The spread of brain oedema in hypertensive brain injury

Severe hypertension in humans may lead to fibrinoid necroses of cerebral blood vessels with small hemorrhages and cystic necroses. Similar lesions have also been reported in the experimental model of stroke-prone spontaneously hypertensive rats (SHRSP). We examined the genesis and spreading pattern of the brain oedema in SHRSP. The extravasation of plasma proteins was visualized with the Evans-Blue or the immunoperoxidase method. Most commonly the leakage occurred in the grey matter of the cerebral cortex or basal ganglia. The spreading pattern followed that of vasogenic brain oedema with a local spread in the grey matter and an extensive one in the white matter. In addition, we detected a novel pathway upwards along the perivascular spaces of the penetrating vessels as well as laterally in the subpial zone. This route is likely to serve also as a drainage channel for the oedema into the cerebrospinal fluid in the subarachnoidal space. Transfer of the extravasated proteins from the white matter to the ventricles was also observed, confirming that this previously described pathway for the resolution of oedema fluid exists in the SHRSP model of vasogenic brain oedema.     

Human brain natriuretic peptide-like immunoreactivity in human brain.

The presence of immunoreactive human brain natriuretic peptide in the human brain was studied with a specific radioimmunoassay for human brain natriuretic peptide-32. This assay showed no significant cross-reaction with human alpha atrial natriuretic peptide, porcine brain natriuretic peptide or rat brain natriuretic peptide. Immunoreactive human brain natriuretic peptide was found in all 5 regions of human brain examined (cerebral cortex, thalamus, cerebellum, pons and hypothalamus) (0.6-6.7 pmol/g wet weight, n = 3). These values were comparable to the concentrations of immunoreactive alpha atrial natriuretic peptide in human brain (0.5-10.1 pmol/g wet weight). However, Sephadex G-50 column chromatography showed that the immunoreactive human brain natriuretic peptide in the human brain eluted earlier than synthetic human brain natriuretic peptide-32. These findings suggest that human brain natriuretic peptide is present in the human brain mainly as larger molecular weight forms.     

Selenium and selenoproteins in the brain and brain diseases

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

Alteration of brain type N-glycans in neurological mutant mouse brain

We have previously detected two brain-specific and development-dependent N-glycans [H. Shimizu, K. Ochiai, K. Ikenaka, K. Mikoshiba, and S. Hase (1993) J. Biochem. 114, 334-338]. In the present study we attempted to analyze specific N-glycans detected in neurological mutant mice. N-glycans in cerebrum and cerebellum obtained from 3-week-old neurological mutant mice (jimpy, staggerer, and shiverer) were compared with those obtained from normal mice. N-glycans liberated from the cerebrum and cerebellum by hydrazinolysis-N-acetylation were pyridylaminated, and pyridylamino derivatives of N-glycans thus obtained were separated into neutral and five acidic fractions by anion exchange chromatography. PA-N-glycans in each fraction were compared with those obtained from normal mice by reversed-phase HPLC, and the following results were obtained. The ratio of the two brain-type N-glycans, Manalpha1-3(GlcNAcbeta1-2Manalpha1-6)(GlcNAcbeta1-4)Manbeta1-4GlcNAcbeta1-4(Fucalpha1-6)GlcNAc (BA-1) to GlcNAcbetaManalpha1-3(GlcNAcbeta1-2Manalpha1-6)(GlcNAcbeta1-4)Manbeta1-4GlcNAcbeta1-4(Fuca1-6)GlcNAc (BA-2), was higher in staggerer mice than other mutant mice and normal mice. Sia-Gal-BA-2, triantennary N-glycans, and bisected biantennary N-glycans were found in the cerebellum of shiverer and staggerer mice but not in normal or jimpy mice. High-mannose type N-glycans were not altered in mutant mice brains. The amounts of disialylbiantennary N-glycans and disialylfucosylbiantennary N-glycans were lower in jimpy mouse cerebellum than in normal mouse cerebellum, but were higher in shiverer mouse. Some alterations of N-glycans specific to mutations were successfully identified, suggesting that expression of component(s) of the N-glycan biosynthetic pathway was specifically affected in neurological mutations.     

Microglia in development: linking brain wiring to brain environment

Microglia are enigmatic non-neuronal cells that infiltrate and take up residence in the brain during development and are thought to perform a surveillance function. An established literature has documented how microglia are activated by pathogenic stimuli and how they contribute to and resolve injuries to the brain. However, much less work has been aimed at understanding their function in the uninjured brain. A series of recent in vivo imaging studies shows that microglia in their resting state are highly motile and actively survey their neuronal surroundings. Furthermore, new data suggest that microglia in their resting state are able to phagocytose unwanted synapses and in this way contribute to synaptic pruning and maturation during development. Coupled with their exquisite sensitivity to pathogenic stimuli, these data suggest that microglia form a link that couples changes in brain environment to changes in brain wiring. Here we discuss this hypothesis and propose a model for the role of microglia during development in sculpting brain connectivity.     

Myelination in rat brain: changes in myelin composition during brain maturation

Abstract— Myelin was isolated from rat brains during development by a procedure giving fractions of constant purity at all ages. The lipid composition of these fractions and of whole brains of littermates was determined. The amount of myelin recovered per brain was a nearly linear function of the logarithm of age from the youngest (15 days) to the oldest (425 days) animals studied. With the exception of the earliest age point, the isolated myelin accounted for approximately 40 per cent of total brain galactolipid, evidence that a constant fraction (calculated to be 60 per cent) of myelin was recovered at all ages. Although the lipid-protein ratio of the myelin was constant with age, marked changes were seen in the amounts of cerebroside, sulphatide, phosphatidylcholine and desmosterol. The total galactolipid increased from 21 per cent of the total lipid at age 15 days to about 31 per cent at maturity. Phosphatidylcholine decreased from 17 to 11 per cent during the same period. Desmosterol decreased from 2.5 per cent of the total sterol to 0.2-0.3 per cent. All of these changes were complete between 2 and 5 months of age; no other ‘lower phase’ lipids showed significant changes with age. Although qualitatively similar to those reported by others, the changes differed in magnitude, with more stability in the levels of cholesterol and phosphatidalethanolamine with development. A sensitive indicator of the maturation of myelin was the mole ratio galactolipid/phosphatidylcholine, which varied from 1.2 at age 15 days to 2.8 at maturity. The maximum rate of myelination occurred at 20 days of postnatal age when myelin was deposited at the rate of 3.5 mg day^?1 brain^?1. However, at this age the rat brain had only 15 per cent of its eventual complement of myelin. The rate of accumulation of cerebroside in the whole brain paralleled that of myelin, and was the only lipid to show this relationship. Myelin deposition appeared to be almost solely responsible for the continued increase in brain weight after about 100 days of age.     

Calmodulin-binding proteins in brain

It is now widely accepted that actions of intracellular Ca²⁺ are mediated by a four-domain Ca²⁺-binding protein, calmodulin. Brain is especially rich in calmodulin, containing about 400 mg (24 μmol) of EGTA-extractable calmodulin per kg of brain. However, only a fraction of the above amount is required for the calmodulin-activated enzymes and most of the rest may be assigned to calmodulin-binding proteins, proteins which are apparently devoid of enzyme activities but undergo Ca²⁺-dependent associations with calmodulin. Several of such proteins have been recently discovered in brain. These include a heat-labile 80 K phosphodiesterase inhibitor protein (calcineurin), a heat-stable 70 K phosphodiesterase inhibitor protein, a 50 K protein, myelin basic protein, tubulin, microtubule τ (tau) factor, a spectrin-like doublet protein (240 plus 235 K) (calspectin; fodrin) and a particle-associated 155 K protein.Functions of these calmodulin-binding proteins have not been fully elucidated yet. Some proteins may be calmodulin-regulated enzymes catalyzing yet unknown biochemical reactions, e.g. a protein phosphatase activity was found for calcineurin. Some proteins may interact with contractile elements or cytoskeleton of the cell, e.g. τ factor and calspectin interacted with tubulin and F-actin, respectively and tubulin itself is a calmodulin-binding protein. So, interesting possibilities are the regulation of the functions of cytoskeleton by calmodulin through these calmodulin-binding proteins. Regulation of microtubule assembly by Ca²⁺-dependent binding of calmodulin to tubulin and/or τ factor and possible involvement of calspectin in the mechanism regulating axonal transport of neuronal proteins have been suggested. Thus, the exploration of the regulating functions of Ca²⁺/calmodulin in brain depends largely upon the further study of the properties of these calmodulin-binding proteins.     

Angiogenesis in brain tumours

Despite aggressive surgery, radiotherapy and chemotherapy, malignant gliomas remain uniformly fatal. To progress, these tumours stimulate the formation of new blood vessels through processes driven primarily by vascular endothelial growth factor (VEGF). However, the resulting vessels are structurally and functionally abnormal, and contribute to a hostile microenvironment (low oxygen tension and high interstitial fluid pressure) that selects for a more malignant phenotype with increased morbidity and mortality. Emerging preclinical and clinical data indicate that anti-VEGF therapies are potentially effective in glioblastoma--the most frequent primary brain tumour--and can transiently normalize tumour vessels. This creates a window of opportunity for optimally combining chemotherapeutics and radiation.     

Uridine nucleotides in brain

—Two uridine nucleotides, UDPG and UDPGA, have been measured in brain by a procedure whereby they are extracted from tissue with subsequent utilization, either directly with (UDPGA) or after dehydrogenation (UDPG), in a glucuronidation reaction with harmol or harmalol as cosubstrate. The concentrations of UDPG and UDPGA in brains of a few species of animals examined are, respectively, 11.5–23.3 μmoles/100 g and 0.7–2.5 μmoles/100 g tissue. The ratios of UDPGA to UDPG range from 4% to 11%. The role and importance of these uridine nucleotides in brain are discussed.