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.     

Galanin in the brain: chemoarchitectonics and brain cartography--a historical review

We present a review of galanin in the brain from a historical perspective of the development of "chemoarchitectonics" and "brain cartography" accomplished in the Histopharmacology Section at the National Institutes of Health. It was the mapping of potential brain neuroregulators that served as a springboard of ideas from which behavioral studies emanate. The integration of the known localization of neurotransmitter/neuromodulatory nerves ("chemoarchitectonic maps") and receptor binding sites with biochemical data derived from brain micropunches coupled with behavioral analysis at the level of discrete brain allows one to define the anatomical circuits which support behavioral changes and which ultimately will improve our understanding of mental disorders.     

Cathepsin H activity in the human brain and human brain neoplasms

The human brain cathepsin H is shown to be a specific cysteine aminopeptidase with the optimum activity at pH 6.0. Human brain tumours of neuroectodermal (astrocytomas and glioblastomas) and epithelial (meningiomas) origin were used to study the cathepsin H activity in the malignant brain tissue. A significant increase in the aminopeptidase cathepsin H activity was found in malignant human brain tumours as compared to benign tumours and normal brain tissues.     

Transport systems of serine at the brain barriers and in brain parenchymal cells

D-Serine is a co-agonist for NMDA-type glutamate receptors. Although D-serine levels in CSF and interstitial fluid (ISF) affect CNS function, the regulatory system remains to be fully understood. Therefore, the purpose of this study was to investigate d-serine transport across the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) and in brain parenchymal cells. D-Serine microinjected into the cerebrum was not eliminated, suggesting a negligible contribution of D-serine efflux transport at the BBB. In contrast, D-serine was taken up from the circulating blood across the BBB via a carrier-mediated process. D-Serine elimination clearance from CSF was fourfold greater than that of d-mannitol, which is considered to reflect CSF bulk flow. The characteristics of D-serine uptake by isolated choroid plexus were consistent with those of Na(+)-independent alanine-serine-cysteine transporter 1 (asc-1). Uptake of D-serine by brain slices appeared to occur predominantly via asc-1 and Na(+)-dependent alanine-serine-cysteine transporter 2. These findings suggest that the regulatory system of D-serine levels in ISF and CSF involves (i) asc-1 at the BCSFB, acting as a major pathway of D-serine elimination from the CSF, (ii) blood-to-brain and blood-to-CSF influx transport of D-serine across the BBB and BCSFB, and (iii) concentrative uptake of D-serine by brain parenchymal cells.     

Relationships between gene expression and brain wiring in the adult rodent brain

We studied the global relationship between gene expression and neuroanatomical connectivity in the adult rodent brain. We utilized a large data set of the rat brain "connectome" from the Brain Architecture Management System (942 brain regions and over 5000 connections) and used statistical approaches to relate the data to the gene expression signatures of 17,530 genes in 142 anatomical regions from the Allen Brain Atlas. Our analysis shows that adult gene expression signatures have a statistically significant relationship to connectivity. In particular, brain regions that have similar expression profiles tend to have similar connectivity profiles, and this effect is not entirely attributable to spatial correlations. In addition, brain regions which are connected have more similar expression patterns. Using a simple optimization approach, we identified a set of genes most correlated with neuroanatomical connectivity, and find that this set is enriched for genes involved in neuronal development and axon guidance. A number of the genes have been implicated in neurodevelopmental disorders such as autistic spectrum disorder. Our results have the potential to shed light on the role of gene expression patterns in influencing neuronal activity and connectivity, with potential applications to our understanding of brain disorders. Supplementary data are available at http://www.chibi.ubc.ca/ABAMS.     

Effect of brain antibodies on the lipid peroxidation process in the brain

The authors studies the effects of blood serum and IgG fraction from dogs immunized with brain and blood sera from patients with multiple sclerosis and schizophrenia on lipid peroxidation in rat brain homogenates. Measured the content of diene conjugates (DC) and malonic dialdehyde (MDA) in the rat brain after administering the IgG fraction. It was established that antioxidant activity of blood sera and IgG fraction from control animals and donors was significantly higher as compared to experimental. Administration of the IgG fraction brought about an increase in the content of DC and MDA in the brain of experimental animals. It is concluded that complement-dependent brain antibodies present in the blood serum of patients with schizophrenia and multiple sclerosis potentiate lipid peroxidation in the cerebral tissue and that the unsophisticated and informative method for antibody determination may be used in clinical practice.     

D-amino acids in the brain: the biochemistry of brain serine racemase

It has been recently established that in various brain regions D-serine, the product of serine racemase, occupies the so-called 'glycine site' within N-methyl D-aspartate receptors. Mammalian brain serine racemase is a pyridoxal-5' phosphate-containing enzyme that catalyzes the racemization of L-serine to D-serine. It has also been shown to catalyze the alpha,beta-elimination of water from L-serine or D-serine to form pyruvate and ammonia. Serine racemase is included within the group of type II-fold pyridoxal-5' phosphate enzymes, together with many other racemases and dehydratases. Serine racemase was first purified from rat brain homogenates and later recombinantly expressed in mammalian and insect cells as well as in Escherichia coli. It has been shown that serine racemase is activated by divalent cations like calcium, magnesium and manganese, as well as by nucleotides like ATP, ADP or GTP. In turn, serine racemase is also strongly inhibited by reagents that react with free sulfhydryl groups such as glutathione. Several yeast two-hybrid screens for interaction partners identified the proteins glutamate receptor interacting protein, protein interacting with C kinase 1 and Golga3 to bind to serine racemase, having different effects on its catalytic activity or stability. In addition, it has also been proposed that serine racemase is regulated by phosphorylation. Thus, d-serine production in the brain is tightly regulated by various factors pointing at its physiologic importance. In this minireview, we will focus on the regulation of brain serine racemase and d-serine synthesis by the factors mentioned above.     

Change in the brain neuron structure of man and other mammals in edema and swelling of the brain substance]

A correlation was made between literature and obtained light microscopy data relative to the problem concerning the central neuron involvement at edema development and brain tissue swelling at different etiological backgrounds. A polymorphism of neuronic variations was demonstrated determined by a variety of causes including specificity of individual reactivity of central nervous system. Attention is drawn both to the non-identity of the notions: "hydropic variation (edema) of a neuron" and the "brain edema", and to a non-characteristic nature of "hard variation" of nerve cells for histological picture of edema-swelling brain tissue at neurooncologic affection, and to the absence of a strict proportionality between the degree of cerebral edema-swelling and variation intensity of the neuron structure.     

Chemokines and their receptors in the brain: pathophysiological roles in ischemic brain injury

Chemokines constitute a large family of structurally-related small cytokines originally identified as factors regulating the migration of leukocytes in inflammatory and immune responses. Production of chemokines and their receptors in the brain has been reported under various pathological conditions. We revealed that mRNA expression for monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha (MIP-1alpha), members of the CC chemokines, was induced in the rat brain after focal cerebral ischemia, and that intracerebroventricular injection of viral macrophage inflammatory protein-II (vMIP-II), a broad-spectrum chemokine receptor antagonist, reduced infarct volume in a dose-dependent manner. These findings suggest that brain chemokines are involved in ischemic injury, and that chemokine receptors are potential targets for therapeutic intervention in stroke. Another potential target to suppress the harmful effect of chemokines is the signal transmission system(s) regulating the chemokine production. However, very little is known about how the production of chemokines is regulated in the ischemic brain. We examined the induction of MCP-1 production by excitotoxic injury via activation of NMDA receptors in the cortico-striatal slice cultures, and found that excitotoxic injury induced MCP-1 production in the slice culture. Almost all of the MCP-1 immunoreactivity was located on astrocytes. On the other hand, NMDA-treatment failed to increase the MCP-1 production in the enriched astrocyte cultures, indicating that NMDA dose not directly act on astrocytes. Some signal(s) is likely sent from the injured neurons to astrocytes to induce the MCP-1 production. These results showed that organotypic slice cultures are useful to investigate the molecular mechanism regulating the chemokine production in the injured brain.