoradiographic 2-deoxyglucose method. Significant correlations were found between Glut1 density and either LCGU or capillary density. Results indicate a tight coupling of Glut1 transporter density and capillary density to the LCGU of different BBB structures in adult rats.

Animals↗