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PubMed1989

Influence of thermal stress and various agents on the brain edema formation in rats following a cryogenic brain lesion.

The influence of cold stress, heat stress, or various agents on the development of brain edema were assessed in rats following a cryogenic brain lesion. Brain edema was induced by local cold injury to the cortex. Cerebral edema was assessed 0.5, 3.0 or 24 h after a cryogenic brain lesion by measuring the water content of two hemispheres. Pretreatment of animals with sodium pentobarbital (15 or 30 mg/kg, i.p.) or lidocaine (15 mg/kg, i.p.) did not influence the development of brain edema. In addition, pretreatment with an external heat stress (heat exposure of 32 degrees C for 6 h) exaggerated significantly the development of brain edema in the rat following a cryogenic brain lesion. On the other hand, pretreatment of animals with either external cold stress (cold exposure of 8 degrees C for 6 h), glycerol (10% 10 ml, i.p.), mannitol (15% 10 ml, i.p.), gamma-hydroxybutyric acid (300 mg/kg, i.p.), metiamide (5 mg/kg, i.p.), dexamethasone (4 mg/kg, i.p.), aminophylline (100 mg/kg, i.p.), or ketamine (30 mg/kg, i.p.) inhibited significantly the brain edema formation.

Animals↗

PubMed1987

[Subacute brain atrophy induced by radiation therapy of malignant brain tumors].

In order to analyze brain atrophy after radiation therapy to the brain tumors, we calculated a CSF-cranial volume ratio on CT scan as an index of brain atrophy, and estimated dementia-score by Hasegawa's method in 91 post-irradiated patients with malignant brain tumors. Radiation-induced brain atrophy was observed in 51 out of 91 patients (56%) and dementia in 23 out of 47 patients (49%). These two conditions were closely related, and observed significantly more often in aged and whole-brain-irradiated patients. As radiation-induced brain atrophy accompanied by dementia appeared 2-3 months after the completion of radiation therapy, it should be regarded as a subacute brain injury caused by radiation therapy.

Adolescent↗

PubMed1985

Influence of the blood-brain pH gradient on brain phenobarbital uptake during status epilepticus.

Brain uptake and blood concentrations of phenobarbital were determined in rats during pentylenetetrazol-induced status epilepticus and compared to nonconvulsing controls. Brain phenobarbital concentrations and the brain-to-blood phenobarbital ratio were increased 2-fold in freely convulsing animals as compared to controls. The degree of systemic acidosis during motor convulsions was greater than the degree of brain acidosis. Because phenobarbital is a weak acid, this pH gradient favors movement of phenobarbital into the brain during status epilepticus. Motor paralysis prevented the development of systemic acidosis and the brain-blood partition of phenobarbital was similar to that of nonconvulsing controls. Blood phenobarbital concentrations were slightly higher in animals paralyzed during status as compared to controls, presumably due to hemodynamic effects of convulsions. These studies, as well as our previous studies with lidocaine, support the idea that the brain-blood pH gradient is an important determinant of drug uptake by the brain during seizures.

Animals↗

PubMed1994

Immunohistochemical study on blood-brain barrier in congenitally hydrocephalic HTX rat brain.

The purpose of the present study is to examine the blood-brain barrier in brain of congenital hydrocephalus HTX rats. We investigated the rat brain from postnatal day 1 to 44 using light and electron microscopy and immunohistochemical methods with monoclonal anti-blood-brain barrier (BBB) antibody. HTX rats developed hydrocephalus at 1-2 days after birth. Most rats succumbed to brain changes within 4-5 weeks. Among 136 HTX rats examined, 45 rats succumbed within 1 week after birth, 29 rats between 1-2 weeks, and 4 rats 27-44 days after birth. Out of 88 hydrocephalic rats 54 showed a marked ventricular dilatation, and 34 showed a mild dilatation. Dilatation of lateral ventricles was mild in the rats at 1-2 days after birth, but 3-14-day-old rats showed moderate or marked dilatation. 15-30 days after birth the rats developed mostly marked dilatation of lateral ventricles and third ventricle. Lateral ventricles and third ventricle showed a symmetric dilatation, but ependymal cell layers were well preserved. Aqueduct exhibited no dilatation in any rat. There were spongy appearances and cystic cavities in the white matter around the lateral ventricles. There were glial fibers and capillaries across the cystic cavities. Cystic lesions were also found in the deep subcortical white matter, consisting of spongy changes with extended extracellular spaces and microcysts in the white matter. Immunohistochemically, the anti-BBB reactivity in the normal control rats was at first weak at 2 weeks after birth and increased with the course of development, prominently 4 weeks after birth. Three- and four-week-old HTX rats with hydrocephalus showed moderate positive anti-BBB reaction in the cerebral cortex, the basal ganglia, and around the aqueduct but only a very weak reaction in the deep subcortical white matter and in the subependymal area of lateral ventricles. Laminin immunoreactivity was not different in the capillaries of hydrocephalic brain as compared with normal brain. Electron microscopically, tight junctions were well formed between endothelial cells of capillaries in the subcortical white matter. Occasionally capillaries with partial defect of basal membrane could be found, where the cytoplasm of endothelial cell was protruding between pericytic cytoplasm. Swelling of astrocytic end-feet were found around the microvessels. The results suggest that at the site of the lesion there is underdevelopment or immaturity of the blood-brain barrier.

Aging↗

PubMed1993

Comparison of O6-methylguanine-DNA methyltransferase activity in brain tumors and adjacent normal brain.

We assayed the activity of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) in 60 human brain tumors to assess the effects of tumorigenesis in brain on DNA repair capability. Activity was not detectable (< 0.5 fmol/10(6) cells, i.e., < 300 molecules/cells) in 27% of the tumors. Measurable MGMT varied by more than 2 orders of magnitude, 0.5-104.1 fmol/10(6) cells. Mean tumor MGMT levels did not differ between the sexes but did vary widely between diagnostic groups. A significant inverse correlation was observed between tumor MGMT activity and patient age. We also assayed MGMT activity in overlying, histologically tumor-free brain resected with 25 tumors. Of these samples, 52% had no detectable MGMT activity, and the remainder had activity comparable to that in tumors ranging from 0.7-21.8 fmol/10(6) cells. MGMT activity in normal brain was also inversely correlated with patient age. For 15 of 25 (60%) paired samples, tumor activity was 2 to > 38-fold greater than that of normal brain; for 4 pairs (16%) tumor activity was 2.5 to > 17-fold lower than that of normal brain; the remaining 6 (24%) had no detectable activity in both tumor and normal tissue. These differences in the magnitudes and distributions of activities for tumor versus normal brain tissue were significant (P = 0.02), demonstrating that tumorigenesis in brain is often accompanied by marked elevation of MGMT.

Adolescent↗

PubMed1985

Auditory brain-stem response in determination of brain death.

A diagnosis of brain death requires evidence of irreversible destruction (or dysfunction) of neurons in the brain stem and cerebrum. The physical examination is not a valid index of brain integrity in patients who are drug-intoxicated or receiving therapeutic paralyzing agents or high-dose barbiturates. We evaluated the use of the auditory brain-stem response (ABR) as an ancillary test in the determination of brain death. A total of 100 combined ABR and nuclear cerebral blood flow studies were completed at bedside with 81 acute, severely brain-injured adults. The ABR and cerebral blood flow outcomes were significantly correlated. We conclude that the ABR is a clinically feasible and useful procedure in the determination of brain death, especially in patients whose medical therapy compromises the neurologic examination.

Adolescent↗

PubMed1988

Blood-brain barrier disruption and exacerbation of ischemic brain edema after restoration of blood flow in experimental focal cerebral ischemia.

The mechanism of exacerbation of ischemic brain edema after blood flow restoration was studied in 20 cats under ketamine and alpha-chloralose anesthesia. Regional cerebral blood flow was measured by the hydrogen clearance method, and the left middle cerebral artery (MCA) was occluded for 6 h in group A, and for 3 h with subsequent 3 h recirculation in group B. Severity of brain edema was assessed by specific gravity measurement of tissue samples taken from coronal brain sections at the MCA area, while severity of blood-brain barrier (BBB) disruption was determined by measuring the amount of extravasated serum albumin by using [125I]albumin and tissue-uptake method in the same samples as those used for gravimetry. Structural and ultrastructural change was correlated with the severity of ischemic brain edema and BBB disruption. The results obtained showed that: (i) ischemic brain edema observed in group A was not associated with BBB opening to serum proteins; (ii) ischemic edema in group B was exacerbated significantly after recirculation in correlation with serum protein extravasation in most of the post-ischemic area; (iii) in the severely edematous area, serum protein extravasation reached a plateau and morphological examination at this type of area revealed cell membrane disruption especially of astrocytes, with leakage of intracellular substances. Our study indicated that the increase of extracellular osmotic pressure due to leakage of serum proteins via the disrupted BBB and of intracellular substances via the ischemically injured cell membrane into the extracellular space is the mechanism responsible for edema fluid accumulation in exacerbated ischemic brain edema.

Animals↗

PubMed1988

Mediators of brain edema and secondary brain damage.

Progress is our understanding of the roles of vasogenic and cytotoxic brain edema in secondary brain damage can be expected from studies of the ability of biochemical factors to open the blood-brain barrier, derange the microcirculation, and cause cell swelling and necrosis. Mediator compounds are considered to form or to become released in an area of primarily damaged brain (necrosis) and to enter the cerebral parenchyma through the broken blood-brain barrier from the intravascular space. Many biochemical factors must be considered. We suggested three criteria for determining the roles of mediators: a) they must inflict brain tissue damage, b) they must occur in pathologic concentrations or in compartments not normally present, and c) specific inhibition should attenuate secondary brain damage. These requirements are met by the kallikrein-kinin system and by glutamate. In the case of arachidonic acid and its many metabolites, the concept is difficult to test because fatty acids may be active only if not bound to proteins, and therapeutic inhibition might be difficult. A variety of mediators may enhance each other in a cascade manner by various initiating reactions that might be amenable for pharmacologic inhibition.

Animals↗

PubMed1999

FasL (CD95L, Apo1L) is expressed in the normal rat and human brain: evidence for the existence of an immunological brain barrier.

Despite the mechanical blood-brain barrier, activated T-cells can cross brain vessels. Thus, the CNS is routinely surveyed by immune competent cells; yet the healthy brain is not a target of antigen-specific immune reactions. Therefore, mechanisms must exist to prevent brain-antigen-specific T-cells from inducing immune responses. Data indicate that activated T-cells entering the CNS may undergo apoptosis rather than leaving the brain to induce immune responses. Applying RT-PCR, Western-blots, and immunocytochemistry, we have demonstrated expression of the apoptosis-inducing protein Fas ligand on astrocytes and neurons of apparently normal rat and human brains. FasL-positive astrocytes were often situated in close vicinity to cerebral blood vessels in vivo and induced apoptosis of Fas expressing Jurkat cells in vitro. We propose that similar to other immune privileged organs FasL-induced apoptosis of activated T-cells in the brain protects the tissue from self damaging immune attacks by forming an immunological brain barrier.

Animals↗

PubMed1985

Developmental expression of 2',3'-cyclic nucleotide 3'-phosphohydrolase in dissociated fetal rat brain cultures and rat brain.

The development in primary dissociated rat brain cultures of 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP) activity, the accumulation of CNP protein, and the number of cells accumulating this protein have been quantitatively determined as a function of time in culture. Parallel determinations have been made for the first two parameters for developing rat brain. The developmental profile of CNP enzymatic activity and amount of CNP protein in culture paralleled that observed in rat brain, in which the period of most active development occurred 7-25 days after birth. Mean CNP activities of 5.6 and 8.1 mumol/min/mg total protein were recorded for the cultures and rat brain, respectively, at their maximal levels. The corresponding mean values for the CNP protein accumulation were calculated to be 138 and 150 pmol/mg total protein, respectively. Thus maximal specific activities of the CNP protein were estimated to be about 800 and 1,000 mumol/min/mg CNP protein for culture and rat brain enzyme, respectively. Approximately three million cells expressing CNP appeared in the cultures per dissociated fetal rat brain seeded. Each CNP+ oligodendrocyte in culture had an average CNP activity of 3.2 pmol/min, and an average CNP protein content of 0.09 fmol (5.4 X 10(7) molecules), values which remained nearly constant during the course of development. Two principal conclusions are drawn from these data. First, the dissociated fetal brain culture system reproduces rather accurately the temporal developmental pattern of CNP expression occurring in the rat brain, but some important quantitative differences occur which suggest the need for additional environmental stimuli missing in these cultures. Second, the quantitative increases in CNP specific activity and amount of CNP protein occurring during oligodendrocyte differentiation in these cultures are primarily the result of increases in the number of CNP+ cells present which upon differentiation express very quickly, via an off-on regulation, steady-state levels of the enzyme.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗

PubMed1993

Chlorpyrifos: assessment of potential for delayed neurotoxicity by repeated dosing in adult hens with monitoring of brain acetylcholinesterase, brain and lymphocyte neurotoxic esterase, and plasma butyrylcholinesterase activities.

Previous work has shown that acute exposures to chlorpyrifos (CPS; diethyl 3,5,6-trichloro-2-pyridyl phosphorothionate) cannot produce > 70% inhibition of brain neurotoxic esterase (NTE) and cause organophosphorus compound-induced delayed neurotoxicity (OPIDN) unless the dose is well in excess of the LD50, necessitating aggressive therapy for cholinergic toxicity. The present study was carried out to determine if repeated doses of CPS at the maximum tolerated daily dose without prophylaxis against cholinergic toxicity could cause cumulative inhibition of NTE and OPIDN. Adult hens were dosed daily for 20 days with CPS (10 mg/kg/day po in 2 ml/kg corn oil) or corn oil (vehicle control) (2 ml/kg/day po) and observed for an additional 4 weeks. Brain acetylcholinesterase (AChE), brain and lymphocyte NTE, and plasma butyrylcholinesterase (BuChE) activities were assayed on Days 0 (control only), 4, 10, 15, 20, and 48. During Days 4-20, brain AChE and plasma BuChE activities from CPS-treated hens were inhibited 58-70% and 49-80% of contemporaneous controls, respectively. At 4 weeks after the end of dosing, brain AChE activity in treated birds had recovered to 86% of control and plasma BuChE activity was 134% of control. Brain and lymphocyte NTE activities of treated animals throughout the study were 82-99% and 85-128% of control, respectively. Neither brain nor lymphocyte NTE activities in treated hens exhibited cumulative inhibition. The 18% inhibition of brain NTE seen on days 10 and 20 was significant, but substantially below the putative threshold for OPIDN.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholinesterase↗

PubMed2000

Chemical heterogeneity of the living human brain: a proton MR spectroscopy study on the effects of sex, age, and brain region.

Brain chemistry was compared between 19 male and female normal volunteers in the age group 19-31 years, across six brain regions and nine metabolites using in vivo proton magnetic resonance spectroscopy. The relative concentrations of N-acetyl aspartate, choline, glutamate, glutamine, GABA, inositol, glucose, and lactate were measured relative to creatine within 8-cm(3) brain voxels. These measurements were performed in six brain regions: thalamus and cingulate, insula, sensorimotor, dorsolateral prefrontal, and orbital frontal cortices in the left hemisphere. Total metabolite concentration was highest in prefrontal regions (28% higher in orbital frontal cortex and 18.7% higher in dorsolateral prefrontal cortex compared with insula and thalamus, P < 10(-7)). Subjects 25-31 years of age demonstrated a significant increase in total metabolite concentration in the orbital frontal cortex (35%, P < 10(-7)) and sensorimotor cortex (16.7%, P < 10(-5)) compared to those 19-20 years of age. These two brain regions also showed gender dependence, with women demonstrating increased metabolite concentrations compared to men (9% increase in sensorimotor cortex, P < 0.002, and 2.1% in orbital frontal cortex). Most other brain regions showed no gender- or age-dependent differences. The results indicate that the living human brain is chemically heterogeneous. The chemical heterogeneity is sex and age dependent and specific for brain region.

Adult↗

PubMed2006

Positive selective brain cooling method: a novel, simple, and selective nasopharyngeal brain cooling method.

Brain damage is worsened by hyperthermia and prevented by hypothermia. Conventional hypothermia is a non-selective brain cooling method that employs cooling blankets to achieve surface cooling. This complicated method sometimes induces unfavorable systemic complications. We have developed a positive selective brain cooling (PSBC) method to control brain temperature quickly and safely following brain injury. Brain temperature was measured in patients with a ventriculostomy CAMINO catheter. A Foley balloon catheter was inserted to direct chilled air (8 to 12 L/min) into each side of the nasal cavity. The chilled air was exhaled through the oral cavity. In most patients, PSBC maintained normal brain temperature. This new technique provides quick induction of brain temperature control and does not require special facilities.

Adult↗

PubMed1997

The relationship between brain temperature and neutrophil accumulation after traumatic brain injury in rats.

Mild hypothermia reduces secondary damage after traumatic brain injury (TBI) in rodent models; however, the mechanisms involved in this beneficial effect remain unclear. We previously reported that TBI induces the upregulation of adhesion molecules and infiltration of neutrophils (PMN) in brain. Since PMN accumulation may be associated with the development of hyperemia and blood-brain barrier injury, we hypothesized that hypothermia would reduce acute inflammation after TBI in rats. To test this hypothesis, rats were anesthetized and subjected to TBI by controlled cortical impact to left parietal cortex. Brain temperature was controlled at 32 degrees C, 37 degrees C, or 39 degrees C (n = 8 per group) for 4 h after TBI, then rats were sacrificed and brain were harvested. Immunohistochemistries were performed on brain sections using antibodies that recognize the adhesion molecules E-selectin and intercellular adhesion molecule-1 (ICAM-1), and PMN. PMN were also quantified using a myeloperoxidase (MPO) assay. PMN accumulation in injured brain was decreased in rats maintained at 32 degrees C vs 39 degrees C (4-fold by immunohistochemistry and 8-fold by MPO, p < 0.05). E-selectin was induced after TBI, but not attenuated by hypothermia. ICAM-1 was not up-regulated at this early time after TBI. Based on these preliminary data, we conclude that mild hypothermia reduces PMN accumulation in injured brain during the initial 4 h after TBI, without decreasing adhesion molecule expression.

Animals↗

PubMed1982

Antibodies against viruses and structural brain components in oligoclonal IgG obtained from multiple sclerosis brain.

Immunoglobulin G (IgG) was isolated from three multiple sclerosis (MS) and two control brains by Protein A Sepharose affinity chromatography and was characterized by thin-layer polyacrylamide gel isoelectric focusing (PAG IEF) and antiserum immunofixation. The three MS brains contained oligoclonal IgG. Immunofixation with measles, herpes simplex, varicella, rubella, mumps and cytomegalovirus as antigens and autoradiography revealed that some of the oligoclonal IgG bands separated by PAG IEF contained antibodies against herpes simplex in one, measles in two and varicella virus in all three MS brains. No antibodies were detected with this technique against structural human (crude saline, lipid-proteolipid, ganglioside, and myelin basic protein extracts of MS and normal human brain) and bovine (purified myelin myelin basic protein and oligodendrocytes of bovine brain) brain components. The finding of viral antibodies and the absence of antibodies against structural brain proteins in oligoclonal MS brain IgG is similar to that previously recorded in MS cerebrospinal fluid (CSF).

Antibodies, Viral↗

PubMed1991

Corticotropin-like immunoreactivity in the brain of intact, hypophysectomized, cortisol- and metopirone-treated eels. Comparison with changes in pituitary corticotropes and brain corticotropin-releasing factor.

An ACTH-like peptidergic system was demonstrated in the brain of three teleost species by immunocytochemistry. In order to investigate the origin of brain ACTH and factors modulating its synthesis, similar techniques were applied to the brain of eels (1) submitted to hypophysectomy in order to suppress pituitary ACTH and plasma cortisol, (2) injected with cortisol to inhibit pituitary ACTH synthesis and release, and (3) injected with metopirone to block cortisol synthesis and stimulate ACTH synthesis and release. Hypophysectomized eels showed a normal distribution of immunoreactive perikarya in the ventral hypothalamus and fibers in the brain, suggesting that brain ACTH does not arise from the pituitary. In cortisol-treated eels immunostaining was markedly reduced in brain perikarya and pituitary corticotropes, suggesting a reduced synthesis. In metopirone-injected eels, one third of the animals showed an increased immunostaining in perikarya and a dense network of immunoreactive fibers, suggesting that ACTH synthesis was increased. Brain ACTH was not affected in other animals. Pituitary corticotropes were rapidly degranulated. Responses of ACTH in the brain and pituitary occur independently when cortisol synthesis is inhibited. These responses are compared to those of the corticotropin-releasing factor system in the same eels.

Adrenocorticotropic Hormone↗

PubMed1989

Effect of momentary stress on brain energy metabolism in weanling mice: apparent use of lactate as cerebral metabolic fuel concomitant with a decrease in brain glucose utilization.

The hypothesis that the anxiety induced by repeated injections affects brain energy metabolism was tested. Normal 19- to 21-day-old mice were stressed by two sham intraperitoneal injections within 4 min, at which time they were decapitated. Noninjected, control littermates were quickly decapitated. Momentary stress increased plasma glucose (12%), glycerol (85%), beta-hydroxybutyrate (108%), and lactate (153%)--a reflection of elevated plasma cortisol (25%) and glucagon (45%). In brain, stress increased levels of glucose-6-P (15%) and fructose-6-P (17%). The brain pyruvate concentration increased 74%; lactate 76%. Citrate, alpha-ketoglutarate, and malate increased 15, 95, and 37%, respectively. Levels of glycogen, glucose, phosphocreatine, ATP, ADP, and AMP were unchanged. The brain lactate/pyruvate ratio was normal but the brain/plasma lactate ratio fell 32%. Metabolite changes in the stressed animals were compatible with a decrease in the glycolytic flux at the phosphofructokinase step and a paradoxical increased flux in the Krebs citric acid cycle. The decreased brain/plasma lactate ratio supported increased uptake of lactate from plasma and increased brain lactate oxidation. Metabolite changes similar to those described above occurred in unstressed mice injected with lactate. Findings confirm a positive effect of stress on brain metabolism, support a role for lactate as an oxidative fuel for brain, and caution that the rate of cerebral glucose utilization may not always reflect brain energy (oxidative) metabolism accurately.

Animals↗

PubMed1994

Brain uptake and distribution of the potential memory enhancer CL 275,838 and its main metabolites in rats: relationship between brain concentrations and in vitro potencies on neurotransmitter mechanisms.

The kinetics, brain uptake and distribution of CL 275,838, a potential memory enhancer, and its main metabolites (II and IV) were evaluated in rats after intraperitoneal doses of 5, 10 and 20 mg/kg. Brain maximum concentrations (Cmax) of the three compounds after pharmacologically active doses were then related to the in vitro concentrations affecting some monoaminergic and amino acid receptor sites to examine the relative importance of these neurotransmitter systems in the pharmacological actions of CL 275,838. After 10 mg/kg CL 275,838, the unchanged compound rapidly entered the brain and distributed almost uniformly in various regions inside the blood-brain barrier. Its disappearance from brain and plasma was almost parallel with a comparable elimination half-life (t 1/2) of about 2 h. Metabolite II entered the brain and equilibrated with plasma more slowly than the parent compound, achieving mean Cmax (0.2 microM) within 3 h of dosing. Metabolite IV was rapidly detected in rat brain but hardly amounted to 10% (0.1 microM) of the parent compound Cmax (1 microM). There was a linear relationship between dose and plasma and brain concentrations of the three compounds up to 20 mg/kg CL 275,838. At micromolar concentrations the parent compound had affinity for serotonin (5-HT) uptake sites, 5-HT2 and dopamine (DA2) receptors. Only at much higher concentrations than those achieved in vivo after pharmacologically active doses did it increase the binding of 3H-glutamate to NMDA (N-methyl-D-aspartate) receptors. Metabolite II has a similar neurochemical profile.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗