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PubMed1986

Glioma cell interactions with fetal rat brain aggregates in vitro and with brain tissue in vivo.

Two malignant rat neurogenic cell lines have been confronted with reaggregation cultures of fetal rat brain in a stationary culture system. In this organ culture system several morphological aspects of the developing brain are imitated. The malignant cell lines showed invasive and progressive growth into the brain tissue, ending with a completely destroyed aggregate within 10 days of coculture. One cell line (BT5C) showed solid invasion with groups of cells replacing different layers of the brain tissue. A considerable degree of normal cell lysis was seen, both at the edge of invasion and at distant parts of the aggregate. This cell line seemed to activate macrophages in the aggregates. In addition, conditioned medium from these cultures caused degeneration of the brain aggregates. The other cell line (BT4Cn) showed invasion by single cells where the replacement and destruction of the tissue was not accompanied by distant lysis. Both cell lines showed the same pattern of invasion in vitro as was seen in the brains of isogeneic animals in vivo, showing that the individual tumor characteristics were also reflected during invasive growth in organ culture.

Animals↗
PubMed1984

Modification of the blood-brain barrier in the chemotherapy of malignant brain tumors.

Inadequate drug delivery to the brain, caused by an intact or partially intact blood-brain barrier (BBB), probably accounts for poor therapeutic responsiveness to cytoreductive drugs by malignant metastatic and primary brain tumors. Drug delivery can be enhanced in normal brains and brains with tumors by administering drugs into the carotid or vertebral circulation after osmotic opening of the BBB. The osmotic procedure in humans involves infusion into the carotid or vertebral arteries of a 25% mannitol solution for 30 s. The procedure is reversible, can be accomplished without long-term neurological deficits, and can be monitored in dogs and humans by means of enhanced computerized tomography. Osmotic BBB disruption, when combined with multiple drug administration, has proved effective in treating brain tumors in a small number of clinical cases.

Adrenal Cortex Hormones↗
PubMed1982

[Nuclear magnetic resonance (NMR) imaging of brain edema from sliced rat brain: preliminary report].

A series of the sliced rat brain were imaged by proton nuclear magnetic resonance (1H-NMR) using a Carr-Purcell-Meiboom-Gill sequence. The slices were obtained from the adult male Wistar rats, normal or suffering from vasogenic brain edema at 2, 6, 24Hr, 2Wk and 2Mo period after the application of cryo-injury. The imaging time was arranged 17 to 22 minutes dependently upon signal to noise ratio. The slice thickness was 1.2 mm, and pixel dimensions were 0.2 X 0.2 mm. Whereas a voxel size in our images is mere 1/1,200 compared to that reported about the prototype human NMR imaging devices, high resolution has been realized. The spatial resolution is very fine, as evidenced by the appearance of major internal structures of rat brain, and the object contrast is so high that cerebral white-gray contrast is excellent, although the difference in water concentration between them is only 7%. It has been impossible to measure serially in vivo change in water concentration of small organs as rat brain, NMR has the capability to generate images in response to tissue state of hydration, therefore we can easily recognize the extent and intensity of the brain edema, which has been defined as an expansion of the brain volume resulting from an increase in its fluid content. And in this study, using the prototype mini-NMR-CT of excellent spatial and contrast resolution, we have been able to show this advantage of NMR as a new tool for research in the field of neurological surgery.

Animals↗
PubMed1994

[Clinical pharmacokinetics of carboplatin and MCNU in malignant brain tumor and normal brain tissues].

We measured the concentrations of MCNU and CBDCA in the serum, brain tumor and normal brain tissue. Six patients with malignant glioma were treated with intravenous chemotherapy using 80mg/m2 MCNU and 300mg/m2 CBDCA during surgery. After drug administration, specimens of serum, tumor and normal brain tissue were collected every 30 min and then the drug concentration in each sample was measured. The highest MCNU levels in all samples were obtained immediately after administration which followed by gradual decrease. On the contrary, the mean CBDCA levels in the tumor and normal tissue remained almost at a constant level, although serum CBDCA level declined rapidly as MCNU. As expected, MCNU seemed to have advantages in the treatment of brain tumors as it distributed with higher concentration in the tumor tissue than in the serum and normal brain tissue. On the contrary, CBDCA in the tumor tissue did not exceed the concentration in the serum. Nevertheless, it remained longer in the tumor tissue with a constant level, suggesting that CBDCA can achieve an effective area under the concentration versus time curve (AUC) in the brain tumor tissue to kill tumor cells.

Aged↗
PubMed1993

4-Hydroxynonenal content lower in brains of 25 month old transgenic mice carrying the human CuZn superoxide dismutase gene than in brains of their non-transgenic littermates.

Basic peroxidation in brains of normal 2 month old mice was compared to that in brains of 25 month old mice by measurement of 4-hydroxy-2-nonenal and protein carbonyl contents. No significant age-related differences in 4-hydroxy-2-nonenal were observed, showing that lipid peroxidation is not a determining factor in cerebral aging. However, protein carbonyls increased with age in brains, indicating accumulation of age-related cell constituent damage. The role of excess CuZn superoxide dismutase in basal lipid peroxidation in mouse brains was studied by comparison of eight 25 month old transgenic mice and eight non-transgenic littermates. Higher 4-hydroxy-2-nonenal concentrations were found in normal mouse brains. These data suggest an increased protective role of CuZn superoxide dismutase against lipid peroxidation in transgenic mouse brains.

Aging↗
PubMed2001

Preservation of neurotrophin expression in microglia that migrate into the gerbil's brain across the blood-brain barrier.

Microglia isolated from a mixed glial culture drawn from neonatal Mongolian gerbils were demonstrated to produce high amounts of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). The gerbil microglia retained the capability to migrate into the brain parenchyma after intra-arterial injection. We found that exogenously migrated microglia retained their BDNF and GDNF productive ability and expressed large amounts of BDNF and GDNF in damaged brain areas which suggests microglia's role as a protectant of damaged neurons. Since peripherally injected microglia exhibit specific affinity for areas of neural damage within the brain, we suggest that microglia are possible tools for cell therapy of brain damage.

Animals↗
PubMed2000

Blockade of histamine H2 receptors attenuate blood-brain barrier permeability, cerebral blood flow disturbances, edema formation and cell reactions following hyperthermic brain injury in the rat.

Role of histamine H2 receptors in blood-brain barrier (BBB) disturbances, cerebral blood flow (CBF), brain edema formation, and cell injury caused by heat stress in a rat model was examined using the pharmacological approach. Blockade of histamine H2 receptors by cimetidine or ranitidine significantly attenuated the BBB permeability to Evans blue albumin and [131]I-sodium extravasation, brain edema formation and cell injury following 4 h heat stress in rats at 38 degrees C. These drug treatments also restored the CBF to near normal values. These beneficial effects in heat stress were most marked in rats treated with ranitidine compared to cimetidine given in identical dosage. Our observations suggest that blockade of histamine H2 receptor is beneficial in hyperthermic brain injury and indicates that histamine is involved in the pathophysiology of heat stress induced brain dysfunction. Our study strongly suggests further need to develop more specific and sensitive histaminergic H2 receptor blockers for the treatment of neurological ailments.

Animals↗
PubMed1996

Developing brain cells produce factors capable of inducing the HT7 antigen, a blood-brain barrier-specific molecule, in chick endothelial cells.

Homeostasis of the neural microenvironment is maintained by the blood-brain barrier (BBB). To analyze the molecular mechanisms by which the BBB is induced during embryonic development, we have taken advantage of an in vivo model of BBB induction based on the expression of the HT7 cell surface protein. This protein is a transmembrane glycoprotein of the immunoglobulin superfamily. It is expressed in the chick BBB-forming endothelial cells, but not in peripheral endothelial cells. Here we show that the HT7 protein is induced in vessels which had vascularized a quail embryonic brain graft transplanted in the coelomic cavity of chick embryo. The quail brain graft was vascularized by both chick and quail-derived vessels. All chick host-derived vessels in the brain transplant were found to express HT7 while the neighboring chick vessels were negative. We conclude that the invading host endothelial cells differentiated into BBB-forming vessels under the influence of developing quail brain cells. This model reproduces the BBB induction during development. It may be useful for further approaches to study the molecular mechanisms involved in BBB induction.

Animals↗
PubMed1998

Does traumatic subarachnoid hemorrhage caused by diffuse brain injury cause delayed ischemic brain damage? Comparison with subarachnoid hemorrhage caused by ruptured intracranial aneurysms.

OBJECTIVE: To examine whether traumatic subarachnoid hemorrhage (TSAH) caused by severe diffuse brain injury leads to delayed ischemic brain damage and secondary deterioration of outcome, as does aneurysmal subarachnoid hemorrhage (ASAH). METHODS: We examined 99 patients with diffuse brain injury with TSAH and 114 patients with ASAH. Computed tomographic (CT) findings, cerebral blood flow, and neurological outcomes were assessed during the acute and subacute phases and were compared between the two groups. RESULTS: The distribution of subarachnoid hemorrhage on the CT scans differed between the two groups. Unlike ASAH, TSAH was not limited to cisterns surrounding the circle of Willis but extended to supratentorial regions and interhemispheric fissures. Computed tomography-detected subarachnoid hemorrhage disappeared very early with TSAH and gradually with ASAH. In the ASAH group, mean cerebral blood flow decreased to 75% of normal during the acute phase and decreased a further 10% during the subacute phase. In the TSAH group, mean cerebral blood flow decreased to 85% of normal during the acute phase and increased slightly during the subacute phase. Neurological deterioration and in-hospital death peaked on Day 0 in association with TSAH and showed twin peaks in association with ASAH. The incidence of low-density areas on the CT scans was significantly higher with ASAH than with TSAH. All low-density areas on the CT scans of patients with ASAH corresponded to vascular territories, but low-density areas on the CT scans of patients with TSAH were rarely associated with vascular territories and contained deep-seated or gliding contusion types. CONCLUSION: The findings suggest that the incidence of vasospasm is low in association with TSAH and that the cause is different compared with ASAH. There is no evidence that the presence of TSAH in cases of diffuse brain injury leads to delayed ischemic brain damage and secondary deterioration of outcome.

Acute Disease↗
PubMed2004

Whole-brain apparent diffusion coefficient in traumatic brain injury: correlation with Glasgow Coma Scale score.

BACKGROUND AND PURPOSE: Patients with traumatic brain injury (TBI) and low Glasgow coma scale (GCS) scores may have severe injury associated with cellular disruption that can be studied with whole-brain apparent diffusion coefficient (ADC) histograms. We retrospectively studied this hypothesis and correlated ADC with GCS. METHODS: Twenty-one patients (37.81 +/- 41.3 years) with TBI were enrolled: Group A had normal MR imaging findings but low GCS scores (n = 6). Group B had brain stem injury with low GCS scores (n = 6). Group C had cortical lesions with normal GCS scores (n = 5), and group D had cortical lesions with low GCS scores (n = 4). Eleven control subjects were enrolled (32.7 +/- 19.2 years). Whole-brain ADC maps and histograms were generated and normalized for each subject. Mean and peak ADCs were determined. A one-sided t test was performed for each parameter. Average GCS scores and corresponding peak and mean ADCs were correlated. RESULTS: Peak histogram values significantly differed between controls and groups A, B, and D (P <.0019, P <.00129, and P <.0148, respectively). In groups A and D, values were significantly skewed compared with control values. Mean ADC was significantly different between the control ADC and group A (P <.013) but not group C. In each group, peak ADC and GCS score were strongly correlated (R(2) = 0.67). CONCLUSION: Whole-brain peak ADCs and GCS scores are significantly correlated in patients with TBI. Although conventional MR images were normal, ADC independently indicated TBI and better represents the degree of neurologic dysfunction.

Adolescent↗
PubMed1991

Experimental evaluation of blood-brain barrier permeability using colloidal gold particles as tracers in early-stage brain injury.

We used 46 rabbits for the study of blood-brain barrier (BBB) permeability quantitatively in early-stage brain injury by a dropping weight method. The animals were divided into two groups: control group and brain injury group. Both Evans' blue and colloidal gold (CG) particles were utilized for evaluation of BBB permeability alteration. Three different sizes of CG 5, 10 and 15 nm in diameter were employed as tracers for a quantitative investigation of BBB changes by light and electron microscopes respectively. In addition, the brain water contents were determined. The preliminary data indicated that an increase of BBB permeability began 30 minutes after the injury with a few of 5 or 10 nm CG particles present in the endocytic pits and endothelial microvilli, and the augmentation of BBB permeability reached its peak 6 hours after the injury. More CG tracers penetrated into the precapillary arterioles, venules or capillaries through the opening of tight junctions of BBB and by vesicular transportation. The variation of the brain water contents was closely correlated to the above-mentioned BBB changes. It is suggested that the vasogenic cerebral edema was mainly caused by the augmentation of BBB permeability.

Animals↗
PubMed2004

Antenatal and postnatal brain magnetic resonance imaging in muscle-eye-brain disease.

BACKGROUND: Muscle-eye-brain disease (MEB) is a rare autosomal recessive disorder characterized by congenital muscular dystrophy, structural eye abnormalities, and type II lissencephaly. Previous reports of brain abnormalities on magnetic resonance images (MRIs) in MEB have been in children older than 1 year. OBJECTIVE: To describe serial antenatal and postnatal brain MRIs in a child with MEB. DESIGN: Case report. PATIENT: We report a 2-year-old white boy with genetically confirmed MEB. Antenatal MRIs at 25 and 35 weeks' gestation showed posterior ventriculomegaly but no cortical dysplasia. A postnatal brain MRI at age 1 week showed frontal cortical dysplasia and abnormal signal intensity within the frontal white matter. A brain MRI at 8 months showed bilateral frontoparietal polymicrogyria. All images demonstrated flattening of the pons and mild hypoplasia of the inferior vermis. The child had no weakness, and muscle involvement was only suspected when the serum creatine kinase level was found to be elevated at age 8 months. CONCLUSION: Cortical dysplasia in MEB may not be evident until several postnatal months; therefore, if MEB is suspected, brain MRI performed in the first few months of life should be interpreted with caution.

Brain↗
PubMed2003

Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects.

BACKGROUND: Suicide is a major public health concern. Although authors of many studies have examined the neurobiological aspects of suicide, the molecular mechanisms associated with suicidal behavior remain unclear. Brain-derived neurotrophic factor (BDNF), one of the most important neurotrophins, after binding with and activating receptor tyrosine kinase B (trk B), is directly involved in many physiological functions in the brain, including cell survival and synaptic plasticity. The present study was performed to examine whether the expression of BDNF and/or trk B isoforms was altered in postmortem brain in subjects who commit suicide (hereafter referred to as suicide subjects) and whether these alterations were associated with specific psychopathologic conditions. METHODS: These studies were performed in prefrontal cortex in Brodmann area 9 and hippocampus obtained in 27 suicide subjects and 21 nonpsychiatric control subjects. Levels of messenger RNA and protein levels of BDNF and trk B were determined with competitive reverse transcriptase-polymerase chain reaction and Western blot technique, respectively. The level of neuron-specific enolase messenger RNA as a neuronal marker was also determined in these brain areas. RESULTS: Messenger RNA levels of BDNF and trk B were significantly reduced, independently and as a ratio to neuron-specific enolase, in both prefrontal cortex and hippocampus in suicide subjects, as compared with those in control subjects. These reductions were associated with significant decreases in the protein levels of BDNF and of full-length trk B but not trk B's truncated isoform. These changes were present in all suicide subjects regardless of psychiatric diagnosis and were unrelated to postmortem interval, age, sex, or pH of the brain. CONCLUSIONS: Given the importance of BDNF in mediating physiological functions, including cell survival and synaptic plasticity, our findings of reduced expression of BDNF and trk B in postmortem brain in suicide subjects suggest that these molecules may play an important role in the pathophysiological aspects of suicidal behavior.

Adult↗
PubMed1999

Discrepancy between regional cerebral blood flow and glucose metabolism of the brain in systemic lupus erythematosus patients with normal brain magnetic resonance imaging findings.

OBJECTIVE: In this study, 2 updated brain-imaging modalities, technetium-99m hexamethylpropylene amine oxime-single-photon-emission computed tomography (HMPAO-SPECT) and fluorine-18 2-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET), were used to simultaneously detect regional cerebral blood flow (rCBF) and glucose metabolism of the brain in patients with systemic lupus erythematosus (SLE). METHODS: Twenty-five female SLE patients, ages 25-40 years, were enrolled in this study and assigned to 1 of 2 groups. Group 1 consisted of 13 patients with neuropsychiatric manifestations (7 had major and 6 had minor manifestations). Group 2 consisted of 12 patients without neuropsychiatric manifestations. Serum levels of anticardiolipin antibodies (aCL) and anti-ribosomal P antibodies (anti-P) were measured. All patients had normal brain magnetic resonance imaging (MRI) findings. Ten healthy female volunteers also underwent brain MRI, HMPAO-SPECT, and FDG-PET for comparison. RESULTS: 99mTc-HMPAO-SPECT revealed hypoperfusion lesions in 11 (44%) of 25 SLE patients, including 9 (69%) of the 13 patients in group 1, 7 (100%) of the 7 patients with major manifestations, 2 (33%) of the 6 patients with minor manifestations, and 2 (17%) of the 12 patients in group 2. Parietal lobes were the areas most commonly involved. FDG-PET revealed hypometabolism in 7 (54%) of the group 1 patients, 6 (86%) of the 7 patients with major manifestations, and 1 (17%) of the 6 patients with minor manifestations. Temporal lobes were the most commonly involved areas. However, no significant hypometabolism brain lesions were found in group 2 patients. All of the 4 patients with headaches and dizziness or headaches alone had normal findings on HMPAO-SPECT and FDG-PET. Nine (36%) of the 25 patients were positive for aCL. However, the presence of aCL was not related to neuropsychiatric manifestations or to HMPAO-SPECT or FDG-PET findings. Five (20%) of the 25 patients had anti-P antibodies and psychosis/depression. CONCLUSION: In patients with normal brain MRI findings, decreases in glucose metabolism coupled with decreases in rCBF are associated with serious neuropsychiatric SLE (NPSLE) presentations, while normal glucose metabolism with decreases in rCBF may be found in SLE patients with or without NPSLE.

Adult↗
PubMed2003

Anatomy and histology of the brain and sense organs of the antarctic plunderfish Dolloidraco longedorsalis (Perciformes: Notothenioidei: Artedidraconidae), with comments on the brain morphology of other artedidraconids and closely related harpagiferids.

In the high-latitude shelf waters of Antarctica, fishes in the perciform suborder Notothenioidei dominate the fish fauna and constitute an adaptive radiation and a species flock. The 25 species of notothenioid plunderfishes, comprising four genera of the family Artedidraconidae, contribute substantially to fish species diversity on the high Antarctic shelf. A mental barbel is an autapomorphy for the family. Dolloidraco longedorsalis is the most abundant artedidraconid at depths over 400 m in these waters. In this article we present the anatomy and histology of the brain and special sense organs of Dolloidraco and compare it to the brains of other artedidraconids, closely related harpagiferids, and more generally to other notothenioids. We provide a detailed drawing of the brain and cranial nerves. The brain of Dolloidraco is simple, without external hypertrophy of sensory or motor regions, but contains several unusual features associated with the ventricular system and CSF, including well-developed circumventricular organs, subependymal expansions, and subarachnoid cisterns; and a ventricle in the corpus cerebellum. The brain of Dolloidraco also contains a lobed chief sensory nucleus of the trigeminal nerve that is correlated across species with barbel length. The eyes are large and contain a small choroid rete, a structure previously thought to be absent from members of this family. We document the histology of the duplex retina, olfactory apparatus, cutaneous taste buds, and barbel musculature and innervation. We discuss the role of pedomorphy in producing simplified brain morphologies. We consider the possibility that Dolloidraco is a somatosensory specialist-an unusual feature among vertebrates-and decide that this is unlikely.

Animals↗
PubMed2001

Blood-brain barrier preservation in the in vitro isolated guinea pig brain preparation.

The morphofunctional preservation of the blood-brain barrier (BBB) was evaluated in the isolated guinea pig brain maintained in vitro by arterial perfusion. Electron microscopy evaluation after 5 hr in vitro demonstrated that cerebral capillaries and BBB specializations in this preparation retain features compatible with structural integrity. BBB-impermeable and -permeable atropine derivatives arterially perfused to antagonize carbachol-induced fast oscillatory activity confirmed the functional preservation of the BBB in vitro. To study BBB function further, changes in extracellular K+ concentration during arterial perfusion of a high-K+ solution were measured with K+-sensitive electrodes positioned in the cortex and, as control, at the brain venous outlet, where the solution perfused through the brain arterial system was collected. After 5 hr in vitro, the [K+](o) values measured during high-K+ perfusion in the piriform and entorhinal cortices were 5.02 +/- 0.17 mM (mean +/- SE) and 5.2 +/- 0.21 mM, respectively (n = 6). Coperfusion of the high-K+ solution with the Na+/K+ pump blocker ouabain (10 microM; n = 4) induced consistently spreading depression preceded by a rise in [K+](o). Finally, sporadic, isolated spots of extravasation of the fluorescent marker fluorescein isothiocyanate (FITC)-dextran preferentially circumscribed to deep cortical layers was observed in brains perfused with FITC-dextran after 5 hr in vitro. The study demonstrates that the in vitro isolated guinea pig brain is viable for studying cerebrovascular interactions and BBB permeability of compounds active in the central nervous system.

Animals↗
PubMed1990

Quantitative brain autoradiography of [9,10-3H]palmitic acid incorporation into brain lipids.

The distribution of radioactivity within brain metabolic compartments was examined following the intravenous injection of [9,10-3H]palmitate into awake rats. Brain radioactivity reached a maximum value by 15 min after [9,10-3H]palmitate injection and remained unchanged for at least 4 hr. Regional differences in radioactivity could be determined with high resolution by quantitative autoradiography, at the level of cell layers within the hippocampus and cerebral cortex, and between striosomes of the caudate nucleus. Regional brain radioactivities were converted to normalized regional radioactivities (k) by dividing them by the integrated plasma fatty acid radioactivity (integrated over the time course of the experiment). These values reflected incorporation mainly into brain phospholipids; radioactivity due to nonlipid components was minimal. Indeed, about 85% of brain radioactivity was within lipids between 5 min and 4 hr postinjection, the remainder being equally divided between protein-associated pellet and aqueous-soluble metabolites. The major lipids labeled were phospholipids, particularly phosphatidylcholine, which contained about 75% of phospholipid radioactivity. The results show that [9,10-3H]palmitate can be used to examine incorporation of plasma palmitate into individual brain regions via quantitative autoradiography. Furthermore, the tracer is a rather selective marker for phosphatidylcholine and can be used to examine turnover and synthesis of this phospholipid. [9,10-3H]palmitate has advantages over [U-14C]palmitate for autoradiographic studies of incorporation; following the 14C-tracer, significant label even at 4 hr after injection is in nonlipid compartments (glutamate and aspartate), and the long path length of 14C limits resolution at the cell layer level.

Animals↗
PubMed2002

Investigation of transport mechanism of pentazocine across the blood-brain barrier using the in situ rat brain perfusion technique.

To characterize pentazocine (PTZ) transport across the blood-brain barrier (BBB), the cerebrovascular permeability-surface area product (PS(inf)) of PTZ was determined by a well-established in situ rat brain perfusion technique. The uptake kinetics of PTZ by the rat brain exhibited saturability, which indicates the simultaneous mechanisms of carrier-mediated transport and passive diffusion. The kinetic parameters were estimated as follows: maximal influx rate (V(max)), 27.2 +/- 5.2 nmol/s/g brain; apparent Michaelis constant (K(m)) for the saturable component of PTZ uptake, 2.9 +/- 0.5 mM; nonsaturable uptake rate constant (K(d)), 1.5 +/- 0.3 microL/s/g brain. BBB transport of PTZ was significantly inhibited by cationic drugs such as diphenhydramine, propranolol, and eptazocine (a narcotic-antagonist analgesic), but not by choline, suggesting that the PTZ transport system is shared by cationic drugs. Furthermore, co-perfusion of verapamil caused a significant (two-fold) increase in the BBB permeability to PTZ. This finding indicates that PTZ may be a substrate of the endogenous BBB efflux transport system, P-glycoprotein. These findings demonstrate that the primary mechanism governing the uptake of PTZ by the brain is carrier-mediated transport, not passive diffusion.

Animals↗