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At least 955 records · Page 53Linked to original sources
PubMed2000

Brain lactate uptake increases at the site of impact after traumatic brain injury.

Although glucose is the main carbohydrate energy substrate for the normal brain, several studies published over the last 10 years now challenge this assumption. The activated brain increases its metabolism to meet increased energy demands by glycolysis after injury. In vitro studies now show that lactate alone can serve as an energy source to maintain synaptic function. In this study, we used 14C-lactate to test the hypothesis that blood lactate is acutely taken up by the injured brain, after fluid percussion injury (FPI) in the rat. 50 microCi radioactive lactate was injected i.v. immediately after FPI, in injured and sham rats. After 30 min, the brain was removed, frozen, and cut into 20 microm sections for autoradiography. Uptake of 14C-label was mainly concentrated at the injury site (2.5 times greater) although uninjured brain also took up the 14C-label. This increased concentration of radioactive lactate at the injury site suggests that the injured brain may use the lactate as an energy source.

Animals↗
PubMed2001

Evaluation of the effect of stress on the blood--brain barrier: critical role of the brain perfusion time.

The Gulf war syndrome has drawn increased attention in the issue of the effect of stress on the blood-brain barrier (BBB). We have applied various stressful modalities and tested BBB disruption as measured by the amount of Evans blue (EB) retained by brain parenchyma. We have evaluated the retention of this marker as a function of the perfusion time of the brain following stress. This was done to distinguish between the marker retained in the lumen of small blood vessels and the marker retained by the brain parenchyma. Mice were exposed to either short swim stress or restraint stress. In mice exposed to either swim or restraint stress that were perfused for 1 min, the amount of EB retained in the brain was significantly higher as compared to non-stressed controls. Fifteen min perfusion markedly reduced the EB brain content to levels found in the non-stressed animals. In rats exposed to neural or metabolic stressful stimuli and perfused for 15 min, the EB content was similar to non-stressed controls. Our results demonstrate that various stress modalities have no effect on the BBB permeability and insufficient wash of blood vessels by perfusion may cause misinterpretation of permeability studies.

Acoustic Stimulation↗
PubMed1999

Blood-brain barrier mechanisms involved in brain calcium and potassium homeostasis.

This study examined the potential roles of the plasma membrane Ca2+-ATPase (PMCA) at the blood-CSF and blood-brain barriers in brain Ca2+ homeostasis and blood-brain barrier Na+/K+-ATPase subunits in brain K+ homeostasis. During dietary-induced hypo- and hypercalcemia (0.59+/-0.06 and 1.58+/-0.12 mM [Ca2+]) there was no significant change in choroid plexus PMCA (Western Blots) compared to normocalcemic rats (plasma [Ca2+]: 1.06+/-0.11 mM). In contrast, PMCA in cerebral microvessels isolated from hypocalcemic rats was 150% greater than that in controls (p<0.001). Comparison of the alpha3 subunit of Na+/K+-ATPase from cerebral microvessels isolated from hypo-, normo- and hyperkalemic rats (2.3+/-0.1, 3.9+/-0.1 and 7. 2+/-0.6 mM [K+]) showed a 75% reduction in the amount of this isoform during hyperkalemia. None of the other Na+/K+-ATPase isoforms varied with plasma [K+]. These results suggest that both PMCA and the alpha3 subunit of Na+/K+-ATPase at the blood-brain barrier play a role in maintaining a constant brain microenvironment during fluctuations in plasma composition.

Animals↗
PubMed2000

Distribution of beta-amyloid and amyloid precursor protein in the brain of spawning (senescent) salmon: a natural, brain-aging model.

Brain amyloid precursor protein (APP), a normal constituent of neurons, glial cells and cerebrospinal fluid, has several proposed functions (e.g., in neuronal growth and survival). It appears, however, that altered processing of APP is an initial or downstream step in the neuropathology of brain aging, Alzheimer's disease (AD), and Down's syndrome (DS). Some studies suggest that proteolytic cleavage of APP, producing beta-amyloid (Abeta(1-42)), could have neurotoxic or neuroprotective effects. In this study, we utilized antibodies to human APP(695) and Abeta(1-42,) and Congo red staining, to search for amyloid deposition in the brain of semelparous spawning kokanee salmon (Oncorhynchus nerka kennerlyi). Intracellular APP(695) immunoreactivity (APP-ir) was observed in brain regions involved in gustation (glomerulosus complex), olfaction (putative hippocampus, olfactory bulb), vision (optic tectum), the stress response (nucleus preopticus and nucleus lateralis tuberis), reproductive behavior (nucleus preopticus magnocellularis, nucleus preopticus periventricularis, ventral telencephalon), and coordination (cerebellum). Intra- and extra-neuronal Abeta(1-42) immunoreactivity (Abeta-ir) were present in all APP-ir regions except the nucleus lateralis tuberis and Purkinje cells of the cerebellum (coordination). Thus, the relationship between APP and Abeta deposition during brain aging could shed light on the processing of APP into Abeta, neurodegeneration, and possible protection of neurons that are functioning in spawning but senescent salmon. Pacific salmon, with their predictable and synchronized life history, could provide research options not available with the existing models for studies of brain aging and amyloidosis.

Aging↗
PubMed2003

The effects of combined fluid percussion traumatic brain injury and unilateral entorhinal deafferentation on the juvenile rat brain.

The current study was designed to address the effects of traumatic brain injury (TBI) on plasticity and reorganization in the juvenile brain. Given that two of the major pathological sequelae of TBI involve a generalized neuroexcitation insult and diffuse axonal injury, we have employed models of these pathologies, delivered either independently or in combination, to examine their effects on injury-induced synaptic reorganization of the dentate gyrus in the developing rat. Postnatal day 28 rats received either sham, central fluid percussion traumatic brain injury (TBI), unilateral entorhinal cortical lesion (UEC), or TBI+UEC (TUEC) injury. Cognitive performance was assessed in the Morris water maze (MWM) between 11 and 15 days post-injury and the brains were processed for synaptophysin immunohistochemistry and routine electron microscopy. The MWM results revealed that TBI or UEC lesions delivered independently do not produce significant morbidity in P28 rats. However, when these injuries are combined, they reveal significant deficits in the MWM, accompanied by measurable changes in the distribution of presynaptic synaptophysin immunoreactivity over the deafferented dentate molecular layer. These observations are further supported by qualitative ultrastructural alterations in synaptic architecture in the same subregions of the dentate neuropil. The present findings show that the resilience of the immature brain following TBI is reduced when neuroexcitatory insult is combined with deafferentation. Moreover, when deafferented tissue is assessed morphologically, evidence exists for aberrant plasticity and abnormal synaptic reorganization in the juvenile brain.

Animals↗
PubMed2001

Amplification of blood-brain barrier GLUT1 glucose transporter gene expression by brain-derived peptides.

Glucose is a critical nutrient for the brain, and the transport of this hexose from blood to brain is mediated by the blood-brain barrier (BBB) GLUT1 glucose transporter. The expression of the BBB-GLUT1 gene is compromised in different pathological conditions and it is modulated by brain trophic factors. The brain-derived peptide preparation Cerebrolysin (Cl, EBEWE, Austria) increases the expression of the BBB-GLUT1 via mRNA stabilization. In order to gain more insights into the mechanism of BBB-GLUT1 gene regulation, the present investigation studied the effect of Cl on the expression of both the GLUT1 protein and GLUT1 reporter genes in brain endothelial cultured cells (ECL). Cl markedly increased the expression of reporter genes containing GLUT1 translational control elements and cis-acting elements involved in the stabilization of the GLUT1 mRNA transcript in a dose dependent manner. Cl produced only marginal effects on the reporter gene control lacking the GLUT1 regulatory elements. In parallel experiments, Cl markedly increased the uptake of 3H-2-deoxy-D-glucose and the levels of the GLUT1 protein measured by ELISA. Data presented here demonstrate: (i) that Cl increases the expression of BBB-GLUT1 reporter genes containing regulatory cis-elements involved in the stabilization and translation of the GLUT1 transcript; (ii) that the effect on both regulatory elements cooperates to increase gene expression; and (iii) that the increased levels of the BBB-GLUT1 reporter genes in Cl-treated ECL cells are associated with an increase in the glucose uptake and in the expression of the GLUT1 protein.

Amino Acids↗
PubMed1997

The biphasic opening of the blood-brain barrier in the cortex and hippocampus after traumatic brain injury in rats.

This study examined the time course of the blood-brain barrier (BBB) opening and correlated this with brain edema formation after a lateral controlled cortical impact (CCI) brain injury in rats. Quantitative measurement of Evans blue (EB) extravasation using fluorescence was employed at 2, 4, 6 h and 1, 2, 3, 4 and 7 days after injury. Brain edema was measured by specific gravity of the tissue at corresponding time points. Two prominent EB extravasations were observed at 4-6 h and 3-day after injury in the injury-site cortex and the ipsilateral hippocampus. Brain edema became progressively more severe over time and peaked at 24 h after injury and began to decline after day 3. These results suggest that there is a biphasic opening of the BBB after CCI brain injury and the second opening of the BBB does not contribute to a further increase in edema formation.

Animals↗
PubMed1999

Transplantation of glial cell progenitors from brains of normal rats and mice into brains of neonatal carbonic anhydrase II-deficient mutant mice.

Carbonic anhydrase II (CAII) is expressed in oligodendrocytes, astrocytes and myelin in brains of rats and normal mice, but not in the brains of CAII-deficient mutant mice. We have transplanted mixed glial-cell suspensions from normal mouse brains, and oligodendrocyte-enriched precursor cells cultured from normal rat brains, respectively, into the brains of neonatal CAII-deficient mutant mice. Some CAII-positive astrocytes and oligodendrocytes developed in the brains of the host CAII-deficient mice at 8, 14 and 18 days posttransplant (DPT). In transplants of either mixed glial cells or oligodendrocyte precursors, CAII-positive oligodendrocytes were less plentiful than CAII-positive astrocytes and appeared to be less healthy. CAII-positive astrocytes developed by 8 DPT, and there were some oligodendrocytes in cerebral cortex at 14 DPT and in brainstem by 18 DPT. The data suggested that if glial-cell progenitors were to be injected into demyelinated lesions, any oligodendrocytes descended from the donor would be accompanied by astrocytes also descended from donor cells.

Animals↗
PubMed2003

Free convection schema defines the shape of the human brain: brain and self-organization.

As a fundamental rule of nature, the shape of a functioning organ should never be considered accidental. Since the principal rules for a self-organizing neural network are not sufficient for determining the shape and anatomic features of the brain, these must be governed by other rules. Ontogeny of the global shape of the brain is guided by radial glial fibers. The rules defining the growth pattern of radial glial fibers, therefore, should be the rules for a self-organization for the shape of the brain. In this work, the overall shape and structural anatomic detail of the human brain was successfully simulated utilizing self-organization rules of heat convection represented by Boussinesq partial differential equations. The result suggests that radial glial fibers may grow in Markovian fashion, guided by gaseous substrates moving miniature distances according to a convection schema. The result also holds implication that the shape of the brain has specific physical meaning in the creation of a virtual sphere, which in turn ensures equivalence of columns within the entire cortex, the well-known vital fundamental of brain organization.

Brain↗
PubMed2000

The role of whole brain radiotherapy and stereotactic radiosurgery on brain metastases from renal cell carcinoma.

PURPOSE: We reviewed our experience with patients who have undergone stereotactic radiosurgery (SRS) for brain metastases secondary to renal cell carcinoma (RCC). Analysis was performed to determine the survival, local control, distant brain failure (DBF), and then to define which tumors may not require upfront whole-brain radiotherapy (WBRT). METHODS AND MATERIALS: Twenty-nine patients with 66 tumors underwent SRS from 1991 to 1998. Median follow-up from time of brain metastases diagnoses relative to each tumor was 12.5 months and 6.8 months from the time of SRS. Median SRS dose was 1,800 cGy to the 60% isodose line. Three patients had undergone SRS for previously treated tumors. RESULTS: Median survival time from diagnosis was 10.0 months. Overall survival was not affected by age, addition of WBRT, number of lesions, tumor volume, or the presence of systemic disease. Of the 23 patients with follow-up neuroimaging, 4 of 47 (9%) tumors recurred. The addition of WBRT did not improve local control. Of the 13 patients who presented with a single lesion, 3 went on to develop DBF (23%), while 6 of the 10 patients who presented with multiple metastases developed DBF (60%). CONCLUSION: Patients with brain metastases secondary to RCC treated by SRS alone have excellent local control. The decision of whether or not to add WBRT to SRS should depend on whether the patient has a high likelihood of developing DBF. Our study suggests that patients who present with multiple brain lesions may be more likely to benefit from the addition of WBRT because they appear to be more than twice as likely to develop DBF as compared to patients with a single lesion.

Adult↗
PubMed1997

Boron neutron capture therapy of brain tumors: enhanced survival following intracarotid injection of sodium borocaptate with or without blood-brain barrier disruption.

PURPOSE: Sodium borocaptate (Na2B12H11SH or BSH) has been used clinically for boron neutron capture therapy (BNCT) of patients with primary brain tumors. The purpose of the present study was to determine if tumor uptake of BSH and efficacy of BNCT could be enhanced in F98 glioma-bearing rats by intracarotid (i.c.) injection of the compound with or without blood-brain barrier disruption (BBB-D). METHODS AND MATERIALS: For biodistribution studies 100,000 F98 glioma cells were implanted stereotactically into the brains of Fischer rats, and 12 days later BBB-D was carried out by i.c. infusion of 25% mannitol, followed immediately thereafter by i.c. injection of BSH (30 mg B/kg body weight). Animals were killed 1, 2.5, and 5 h later, and their brains were removed for boron determination. For BNCT experiments, which were initiated 14 days after intracerebral implantation of 1000 F98 cells, BSH (30 mg B/kg b.wt. was administered intravenously (i.v.) without BBB-D, or i.c. with or without BBB-D. The animals were irradiated 2.5 h later with a collimated beam of thermal neutrons at the Brookhaven National Laboratory Medical Research Reactor. RESULTS: The mean tumor boron concentration after i.c. injection with BBB-D was 48.6 +/- 17.2 microg/g at 2.5 h compared with 30.8 +/- 12.2 microg/g after i.c. injection without BBB-D and 12.9 +/- 4.2 microg/g after i.v. injection. The best composite tumor to normal tissue ratios were observed at 2.5 h after BBB-D, at which time the tumor:blood (T:B1) ratio was 5.0, and the tumor: brain (T:Br) ratio was 12.3, compared to 1.1 and 4.6, respectively, in i.v. injected rats. The mean survival time for untreated control rats was 24 +/- 3 days, 29 +/- 4 days for irradiated controls, 33 +/- 6 days for those receiving i.v. injection of BSH, 40 +/- 8 days for rats receiving i.c. BSH without BBB-D, and 52 +/- 13 days for BBB-D followed by BNCT (p = 0.003 vs. i.v. injected BSH). CONCLUSIONS: Intracarotid administration of BSH with or without BBB-D significantly increased tumor uptake of BSH and enhanced survival of F98 glioma-bearing rats following BNCT. BBB-D may be a useful way to enhance the delivery of both low and high molecular weight boron compounds to brain tumors. Further studies are in progress to assess this approach with other boron delivery agents.

Animals↗
PubMed1999

How did the human brain evolve? A proposal based on new evidence from in vivo brain imaging during attention and ideation.

It is proposed that brain evolution in nonhuman primates and humans was facilitated by heritable differences in neuroplasticity and in the number of neurons and synapses available during childhood and adolescence, therefore, in differences in modifiability and elaboration of neuronal networks in brains of immature primate genotypes. These differences were exploited when a primate population was forced to adapt to a new cognitively or behaviorally demanding milieu, to select more cognitively and brain competent adults who could best compete and reproduce in this new milieu, extending their genes within the population. Two recently solidified concepts suggest a mechanism for this evolutionary process: (1) "Association" neocortex can be activated by attention and ideation in the absence of sensory or motor contributions, as demonstrated by in vivo imaging and direct brain recording. (2) Activation of the immature brain can promote and stabilize neuronal networks that would disappear or otherwise lose their function by adulthood. Taking these two ideas together, it is proposed that the "thought" processes of attention and ideation, when used by immature primates to adapt to new cognitive or behavioral stresses, led by the repeated selection of genotype to more cognitively able, larger-brained species with more extensive "association" cortex and related regions.

Adolescent↗
PubMed2000

Primary cultures of brain microvessel endothelial cells: a valid and flexible model to study drug transport through the blood-brain barrier in vitro.

Studies on drug entry into the brain and permeation of the blood-brain barrier start to gain more and more importance in neuropharmaceutical research in order to develop new drugs for the therapy of central nervous system diseases. Procedures that provide quick access to permeation properties of those drugs with high throughput are difficult to achieve with animal models. Although various useful cell culture models approaching this issue have been described, results are often not comparable among each other unless determined with an equal experimental setup. Reproducibility of cell culture methods as well as corresponding findings gathered with these tools are often impeded due to the lack of details in experimental manuals. Here we present a precise manual for preparation and maintenance of porcine brain microvessel endothelial cells, serving as a culture model of the blood-brain barrier. Furthermore experimental details for blood-brain barrier transport investigations are presented. Validation of this model was carried out by determination of bioelectric properties and permeation experiments using various marker molecules reflecting paracellular and transcellular blood-brain barrier penetration. Results obtained with our model are closely resembling the in vivo-situation although astrocytes are not included. This simplification of the system is one of the major advantages towards robot derived cell cultures necessary for high throughput screening.

Animals↗
PubMed1998

Blood-brain barrier carrier-mediated transport and brain metabolism of amino acids.

The transport of neutral amino acids through the brain capillary endothelial wall, which makes up the blood-brain barrier (BBB) in vivo, is an important control point for the overall regulation of cerebral metabolism, including protein synthesis and neurotransmitter production. The Michaelis-Menten kinetics of BBB amino acid transport have been investigated in vivo with the brain uptake index (BUI) technique, and in vitro with the isolated human brain capillary preparation. The only amino acid that is albumin-bound is tryptophan, and the majority of albumin-bound tryptophan in the plasma is available for transport through the BBB via an enhanced dissociation mechanism that operates at the surface of the brain capillary endothelium. The availability in brain of amino acids is predicted from the BBB Km values to be sharply influenced by supra-physiological concentrations of phenyalanine in the 200-500 microM range. Moreover, the measurement of cerebral protein synthesis with an internal carotid artery perfusion technique and HPLC-based measurements of aminoacyl-transfer RNA specific activities shows an inverse relationship between cerebral protein synthesis and plasma phenyalanine concentrations in the 200-500 microM range. These findings indicate the neurotoxicity of hyperphenylalninemia is not restricted to the phenylketonuria range of approximately 2000 microM, but is exerted in the supra-physiological range of 200-500 microM.

Amino Acids↗
PubMed1982

Influence of blood glucose concentration on brain lactate accumulation during severe hypoxia and subsequent recovery of brain energy metabolism.

The effects of hypoxaemia on regional cerebral blood flow (CBF) and brain cortical metabolite concentrations were investigated at different blood glucose concentrations in rats under nitrous oxide anaesthesia. Tissue hypoxia of 15-min duration was induced by a combination of arterial hypoxaemia, hypotension, and clamping of the right carotid artery. Blood glucose concentrations were manipulated by varying the food intake in the 24 h before the experiment, and by glucose administration. Cortical CBF doubled during hypoxia on the intact side, but did not differ significantly from control values on the clamped side. In the clamped hemisphere there was a substantial decrease in adenylate energy charge. At brain tissue glucose concentration of 1 mumol g-1 and above, there was an inverse correlation between adenylate energy charge and brain lactate concentration. In starved animals with mean brain glucose of 0.32 +/- 0.00 mumol g-1, lactate concentration was significantly lower, in spite of equally severe disruption of energy state. Recovery of brain adenylate energy charge was worse in fed and glucose-infused groups than in the fasted group. These results demonstrate that limitation of substrate supply during severe hypoxia in the rat allows enhanced recovery of brain energy metabolism following the hypoxic episode.

Animals↗
PubMed1993

Blockade of AMPA receptors reduces brain edema following opening of the blood-brain barrier.

The aim of our study was to evaluate whether blockade of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors could reduce brain edema in two experimental models of edema following opening of the blood-brain barrier (BBB). The brain specific gravity was determined 2 h after opening the BBB by a 30-s infusion of protamine sulfate (10 mg in 200 microliters 0.9% NaCl) or arabinose (1.5 or 1.8 mol/L, 0.06 ml.s-1) into the right internal carotid artery. Cisternal CSF was withdrawn for albumin determination before the carotid infusion and before killing 2 h later. After infusion of protamine sulfate or arabinose, CSF albumin increased in all groups. The brain specific gravity was significantly lower in the right than in the left (control) frontal, parietal, and occipital cortex and striatum. NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenxo(F)quinoxaline), an AMPA receptor antagonist, given intravenously 10 min after opening the BBB (5 mg/kg), significantly increased the specific gravity in the treated rats (p < 0.01 for the difference from control rats) without reducing CSF albumin or albumin extravasation in the brain as evaluated with Evans blue. We hypothesize that intracerebral (glial?) AMPA receptors may play a role in brain edema following opening of the BBB.

Animals↗
PubMed2002

Brain engraftment of autologous macrophages transduced with a lentiviral flap vector: an approach to complement brain dysfunctions.

Transplantation of ex vivo gene-corrected autologous cells represents an attractive therapeutic approach for brain diseases. Among the cells of the central nervous system, brain macrophages are promising candidates due to their role in tissue homeostasis and their implication in several neurological diseases. Up to now, gene transfer into macrophages has proven difficult by most currently available gene delivery methods. We describe herein, an efficient transduction of rat bone marrow-derived and brain macrophages with an HIV-1-derived vector containing a central DNA flap and encoding the GFP reporter gene (TRIP-DeltaU3-GFP). In primary cultures of macrophages our results show that more than 90% of the cells were transduced by the TRIP vector and that GFP expression remained stable for 1 month without cytopathic effect. In vivo, transplants of transduced macrophages into the striatum of adult rats exhibited long-term expression of GFP up to 3 months. Transduced macrophages were observed around the brain injection site and exhibited the brain macrophage/microglia phenotype. There was no significant sign of astrogliosis around the graft. These results confirm the potential of lentiviral vectors for efficient and stable ex vivo transduction of macrophages. Moreover, transduced autologous macrophages appear as a valuable vehicle for long-term and localized gene expression into the brain.

Animals↗
PubMed2000

Spatial, temporal and subcellular localization of islet-brain 1 (IB1), a homologue of JIP-1, in mouse brain.

Islet-brain 1 (IB1) was recently identified as a DNA-binding protein of the GLUT2 gene promoter. The mouse IB1 is the rat and human homologue of the Jun-interacting protein 1 (JIP-1) which has been recognized as a key player in the regulation of c-Jun amino-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathways. JIP-1 is involved in the control of apoptosis and may play a role in brain development and aging. Here, IB1 was studied in adult and developing mouse brain tissue by in situ hybridization, Northern and Western blot analysis at cellular and subcellular levels, as well as by immunocytochemistry in brain sections and cell cultures. IB1 expression was localized in the synaptic regions of the olfactory bulb, retina, cerebral and cerebellar cortex and hippocampus in the adult mouse brain. IB1 was also detected in a restricted number of axons, as in the mossy fibres from dentate gyrus in the hippocampus, and was found in soma, dendrites and axons of cerebellar Purkinje cells. After birth, IB1 expression peaks at postnatal day 15. IB1 was located in axonal and dendritic growth cones in primary telencephalon cells. By biochemical and subcellular fractionation of neuronal cells, IB1 was detected both in the cytosolic and membrane fractions. Taken together with previous data, the restricted neuronal expression of IB1 in developing and adult brain and its prominent localization in synapses suggest that the protein may be critical for cell signalling in developing and mature nerve terminals.

Adaptor Proteins, Signal Transducing↗