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PubMed1990

The importance of brain temperature in alterations of the blood-brain barrier following cerebral ischemia.

We studied whether small variations in intraischemic brain temperature influence the response of the blood-brain barrier (BBB) to transient forebrain global ischemia. Six animal subgroups included rats whose brain temperature was maintained at 30, 33, 36 or 39 degrees C during 20 minutes (min) of 4-vessel occlusion. Control rats without ischemia had brain temperature maintained between 30 and 39 degrees C for a 20 min period. After a 45 min postischemic recirculation period, rats were injected with the protein tracer, horseradish peroxidase (HRP), and perfusion fixed 5 or 15 min later. Control rats showed no leakage of the tracer protein. Postischemic rats in which brain temperature was controlled at either 30 or 33 degrees C failed to demonstrate consistent BBB alterations. In contrast, foci of cortical HRP extravasation were consistently documented in rats whose intraischemic brain temperature was 36 degrees C. Permeability alterations were more widespread in the 39 degrees C ischemic group and occurred in cortical, thalamic, hippocampal and striatal regions. The HRP extravasation frequently involved arterioles surrounded by perivascular spaces. Routes of increased permeability to HRP included endothelial pinocytosis, opening of the interendothelial tight junctions and diffuse leakage through damaged endothelial cells. These results demonstrate that brain temperature is a critical factor in determining whether BBB dysfunction is an acute consequence of a transient cerebral ischemic insult.

Animals↗

PubMed1995

The effect of hypertonic fluid resuscitation on brain edema in rabbits subjected to brain injury and hemorrhagic shock.

Small-volume resuscitation with 7.2% NaCl/10% dextran 60 (HHS) restores cardiovascular stability faster than all other therapeutic modalities currently known. This study was undertaken to elucidate the effects of HHS on the brain, specifically on the formation of posttraumatic brain edema. HHS was administered to anesthetized albino rabbits with or without a focal cryogenic brain lesion and hemorrhagic shock. Specific gravity of small tissue samples was determined 4 h after injury and values were topographically assembled to form a color-coded map of both hemispheres, allowing for a high resolution mapping of brain edema. Cerebral blood flow on the side of the lesion, as assessed by the H2 clearance method, increased transiently after injury but remained unchanged from baseline during shock and after infusion of HHS, indicating intact cerebrovascular autoregulation. The cryogenic lesion without subsequent HHS infusion resulted in significant brain edema formation in grey and white matter of the exposed hemisphere. In injured animals, resuscitation with HHS led to a global reduction of brain water content in both hemispheres. We conclude that small-volume resuscitation with HHS does not worsen posttraumatic brain edema. To the contrary, our results show that it decreases cerebral water content even in regions close to the injury. This makes it worthwhile to investigate the benefits of HHS for the treatment of intracranial hypertension.

Animals↗

PubMed2006

Opposed effects of hypertonic saline on contusions and noncontused brain tissue in patients with severe traumatic brain injury.

OBJECTIVE: The aim of this study was to quantify the effect of hypertonic saline solution on contused and noncontused brain tissue in patients with traumatic brain injury. We hypothesize that hypertonic saline would increase the volume of brain contusion while decreasing the volume of noncontused hemispheric areas. DESIGN: Prospective observational study. SETTING: Neurosciences critical care unit of a university hospital. PATIENTS: Fourteen traumatic brain injury patients with increased intracranial pressure. INTERVENTIONS: A computed tomography scan was performed before and after a 20-min infusion of 40 mL of 20% saline. MEASUREMENTS AND MAIN RESULTS: The volume, weight, and specific gravity of contused and noncontused hemispheric areas were assessed from computed tomography DICOM images by using a custom-designed software (BrainView). Physiologic variables and natremia were measured before and after infusion. Hypertonic saline significantly increased natremia from 143 +/- 5 to 146 +/- 5 mmol/L and decreased intracranial pressure from 23 +/- 3 to 17 +/- 5 mm Hg. The volume of the noncontused hemispheric areas decreased by 13 +/- 8 mL whereas the specific gravity increased by 0.029 +/- 0.027%. The volume of contused hemispheric tissue increased by 5 +/- 5 mL without any con-comitant change in density. There was a wide interindividual variability in the response of the noncontused hemispheric tissue with changes in specific gravity varying between -0.0124% and 0.0998%. CONCLUSIONS: Three days after traumatic brain injury, the blood- brain barrier remains semipermeable in noncontused areas but not in contusions. Further studies are needed to tailor the use of hypertonic saline in patients with traumatic brain injury according to the volume of contusions assessed on computed tomography.

Adolescent↗

PubMedDate not supplied

Chronological sequences and blood-brain barrier permeability changes in local injury as assessed by nuclear magnetic resonance (NMR) images from sliced rat brain.

Two experiments were done with a prototype mini-NMR imager to evaluate the potential application of nuclear magnetic resonance (NMR) imaging in neuropathology. Cryo-injury-induced brain edema in brain slices from 22 adult male rats was imaged for observing the chronological sequences. Blood-brain barrier permeability changes were evaluated in 12 other brain slice images. EDTA-2Na-Mn solution was intravenously injected as an indicator of blood-brain barrier permeability. Contrast enhancement was achieved by changing the NMR imaging parameters. High resolution imaging permitted visualization of the corpus callosum, the thickness of which was only 0.2-0.4 mm. The extent of edema in gray matter was clearly shown with a striking contrast; no consistent findings were seen with slight differences in water content between edema and the surrounding normal cortex. As a result, the chronological sequences of brain edema were clearly observed. Mn-EDTA leaking from the circulating blood through the damaged capillary wall had a "paradoxical enhancement" effect on the NMR images; this effect might be suitable for evaluating blood-brain barrier permeability changes in NMR images.

Animals↗

PubMed2002

Isolation and molecular characterization of brain microvascular endothelial cells from human brain tumors.

Brain tumor formation and growth is accompanied by the proliferation and infiltration of blood capillaries. The phenotypes of endothelial cells that make up capillaries are known to differ not only in the tissues in which endothelial cells are located but also as a result of the microenvironment to which they are exposed. For this reason, primary cultures of brain endothelial cells were isolated from human brain tumors removed by surgery and compared with cells from normal tissue. The primary confluent monolayers that grew out of isolated capillary fragments consisted of closely associated, elongated, fusiform-shaped cells. But brain tumor-derived endothelial cells in culture exhibited significantly less expression of endothelial-specific Factor VIII-related antigen compared with cells isolated from normal tissue. Cultured cells that exhibited binding of Ulex europaeus lectin were shown to take up Dil-Ac-Ldl and formed continuous monolayers that were joined together by tight junctions. The cells also exhibited characteristics of the cells of the brain microvasculature in vitro as seen by the presence of large numbers of mitochondria and few pinocytotic vesicles and by the absence of Weibel-Palade bodies within the cells. The expression of vascular cell adhesion molecule-1, E-Selectin, and the tight junction associated protein ZO-1 but not intercellular adhesion molecule-1 was demonstrated by immunohistological staining or reverse transcriptase-polymerase chain reaction methodologies. Comparative studies of these endothelial cells with endothelial cells from normal tissue will be useful for determining and understanding how the blood-brain barrier differs and functions in tumor and healthy tissues and may lead to strategies for brain tumor therapeutic approaches.

Blood-Brain Barrier↗

PubMed1981

Monitoring of methotrexate delivery in patients with malignant brain tumors after osmotic blood-brain barrier disruption.

Reversible transient osmotic blood-brain barrier disruption was used to increase drug delivery to the brain. Methotrexate was administered 33 times to six patients with brain tumors after barrier disruption. No permanent complications were seen. Serial enhanced computed tomographic (CT) scans and quantification by CT tomographic number indicated that disruption increased drug delivery to the tumor and immediate surrounding brain. Neuroradiologic evaluation showed that drug in the tumor persisted longer after barrier disruption than when delivered without disruption. The concentration of methotrexate in spinal fluid did not correlate with the degree of barrier disruption measured by CT and radionuclide scans. In one patient an anatomic variation in the circle of Willis resulted in barrier disruption extending into the posterior fossa without ill effect. Osmotic blood-brain barrier disruption appears to be a safe procedure in man, able to increase drug delivery to both malignant brain tumors and surrounding brain parenchyma.

Blood-Brain Barrier↗

PubMed2003

Auditory brain stem responses in the detection of brain death.

OBJECTIVES: We evaluated comatose patients by auditory brain stem responses (ABR) to determine the role of ABR in the diagnosis of impending brain death. PATIENTS AND METHODS: Sixty comatose patients in the intensive care unit were evaluated by brain stem evoked response audiometry. Correlations were sought between the absence or presence of ABRs and the presenting pathology, the Glasgow Coma Scale (GCS) scores, and ultimate diagnoses. RESULTS: The brain stem responses were totally absent in 41 patients. Presence of wave I could be obtained in only 10 patients. All the waveforms were found in nine patients; however, in eight patients the potentials disappeared as the GCS scores decreased to 3. Detection of wave I alone strongly suggested dysfunction of the brain stem. However, loss of wave I particularly in trauma patients aroused doubt as to whether the absence was associated with auditory end organ injury or brain stem dysfunction. CONCLUSION: The results suggest that evaluation of ABR may support brain death in a comatose patient (i) when wave I is present alone, (ii) the absence of wave I is accompanied by a documented auditory end organ injury, or (iii) when previously recorded potentials are no longer detectable.

Adolescent↗

PubMed1988

[Effect of glycerol administration on experimental cerebral ischemia--Part 1. Studies on lipid peroxides, prostaglandins, brain edema and brain metabolites].

Using two different models of non ischemic and transient cerebral ischemia in SHR, the effect of hyperosmolar solution with intravenous 10% glycerol on serum lipid peroxides, plasma prostaglandins (TXA2, PGI2), brain water content and brain metabolites were studied. Glycerol did not influence the levels of lipid peroxides, plasma prostaglandins and brain water content in the non ischemic rats. In the transient ischemia group, on the other hand, serum lipid peroxides were significantly reduced in the glycerol administrated group. On the study of plasma prostaglandins, there was no difference of TXA2 levels between two groups, but PGI2 levels were significantly increased in the glycerol administrated group. Brain water content was significantly decreased. And on the study of brain metabolites, ATP concentrations remained higher and lactate concentrations were lower in the glycerol administrated group compared with those in the control group. But there was no difference with pyruvate concentrations between two groups, furthermore L/P ratio improved in the glycerol administrated group. Besides the effect on reduction of brain edema as for hyperosmolar solution, glycerol may indicate improvement of ischemic impediments on brain by the action of antioxidation and reinforcement of PGI2.

Animals↗

PubMed1993

Brain vessels near muscle autografts are sites for entry of isogeneic macrophages into brain.

An autograft of skeletal muscle on rat dorsal medulla is a permanent opening in the blood-brain barrier to solutes. Is the graft also a site for the entry of exogenous, isogeneic leukocytes? Five weeks after inserting the graft, peritoneal macrophages (M phi) from inbred Fischer rats were activated by phorbol myristate acetate, labeled with a fluorescent dye, and infused as a bolus of about 2 x 10(6) cells into the axillary artery of Fischer hosts. The cells circulated for 2 h. The brains were then fixed, frozen, and sectioned. Only when M phi had been activated and a muscle autograft inserted did appreciable numbers of M phi enter the medulla. Nonactivated M phi invaded the grafts but very few entered the brain at 2 h. In rats with gel foam grafts, only a few activated M phi invaded gel and brain. Before entering tissues, M phi must adhere to the lumenal face of vessels. Cell adhesion molecules, e.g., I-CAM-1 and its ligand adhesion molecule, leukocyte function antigen (LFA-1), are known to mediate adhesion. I-CAM-1, detected immunohistochemically, increased in graft vessels and in nearby brain vessels. The rise may have been mediated by cytokines, interleukin-6, and tumor necrosis factor-beta, found in the grafts. LFA-1, however, assayed by fluorescence-activated cell sorting, was on both activated and nonactivated, exogenous M phi. Thus, M phi-endothelial attachment may have involved other adhesion molecules, e.g., selectins. The autograft also induced major histocompatibility complex class I on microglia and classes I and II on brain vessels near the graft. These vessels, by expressing adhesion molecules, are entry routes into brain for activated, isogeneic leukocytes that can then migrate for a limited distance of 1-2 mm in an otherwise intact brain.

Animals↗

PubMed1984

Gonadotropin release from the pars distalis of goldfish, Carassius auratus, transplanted beside the brain or into the brain ventricles: additional evidence for gonadotropin-release-inhibitory factor.

The pars distalis of the pituitary was transplanted from one goldfish to another, of matched gonadal condition and body size, either beside the brain ("juxta" location) or into the brain ventricle in the preoptic region or under the optic tectum. Recipients of a pars distalis had significantly higher serum gonadotropin (GtH) levels than sham-operated controls without transplants; following removal of the transplants, serum GtH levels decreased to levels found in controls within 24 hr. This demonstrates that the pars distalis releases GtH spontaneously when removed from its normal connections with the hypothalamus providing evidence for tonic inhibition of GtH release by a GtH-release-inhibitory factor (GRIF). The juxta-transplanted pars distalis of sexually recrudescing and mature (= completed recrudescence) females released more GtH than the pars distalis of sexually regressed females. The juxta-transplanted pars distalis of sexually mature males released more GtH than the pars distalis of males in early stages of testicular recrudescence. These results demonstrate a seasonal variation in the ability to release GtH independent of GRIF. This may be due to the greater content of GtH in the pituitary, and a greater ability to synthesize GtH by the pituitary in sexually mature and recrudescing goldfish compared to sexually regressed fish. In sexually recrudescing and mature males and females, transplantation of the pars distalis into the brain ventricle in either the preoptic region or ventral to the optic tectum resulted in significantly lower serum GtH levels in recipients than transplantation beside the brain. This demonstrates the presence of some factor in the brain that inhibits GtH release, supporting the idea of GRIF. In sexually regressed female goldfish, GtH release from the transplanted pars distalis was not influenced by location in the brain ventricles versus beside the brain. This suggests a seasonal variation in GRIF activity in the brain, with reduced activity in sexually regressed females coincident with less ability to release GtH by the pars distalis.

Animals↗

PubMed2004

Effect of mild hypothermia on brain dialysate lactate after fluid percussion brain injury in rodents.

OBJECTIVE: To investigate the effects of mild hypothermia on brain microdialysate lactate after fluid percussion traumatic brain injury (TBI) in rats. METHODS: Brain dialysate lactate before and after fluid percussion brain injury (2.1 +/- 0.2 atm) was measured in rats with preinjury mild hypothermia (32 degrees C), postinjury mild hypothermia (32 degrees C), injury normothermia (37 degrees C), and the sham control group. Mild hypothermia (32 degrees C) was induced by partial immersion in a water bath (0 degrees C) under general anesthesia and maintained for 2 hours. RESULTS: In the normothermia TBI group, brain extracellular fluid lactate increased from 0.311 +/- 0.03 to 1.275 +/- 0.08 mmol/L within 30 minutes after TBI (P < 0.01) and remained at a high level (0.546 +/- 0.05 mmol/L) (P < 0.01) at 2 hours after injury. In the postinjury mild hypothermic group, brain extracellular fluid lactate increased from 0.303 +/- 0.03 to 0.875 +/- 0.05 mmol/L at 15 minutes after TBI (P < 0.01) and then gradually decreased to 0.316 +/- 0.04 mmol/L at 2 hours after TBI (P > 0.05). In the preinjury mild hypothermic group, brain extracellular fluid lactate remained at normal levels after injury (P > 0.05). CONCLUSION: The cerebral extracellular fluid lactate level increases significantly after fluid percussion brain injury. Preinjury mild hypothermia completely inhibits the cerebral lactate accumulation, and early postinjury mild hypothermia significantly blunts the increase of cerebral lactate level after fluid percussion injury.

Animals↗

PubMed1996

Brain and body oxygen requirements of Gnathonemus petersii, a fish with an exceptionally large brain

Vertebrates have repeatedly been noted for having remarkably constant ratios of brain to body O2 consumption, the brain using 2-8 % of resting body O2 consumption, suggesting that evolution has put strict limits on the energetic cost of brain function. Only man, with a value of 20 %, is an exception to this rule. However, the results presented here suggest that, in the electric fish Gnathonemus petersii, the brain is responsible for approximately 60 % of body O2 consumption, a figure three times higher than that for any other vertebrate studied, including man. The exceptionally high energetic cost of the G. petersii brain appears to be a consequence both of the brain being very large and of the fish being ectothermic. It was also found that G. petersii has a high ability to utilise O2 at low levels. Thus, during falling [O2], this species was found to maintain both its O2 uptake and its electric discharge rate down to an ambient O2 level of 0.8 mg l-1 (at 26 °C), although it was unable to tolerate an [O2] below 0.3 mg l-1. During severe hypoxia (<0.8 mg l-1), G. petersii attempted to gulp air from the water surface. These results establish a new record for the energetic cost of a vertebrate brain and they show that the species possessing such a brain has a high capacity for utilising O2 at very low ambient concentrations.

Journal Article↗

PubMed2002

Application of in vivo brain microdialysis to the study of blood-brain barrier transport of drugs.

Recent advances in blood-brain barrier (BBB) research have led to a new understanding of drug transport processes at the BBB. The BBB acts as a dynamic regulatory interface at which nutrients necessary for neural activity are actively taken up into the brain from the blood circulation, and actively excludes metabolites that might interfere with the maintenance of brain homeostasis. Such influx and efflux transport functions at the BBB would also control the concentrations of various drugs in the brain interstitial fluid (ISF), which are an important determinant of the central nervous system (CNS) effects. Thus, direct measurement of the brain ISF concentration of drugs can provide significant information for clarifying the influx and efflux transport functions of drugs across the BBB. Although several experimental techniques have been developed to investigate transport functions across the BBB, in vivo brain microdialysis seems to be one of the most suitable techniques for characterizing the influx and efflux transport functions across the BBB under physiological and pathological conditions. This review covers studies during the past decade, in which the influx and efflux transport of drugs across the BBB was kinetically and mechanistically evaluated by means of the brain microdialysis technique. Some applications of brain microdialysis to studies on neuronal function and neurotherapeutics are also included.

Journal Article↗

PubMed1993

The end point of the sylvian fissure is higher on the right than the left in cat brain as in human brain.

The height of the end point of the sylvian fissure (SF) was analyzed in the right and left brains of male and female adult cats. A corrected SF asymmetry coefficient (AC) was computed for each brain. An AC larger than zero (AC+) showed a rightward asymmetry, and an AC smaller than zero (AC-) a leftward asymmetry. In the total sample, ACs fit a normal distribution with a mean significantly larger than zero. Of these brains, 75% had ACs larger than zero median; 23.4% had ACs smaller than zero median. Of 11 right-pawed cats, 90.9% had ACs larger than zero. Of 13 left-pawed male cats, there was no significant difference between AC+ and AC- brains. In right-pawed female cats, the right SF was also higher in most animals, but the difference did not reach the 5% significance level. In left-pawed female cats, the number of AC+ brains significantly exceeded that of AC-brains. Thus, the brains of the left-pawed male cats resembled those of the right-pawed female cats; right-pawed male cats resembled left-pawed female cats with regard to asymmetries in SF height. It was concluded that the human brain is not unique in SF asymmetries, which may be linked to manual asymmetry and sex hormones.

Animals↗

PubMed2000

SPECT brain perfusion findings in mild or moderate traumatic brain injury.

BACKGROUND: The purpose of this manuscript is to present the findings in the largest series of SPECT brain perfusion imaging reported to date for mild or moderate traumatic brain injury. PATIENTS AND METHODS: This is a retrospective evaluation of 228 SPECT brain perfusion-imaging studies of patients who suffered mild or moderate traumatic brain injury with or without loss of consciousness (LOC). All patients had no past medical history of previous brain trauma, neurological, or psychiatric diseases, HIV, alcohol or drug abuse. The patient population included 135 males and 93 females. The ages ranged from 11-88 years (mean 40.8). The most common complaints were characteristic of the postconcussion syndrome: headaches 139/228 (61%); dizziness 61/228 (27%); and memory problems 63/228 (28%). LOC status was reported to be positive in 121/228 (53%), negative in 41/228 (18%), and unknown for 63/228 (28%). RESULTS: Normal studies accounted for 52/228 (23%). For abnormal studies (176/228 or 77%) the findings were as follows: basal ganglia hypoperfusion 338 lesions (55.2%); frontal lobe hypoperfusion 146 (23.8%); temporal lobes hypoperfusion 80 (13%); parietal lobes hypoperfusion 20 (3.7%); insular and or occipital lobes hypoperfusion 28 (4.6%). Patients' symptoms correlated with the SPECT brain perfusion findings. The SPECT BPI studies in 122/228 (54%) were done early within 3 months of the date of the accident, and for the remainder, 106/228 (46%) over 3 months and less than 3 years from the date of the injury. In early imaging, 382 lesions were detected; in 92 patients (average 4.2 lesions per study) imaging after 3 months detected 230 lesions: in 84 patients (average 2.7 lesions per study). CONCLUSIONS: Basal ganglia hypoperfusion is the most common abnormality following mild or moderate traumatic brain injury (p = 0.006), and is more common in patients complaining of memory problem (p = 0.0005) and dizziness (p = 0.003). Early imaging can detect more lesions than delayed imaging (p = 0.0011). SPECT brain perfusion abnormalities can occur in the absence of LOC.

Journal Article↗

PubMed1985

Positron emission tomographic measurement of blood-to-brain and blood-to-tumor transport of 82Rb: the effect of dexamethasone and whole-brain radiation therapy.

Unidirectional blood-to-brain and blood-to-tumor transport rate constants for rubidium 82 were determined using dynamic positron emission tomography in patients with primary or metastatic brain tumors. Regional influx rate constants (K1) and plasma water volume (Vp) were estimated from the time course of blood and brain radioactivity following a bolus injection of tracer. Eight patients were studied before and 24 to 72 hours after treatment using pharmacological doses of dexamethasone, and 6 additional patients with metastatic brain tumors were studied before and within 60 to 90 minutes after 200- to 600-rad whole-brain radiation therapy. Steroid treatment was associated with a 9 to 48% decrease in tumor K1 and a 21% mean decrease in tumor Vp. No consistent changes in K1 or Vp were observed in control brain regions. Tumor K1 and Vp did not increase in patients undergoing whole-brain radiation therapy, all of whom were taking dexamethasone at the time of study. These data suggest that corticosteroids decrease the permeability of tumor capillaries to small hydrophilic molecules (including those of some chemotherapeutic agents) and that steroid pretreatment prevents acute, and potentially dangerous, increases in tumor capillary permeability following cranial irradiation.

Adult↗

PubMed1995

Induction of blood-brain barrier differentiation in a rat brain-derived endothelial cell line.

An immortalized brain capillary endothelial cell line displaying blood-brain barrier characteristics may represent a useful tool for studying blood-brain barrier endothelial cell differentiation and for the in vitro prediction of drug brain penetration. In the present study, we have established a rat cerebral capillary endothelial cell line (CR3) by genomic introduction of the immortalizing SV40 large T gene under the control of the human vimentin promoter. The CR3 cell line displayed endothelial morphological and biochemical characteristics for up to 30 passages. However, the CR3 cell line did not spontaneously express the specific blood-brain barrier markers gamma-glutamyl transpeptidase and mdr P-glycoprotein. However, when the cells were treated with the cell differentiating agent all-trans-retinoic acid, the blood-brain barrier markers were induced. Retinoic acid-treated CR3 cells may thus represent a useful tool for biological and pharmacological research related to the blood-brain barrier.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1979

The role of blood-brain barrier transport of tryptophan and other neutral amino acids in the regulation of substrate-limited pathways of brain amino acid metabolism.

Many pathways of essential neutral amino acid metabolism in the CNS are influenced by precursor availability. Since the delivery of circulating amino acids to brain cells is primarily controlled by the rate of amino acid transport through the blood-brain barrier (BBB), pathways of brain amino acid metaboliransport system. The Km of BBB transport is in the 0.1--0.6 mM range, which approximates the physiologic plasma levels and forms the basis of the unusual sensitivity of the brain to competition effects on neutral amino acid transport. Unlike the brain, the Km of amino acid transport into other organs is in the 1--10 mM range or greater, which frees these tissues from competition effects in the physiologic range of plasma amino acids. Tryptophan circulates 80--90% bound to albumin; however, the capacity/affinity ratio of the BBB neutral amino acid transport system exceeds the capacity/affinity ratio of albumin binding of tryptophan, which enables the carrier to strip tryptophan off albumin as it traverses the brain capillary. The activity of the BBB neutral amino acid transport system is probably not modulated by insulin, but is influenced by changes in thyroid hormone status; the transport system is also induced in states of hepatic encephalopathy and this induction process is the primary cause of the increased brain tryptophan and serotonin levels in cirrhosis.

Animals↗