Riboflavin Homeostasis in the Central Nervous System

Abstract: The mechanisms by which riboflavin, which is not synthesized in mammals, enters and leaves brain, CSF, and choroid plexus were investigated by injecting [¹⁴C]riboflavin intravenously or intraventricularly. Tracer amounts of [¹⁴C]riboflavin with or without FMN were infused intravenously at a constant rate into normal, starved, or probenecid-pretreated rabbits. At 3 h, [¹⁴C]riboflavin readily entered choroid plexus and brain, and, to a much lesser extent, CSF. Over 85% of the [¹⁴C]riboflavin in brain and choroid plexus was present as [¹⁴C]FMN and [¹⁴C]FAD. The addition of 0.2 mmol/kg FMN to the infusate markedly depressed the relative entry of [¹⁴C]riboflavin into brain, choroid plexus, and, less so, CSF, whereas starvation increased the relative entry of [¹⁴C]riboflavin into brain and choroid plexus. After intraventricular injection (2 h), most of the [¹⁴C]riboflavin was extremely rapidly cleared from CSF into blood. Some of the [¹⁴C]riboflavin entered brain, where over 85% of the ¹⁴C was present as [¹⁴C]FMN plus [¹⁴C]FAD. The addition of 1.2³μmol FAD (which was rapidly hydrolyzed to riboflavin) to the injectate decreased the clearance of [¹⁴C]riboflavin from CSF and the phosphorylation of [¹⁴C]riboflavin in brain. Probenecid in the injectate also decreased the clearance of [¹⁴C]riboflavin from CSF. These results show that the control of entry and exit of riboflavin is the mechanism, at least in part, by which total riboflavin levels in brain cells and CSF are regulated. Penetration of riboflavin through the blood-brain barrier, saturable efflux of riboflavin from CSF, and saturable entry of riboflavin into brain cells are three distinct parts of the homeostatic system for total riboflavin in the central nervous system.     

Cytokine Actions in the Central Nervous System

Cytokines and chemokines have been implicated in contributing to the initiation, propagation and regulation of immune and inflammatory responses. Also, these soluble mediators have important roles in contributing to a wide array of neurological diseases such as multiple sclerosis, AIDS Dementia Complex, stroke and Alzheimers disease. Cytokines and chemokines are synthesized within the central nervous system by glial cells and neurons, and have modulatory functions on these same cells via interactions with specific cell-surface receptors. In this article, I will discuss the ability of glial cells and neurons to both respond to, and synthesize, a variety of cytokines. The emphasize will be on three select cytokines; interferon-gamma (IFN-γ), a cytokine with predominantly proinflammatory effects; interleukin-6 (IL-6), a cytokine with both pro- and anti-inflammatory properties; and transforming growth factor-beta (TGF-β), a cytokine with predominantly immunosuppressive actions. The significance of these cytokines to neurological diseases with an immunological component will be discussed.     

TWEAK and the Central Nervous System

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily that acts on responsive cells via binding to a cell surface receptor named fibroblast growth factor-inducible 14 (Fn14). TWEAK can regulate numerous cellular responses in vitro and in vivo. Recent studies have indicated that TWEAK and Fn14 are expressed in the central nervous system (CNS), and that in response to a variety of stimuli, including cerebral ischemia, there is an increase in TWEAK and Fn14 expression in perivascular astrocytes, microglia, endothelial cells, and neurons with subsequent increase in the permeability of the blood–brain barrier (BBB) and cell death. Furthermore, there is a growing body of evidence indicating that TWEAK induces the activation of the NF-κB in the CNS with release of proinflammatory cytokines and matrix metalloproteinases. In addition, inhibition of TWEAK activity by either treatment with a Fn14-Fc fusion protein or neutralizing anti-TWEAK antibodies has shown therapeutic efficacy in animal models of ischemic stroke, cerebral edema, and multiple sclerosis.     

Cytokine-Induced Inflammation in the Central Nervous System Revisited

Cytokines play an essential role as mediators of the immune response. They usually function as part of a network of interactive signals that either activate, enhance, or inhibit the ensuing reaction. An important contribution of this cytokine cascade is the induction of an inflammatory response that recruits and activates subsets of leukocytes that function as effector cells in the response to the sensitizing antigen. Proinflammatory cytokines activate endothelial cells (EC) to express adhesion molecules and induce the release of members of the chemokine family, thus focusing and directing the inflammatory response to sites of antigen recognition. However, the vasculature of the central nervous system (CNS) is highly specialized and restricts the access of components of the immune system to the CNS compartment. In this review, we address the question as to whether endothelial cells in the CNS respond differently to specific cytokines known to induce either a proinflammatory effect or a regulatory effect in systemic vascular beds.     

The Glycosphingolipid Hydrolases in the Central Nervous System

Glycosphingolipids are a large group of complex lipids particularly abundant in the outer layer of the neuronal plasma membranes. Qualitative and quantitative changes in glycosphingolipids have been reported along neuronal differentiation and aging. Their half-life is short in the nervous system and their membrane composition and content are the result of a complex network of metabolic pathways involving both the de novo synthesis in the Golgi apparatus and the lysosomal catabolism. In particular, most of the enzymes of glycosphingolipid biosynthesis and catabolism have been found also at the plasma membrane level. Their action could be responsible for the fine tuning of the plasma membrane glycosphingolipid composition allowing the formation of highly specialized membrane areas, such as the synapses and the axonal growth cones. While the correlation between the changes of GSL pattern and the modulation of the expression/activity of different glycosyltransferases during the neuronal differentiation has been widely discussed, the role of the glycohydrolytic enzymes in this process is still little explored. For this reason, in the present review, we focus on the main glycolipid catabolic enzymes β-hexosaminidases, sialidases, β-galactosidases, and β-glucocerebrosidases in the process of the neuronal differentiation.     

Electroneutral Cation-Chloride Cotransporters in the Central Nervous System

Several members of the cation-chloride cotransporter (solute carrier family 12, SLC12) gene family are expressed within the central nervous system, with one family member, the K+-Cl- cotransporter KCC2, exclusive to neurons. These transporters are best known for their roles in cell volume regulation and epithelial salt transport, but are increasingly receiving attention in neuroscience. In particular, intracellular chloride activity and hence the neuronal response to GABA and glycine appears to be determined by a balance between chloride efflux and influx through KCC2 and the Na+-K+-2Cl- cotransporter NKCC1, respectively. This relationship has important implications for neuronal development, sensory perception, neuronal excitability, and the response to neuronal injury. Finally, the association between loss of function in the K+-Cl- cotransporter KCC3, with a severe peripheral neuropathy associated with agenesis of the corpus callosum, has revealed an unexpected role for K+-Cl- cotransport in the development and/or maintenance of both the central and peripheral nervous systems.     

Prologue: Expressing the Central Nervous System

Neurochemical Research -     

基质金属蛋白酶与中枢神经系统感染

基质金属蛋白酶(MMPs)是一组合锌的能降解细胞外基质的中性蛋白酶家族.目前认为MMPs尤其是明胶酶(MMP-2,MMP-9)与中枢神经系统感染关系密切.通常它们以酶原的形式存在,一旦活化,则迅速攻击血脑屏障,降解基底膜的一些基质蛋白,破坏内皮细胞的紧密连接蛋白,促进脑水肿的形成和炎细胞的浸润.近年来研究发现,中枢神经系统感染后MMPs表达增加.导致血脑屏障损害及血管源性脑水肿,并参与中枢神经系统免疫反应,促进感染的病理生理过程.     

Lectin Receptors in Central Nervous System Myelin

Abstract: Proteins from central nervous system myelin were separated by high-resolution, sodium dodecyl sulfate-pore gradient slab gel electrophoresis and the glycoproteins were detected by autoradiography after direct application of radioiodinated lectins. A surprising heterogeneity of lectin binding proteins was found associated with this highly purified membrane fraction. Iodinated wheat germ agglutinin, which has a monosaccharide specificity for N-acetyl-D-glucosamine and N-acetylneuraminic acid, revealed six major bands and two minor bands. By correlating the molecular weights (M_r) of radioiodinated protein standards with the gel concentration at the position reached by the protein (%T) using the relationship log(M_r) versus log(%T) for gradient gel systems, molecular weight estimates of 128, 300, 109, 800, 75, 300, 48, 800, 26, 100 and 23, 700 were obtained for the major glycoprotein bands and molecular weights of 98, 300 and 86, 600 for the minor bands. When the isolated myelin was extracted with chloroform-methanol-a procedure that removes the major myelin proteins, including the proteolipid protein and most of the basic proteins and hence concentrates the minor high molecular weight proteins-and analyzed after gradient gel electrophoresis, additional glycoproteins of molecular weights 607, 700, 196, 900, 175, 100, 61, 800, 52, 200 and 42, 600 were resolved with this lectin. Radioiodinated soybean agglutinin, which has a specificity for N-acetyl-D-galactosamine and D-galactose, revealed seven bands, three of which were unique to this lectin (19, 600, 19, 100 and 17,000). Iodinated concanavalin A (d -mannose, d -glucose) revealed bands similar to the wheat germ agglutinin as well as additional bands of 40, 300, 37, 300, 35, 700, 21, 800 and 20, 400. The glycoprotein specificity for these lectin binding components was demonstrated by hapten carbohydrate binding inhibition and by organic solvent extraction for removal of glycolipids. Based on these experiments using three lectins with different carbohydrate specificity, 22 lectin-reactive components were identified; however, six of these bands were removed by chloroform-methanol extraction. The variations observed in the lectin binding capacity for these different bands suggest possible carbohydrate heterogeneity for these individual glycoproteins. Although many of these bands may be dissociated subunits (monomeric polypeptides) of oligomeric complexes, the observed multiplicity of these quantitatively minor glycoproteins associated with the purified myelin membrane implies a more intricate molecular organization for the myelin sheath complex than previously believed.     

Central Nervous System Manifestations of Chickenpox

A study of 57 cases of affection of the central nervous system associated with chickenpox diagnosed and treated at The Hospital for Sick Children in Toronto between 1956 and 1967, inclusive, is presented. The commonest type, the cerebellar variety (50%), had an excellent prognosis. In the next commonest, the cerebral type (40%), the mortality rate was 35% but there was a low incidence of permanent sequelae in the surviving patients. A small group classed as aseptic meningitis was defined and one case of myelitis was reviewed.     

Caspase与神经系统疾病

近年来,细胞凋亡发生机制的研究已取得众多进展。研究表明,许多神经系统疾病与caspase家族有着密切联系。现将细胞凋亡的最新研究结果及其与神经系统疾病的关系,尤其是caspase家族在神经系统疾病中的主导地位作简单综述,希望由此了解神经元细胞凋亡的内在机制并达到治疗目的。