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CNS &
Neurological Disorders -Drug Targets
ISSN: 1871-5273
CNS & Neurological Disorders
- Drug Targets
Volume 5, Number 4, August 2006
Contents
Glycobiological Approach to Neurological Disorders
Guest Editor: Keiko Kato
Editorial Pp. 373
Role of Glycosphingolipids and Therapeutic Perspectives
on Alzheimer’s Disease Pp. 375-380
Tatsuro Mutoh, Yoshio Hirabayashi, Takateru Mihara, Madoka
Ueda, Hiroshi Koga, Akihiro Ueda, Takako Kokura and Hiroko
Yamamoto
[Abstract]
Glycoconjugates: Roles in Neural Diseases Caused
by Exogenous Pathogens Pp. 381-389
Cara-Lynne Schengrund
[Abstract]
Ganglioside Mimicry as a Cause of Guillain-Barré
Syndrome Pp. 391-400
Tomoko Komagamine and Nobuhiro Yuki
[Abstract]
Molecular Pathologies of and Enzyme Replacement
Therapies for Lysosomal Diseases Pp. 401-413
Hitoshi Sakuraba, Makoto Sawada, Fumiko Matsuzawa, Sei-ichi
Aikawa, Yasunori Chiba, Yoshifumi Jigami and Kohji Itoh
[Abstract]
Glycobiology of Neural Stem Cells Pp.
415-423
Robert K. Yu and Makoto Yanagisawa
[Abstract]
Sialic Acid and the Central Nervous System: Perspectives
on Biological Functions, Detection, Imaging Methods and Manipulation
Pp. 425-440
Srinivasa-Gopalan Sampathkumar, Adrienne Li and Kevin
J. Yarema
[Abstract]
Neurological Disorders in Mice Lacking Glycogenes
that are Mainly Expressed in Brain Pp. 441-444
Hisashi Narimatsu
[Abstract]
General Articles
Pharmacological Profile of Antipsychotics at Monoamine Receptors:
Atypicality Beyond 5-HT2A
Receptor Blockade Pp. 445-452
Martyn D. Wood, Claire Scott, Kirsten Clarke, Katherine
J. Cato, Nisha Patel, Jennie Heath, Angela Worby, Laurie Gordon,
Lorraine Campbell, Graham Riley, Ceri H. Davies, Andrew Gribble
and Declan N.C. Jones
[Abstract]
Corticotropin Releasing Factor (CRF) Receptor
Signaling in the Central Nervous System: New Molecular Targets
Pp. 453-479
Richard L. Hauger, Victoria Risbrough, Olaf Brauns and
Frank M. Dautzenberg
[Abstract]
Abstracts
[Back to top]
Editorial
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-Barré 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.
Keiko Kato
Department of Structural and
Functional Biosciences for Animals
Graduate School of Life and
Environmental Sciences
Osaka Prefecture University
Japan
E-mail: kato@vet.osakafu-u.ac.jp
[Back to top]
Role of Glycosphingolipids and Therapeutic Perspectives
on Alzheimer’s Disease
Tatsuro Mutoh, Yoshio Hirabayashi, Takateru Mihara, Madoka
Ueda, Hiroshi Koga, Akihiro Ueda, Takako Kokura and Hiroko
Yamamoto
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.
[Back to top]
Glycoconjugates: Roles in Neural Diseases Caused
by Exogenous Pathogens
Cara-Lynne Schengrund
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.
[Back to top]
Ganglioside Mimicry as a Cause of Guillain-Barré
Syndrome
Tomoko Komagamine and Nobuhiro Yuki
Guillain-Barré 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(NeuAcα2-3)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 anti-ganglioside antibody response
in mice. These genes are crucial for the induction of neuropathogenic
cross-reactive anti-bodies. 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.
[Back to top]
Molecular Pathologies of and Enzyme Replacement
Therapies for Lysosomal Diseases
Hitoshi Sakuraba, Makoto Sawada, Fumiko Matsuzawa, Sei-ichi
Aikawa, Yasunori Chiba, Yoshifumi Jigami and Kohji Itoh
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.
[Back to top]
Glycobiology of Neural Stem Cells
Robert K. Yu and Makoto Yanagisawa
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.
[Back to top]
Sialic Acid and the Central Nervous System: Perspectives
on Biological Functions, Detection, Imaging Methods and Manipulation
Srinivasa-Gopalan Sampathkumar, Adrienne Li and Kevin
J. Yarema
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.
[Back to top]
Neurological Disorders in Mice Lacking Glycogenes
that are Mainly Expressed in Brain
Hisashi Narimatsu
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.
[Back to top]
Pharmacological Profile of Antipsychotics
at Monoamine Receptors: Atypicality Beyond 5-HT2A
Receptor Blockade
Martyn D. Wood, Claire Scott, Kirsten Clarke, Katherine
J. Cato, Nisha Patel, Jennie Heath, Angela Worby, Laurie Gordon,
Lorraine Campbell, Graham Riley, Ceri H. Davies, Andrew Gribble
and Declan N.C. Jones
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.
[Back to top]
Corticotropin Releasing Factor (CRF) Receptor
Signaling in the Central Nervous System: New Molecular Targets
Richard L. Hauger, Victoria Risbrough, Olaf Brauns and
Frank M. Dautzenberg
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 depression-like 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.
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