CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 5, Issue 4, 2006

The first glycobiology investigation into neurological disorders showed that ganglioside was a novel glycolipid in the brain of a Tay-Sachs patients in 1939. In the 1960's or later, the finding led to further glycobiology studies into neurological disorders. Advances in this area have continued at a steady rate during most of the twentieth century, based on investigations into the interactions of the highly complicated carbohydrate structures of glycoproteins and glycolipids with the physiological and structural complexity of brain. However, there has recently been an unparalleled explosion of new knowledge. There are many reasons for this acceleration of progress including; (1) collaborative studies using genetically engineered knock-out and knock-in mice along with classical biological and pharmacological approaches, (2) great technical advances in the mass spectroscopy of carbohydrates, and (3) accumulation of genomic and proteomic information, followed by molecular information regarding enzymes involved in sugar metabolism and in the sorting, processing and degradation of oligosaccharides, proteoglycans, and glycolipids. More recently, the important role of glycans has been underscored by the growing list of human diseases that result from defects and mutations in glycosylation. The overall aim of the reviews in this issue is to highlight the most exciting information on glycobiological neurology, and developments in neuroprotective drugs that affect glycosylation and markers of diseases based on glycobiological approach. There has been an increased number of reports describing imbalances of sphingoglycolipids-cholesterol-rich membrane microdomains, or rafts causing disfunctions in brain, where sphingoglycolipids containing gangliosides are rich. The review by Mutoh et al. focuses on the involvements of sphingoglycolipids with risk factors for Alzheimer's diseases (AD) and proposals for glycobiological approaches as future therapies. Schengrund focuses on pathogens that affect the nervous system and require carbohydrates during any process of the infectious machinery. While there is a recent example of Tamiflu, an inhibitor of the enzyme neuraminidase (sialidase), which is effective for the treatment of influenza A and B in the peripheral system, there is little effective drug against pathogens in the nervous system. This review provides hints for the development of carbohydrate- based drugs against pathogens in the nervous system. Furthermore, Komagamine and Yuki focus on the latest findings about Guillain-Barre syndrome, characterized by auto-immune diseases induced following infection with C. jejuni. Concerning therapeutic approach, Sakuraba et al. describe very recent trials of enzyme-replacement therapy and the development of a brain-specific delivery system for several metabolic diseases that cause neurological disorders. Alternatively, Yu and Yanagisawa review knowledge of neural stem cells analyzed from a glycobiological dimension in order to use these as cell therapy in the future. The sialylated group possesses a negative charge at the terminal position of sugar linkages on sphingoglycolipids and glycoproteins. Sampathkumar et al. describe perspectives of sialic acids as diagnostic and therapeutic reagents for neurological disorders. Finally, Narimatsu et al. review the nervous symptoms of knock-out mice with targeted deletions of glycosyltransferase genes and their usefulness as animal models for neurological disorders. Taken together, the sharing of information concerning glycobiological neurology could facilitate explorations into novel drugs based on glycobiology to treat neurological diseases induced by a variety of causes, in addition to inborn errors that cause neurological disorders. I would like to thank Dr. Masao Iwamori for giving advice for determination of the present authors. I would like to thank Dr. Matthew Honan, the Editorial Director; Dr. Mark Varney, the Editor-in-Chief; Miss Saima Ghaffar Rao, the Manager Publications; and the staff at Bentham Science Publishers for their assistance, efforts and time.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder dividing into two forms, early onset familial and late onset sporadic forms. Early onset genetic cases (familial AD (FAD)) constitute about 10% of all AD cases. Heretofore, highly fibrillinogenic and pathological Aβ peptide formation is regarded as the fundamental molecular basis for this disorder. Recent enormous efforts to find out a pathogenesis, however, have revealed that this disorder has a multiplicity of causes such as glycosphingolipids abnormalities, impairment of neurotrophin signaling, protein trafficking, and protein turnover. Most of these aspects were disclosed by the studies on FAD-related presenilin. In this review, we will focus on the current knowledge of many abnormal aspects of cellular lipids, especially glycosphingolipids other than a pathogenic Aβ production caused by the mutant presenilins as a model system. Moreover, we will discuss how these glycosphingolipids abnormalities cause the pathological conditions found in this disorder.

Numerous reports indicate that lipid or protein associated carbohydrates are essential for infection of cells by various viruses, bacteria, or bacterial toxins, some of which affect the nervous system. Examples of such pathogens include tetanus and botulinum neurotoxin, Shiga and Shiga-like toxins, Borrelia burgdorferi, Mycobacterium leprae, and human immunodeficiency virus. This review discusses evidence indicating that carbohydrates are essential for these pathogens to induce their deleterious effects, the putative function of the carbohydrates, and how this knowledge might be used to combat the effects of the pathogen.

Guillain-Barre syndrome (GBS), characterized by acute progressive limb weakness and areflexia, is the prototype of postinfectious autoimmune diseases. Campylobacter jejuni is the most frequently identified agent of infection in GBS patients, often preceding acute motor axonal neuropathy (AMAN), a variant of GBS. Anti-GM1, anti-GM1b, anti- GD1a, and anti-GalNAc-GD1a IgG antibodies are associated with AMAN. Carbohydrate mimicry [Galβ1-3GalNAcβ1- 4(NeuAcα 2-3)Galβ1-] was seen between the lipo-oligosaccharide of C. jejuni isolated from an AMAN patient and human GM1 ganglioside. Sensitization with the lipo-oligosaccharide of C. jejuni induces AMAN in rabbits as does sensitization with GM1 ganglioside. Paralyzed rabbits have pathological changes in their peripheral nerves identical to changes seen in human GBS. C. jejuni infection may induce anti-ganglioside antibodies by molecular mimicry, eliciting AMAN. This is the first verification of the causative mechanism of molecular mimicry in an autoimmue disease. To express ganglioside mimics, C. jejuni requires specific gene combinations that function in sialic acid biosynthesis or transfer. The knockout mutants of these landmark genes of GBS show reduced reactivity with GBS patients' sera, and fail to induce an antiganglioside antibody response in mice. These genes are crucial for the induction of neuropathogenic cross-reactive antibodies. An approach for evaluating intravenous immune globulin, a treatment for GBS, based on our animal model of AMAN is also discussed in this review, and recent advances made in this field are described.

Lysosomal diseases comprise a group of inherited disorders resulting from defects of lysosomal enzymes and their cofactors, and in many of them the nervous system is affected. Recently, enzyme replacement therapy with recombinant lysosomal enzymes has been clinically available for several lysosomal diseases. Such enzyme replacement therapies can improve non-neurological disorders but is not effective for neurological ones. In this review, we discuss the molecular pathologies of lysosomal diseases from the protein structural aspect, current enzyme replacement therapies, and attempts to develop enzyme replacement therapies effective for lysosomal diseases associated with neurological disorders, i.e., production of enzymes, brain-specific delivery and incorporation of lysosomal enzymes into cells.

The mammalian central nervous system is organized by a variety of cells, such as neurons and glial cells, that are generated from a common progenitor, the neural stem cell (NSC). NSCs are defined as undifferentiated neural cells that are characterized by their high proliferative potential while retaining the capacity for self-renewal and multipotency. NSCs and their progeny may be distinguished by the expression of glycoconjugates (e.g., glycoproteins, glycolipids, and proteoglycans). The carbohydrate antigens carried by glycoconjugates are mainly localized on the plasma membrane surface of the cells and they serve as excellent biomarkers for various stages of cellular differentiation. Thus, they have been utilized as ligands for sorting NSCs or their progeny by cell cytometry. Methods have been established for utilizing polysialic acid-neural cell adhesion molecule (PSA-NCAM), stage-specific embryonic antigen-1 (SSEA-1), and gangliosides for cell sorting. Furthermore, glycoconjugates have also been suggested to have a wide range of receptor and signaling functions in NSCs. For example, basic fibroblast growth factor, an important mitogen of NSCs, requires heparan sulfate proteoglycans and glycosylated cystatin C for activity. Notch signaling, which regulates a wide variety of developmental processes in various cells including NSCs, is modulated by the O-fucose glycan modification. In peripheral nervous system (PNS), the human natural killer-1 (HNK-1) antigen regulates the migration of neural crest cells, cell populations containing the stem cells. Thus, glycoconjugates serve not only as marker molecules, but also as functional molecules as well. In the present review, we discuss the expression pattern and possible functions of glycoconjugates in NSCs.

Glycobiology, broadly defined as the study of sugars in living systems, is becoming increasingly important for understanding the basic biology of the central nervous system (CNS) and diagnosing and devising new treatments for neurological disorders. Decades of research have uncovered many roles for both glycolipids and glycoproteins in the proper functioning of the brain; moreover many diseases are characterized by abnormalities in either the biosynthesis or catabolism of these cellular components. In many cases, however, only a rudimentary understanding of the basic biological roles of sugars in neural function exists. Similarly, methods to detect and diagnose glycosylation disorders are far from state-of-the-art compared to many facets of modern medicine. This review focuses on sialic acid, arguably the most important monosaccharide in CNS, and describes how recent advances in its manipulation by chemical and metabolic methods hold the possibility to converge with advanced instrumentation such as magnetic resonance imaging, positron emission tomography, diffusion tensor imaging, and single photon emission computerized tomography now used for imaging of the CNS in human subjects. Specifically, methods are under development for tagging sialic acids in living systems with contrast agents suitable for magnetic resonance imaging, in essence allowing for the functional imaging of sugars at a molecular level. One of these methods, biochemical engineering of sialic acids by use of small molecule metabolic substrates, also holds promise for the manipulation of sialic acids for the development of novel therapies for neurological disorders.

At the present time, 160 human glycogenes encoding glycosyltransferases and sulfotransferases, which add sulfate to carbohydrates, have been cloned and analyzed for their substrate specificity. Mice have almost all genes orthologous to them, and some are specifically expressed in neuronal tissues. In this review, neurological disorders of mice deficient for the glycogenes that synthesize interesting carbohydrate epitopes in neuronal tissues are described and summarized.

Antipsychotic drugs (APD) are widely prescribed for the treatment of schizophrenia. The APD are differentiated into typical and atypical based on the lower incidence of extra-pyramidal side-effects associated with the newer atypical APD. It was suggested that atypicality may arise from an interaction with the 5-hydroxytryptamine (5-HT)2 receptor and specifically on the 5-HT2:dopamine D2 affinity ratio. It is now realised that multiple subtypes of these receptors exist and that in addition, atypical APD interact with many monoamine receptors. The aim of the present study was to characterise the interaction of APD with a variety of monoamine receptors in terms of both affinity and efficacy. The data produced has highlighted that the atypical profile of APD such as olanzapine and clozapine may reflect antagonism of the 5-HT2A and 5-HT2C receptors, whilst that of, ziprasidone and quetiapine may reflect partial agonist activity at the 5-HT1A receptor, and that of aripiprazole may reflect partial agonist activity at the 5-HT1A receptor as well as is its claimed partial agonist activity at the dopamine D2 receptor.

Corticotropin-releasing factor (CRF) and the related urocortin peptides mediate behavioral, cognitive, autonomic, neuroendocrine and immunologic responses to aversive stimuli by activating CRF1 or CRF2 receptors in the central nervous system and anterior pituitary. Markers of hyperactive central CRF systems, including CRF hypersecretion and abnormal hypothalamic-pituitary-adrenal axis functioning, have been identified in subpopulations of patients with anxiety, stress and depressive disorders. Because CRF receptors are rapidly desensitized in the presence of high agonist concentrations, CRF hypersecretion alone may be insufficient to account for the enhanced CRF neurotransmission observed in these patients. Concomitant dysregulation of mechanisms stringently controlling magnitude and duration of CRF receptor signaling also may contribute to this phenomenon. While it is well established that the CRF1 receptor mediates many anxiety- and depression-like behaviors as well as HPA axis stress responses, CRF2 receptor functions are not well understood at present. One hypothesis holds that CRF1 receptor activation initiates fear and anxiety-like responses, while CRF2 receptor activation re-establishes homeostasis by counteracting the aversive effects of CRF1 receptor signaling. An alternative hypothesis posits that CRF1 and CRF2 receptors contribute to opposite defensive modes, with CRF1 receptors mediating active defensive responses triggered by escapable stressors, and CRF2 receptors mediating anxiety- and depressionlike responses induced by inescapable, uncontrollable stressors. CRF1 receptor antagonists are being developed as novel treatments for affective and stress disorders. If it is confirmed that the CRF2 receptor contributes importantly to anxiety and depression, the development of small molecule CRF2 receptor antagonists would be therapeutically useful.