Central
Nervous System Agents in Medicinal Chemistry
ISSN: 1871-5249
Central Nervous System Agents
in Medicinal Chemistry
Volume 9, Number 2, June 2009
Contents
New Antiepileptic Drugs: Molecular Targets Pp.
79-86
Marco Mula
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Estrogens as Potential Therapeutic Agents in Multiple
Sclerosis Pp. 87-94
Masaaki Niino, Makoto Hirotani, Toshiyuki
Fukazawa, Seiji Kikuchi and Hidenao Sasaki
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The Insulin-like Growth Factor-1 Axis and its
Potential as a Therapeutic Target in Central Nervous System
(CNS) Disorders Pp. 95-109
Olivia Bibollet-Bahena, Qiao-Ling Cui and
Guillermina Almazan
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Endogenous Regulation of Neural Stem Cells in
the Adult Mammalian Brain Pp. 110-118
Valerie Coronas
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Biochemistry and Neurobiology of Prosaposin: A
Potential Therapeutic Neuro-Effector Pp.
119-131
Roberta Misasi, Isao Hozumi, Takashi Inuzuka,
Antonella Capozzi, Vincenzo Mattei, Yukako Kuramoto, Hiroshi
Shimeno, Shinji Soeda, Norihiro Azuma, Toyoaki Yamauchi and
Masao Hiraiwa
[Abstract] [Purchase
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Histamine H3-Receptor Inverse Agonists as Novel
Antipsychotics Pp. 132-136
Chihiro Ito
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Therapeutic Strategies in HTLV-I-Associated Myelopathy/Tropical
Spastic Paraparesis (HAM/TSP) Pp. 137-149
Tatsufumi Nakamura, Yoshihiro Nishiura
and Katsumi Eguchi
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The Trigeminal System in Birds and Nociception
Pp. 150-158
Jacob Leendert Dubbeldam
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Abstracts
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New Antiepileptic Drugs: Molecular Targets
Marco Mula
In the past 20 years, a number of new antiepileptic drugs
(AEDs) have been introduced and other molecules are in development,
some of which are advantageous in terms of pharmacokinetics,
tolerability and potential for drug interactions. These drugs
are regarded as second generation compared to older agents
such as barbiturates, phenytoin, carbamazepine, ethosuximide
and valproic acid. Although some of these second generation
compounds may be advantageous in terms of kinetics, tolerability
and potential for drug interactions, all of them still target
voltage-gated channels or GABA-mediated inhibition, predominantly,
without any real improvement in epilepsy therapy.
Studies on mechanisms of seizure generation and propagation
have identified new potential targets for AEDs. The growing
understanding of the pathophysiology of epilepsy and the structural
and functional characterization of the molecular targets provide
many opportunities to create improved epilepsy therapies.
In this review the molecular targets for new AEDs are discussed,
providing further suggestions on how future research can be
improved.
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Estrogens as Potential Therapeutic Agents in Multiple
Sclerosis
Masaaki Niino, Makoto Hirotani, Toshiyuki Fukazawa, Seiji
Kikuchi and Hidenao Sasaki
The disease activity of multiple sclerosis (MS) is known
to be ameliorated during pregnancy, and pregnancy is also
found to be protective in experimental autoimmune encephalomyelitis
(EAE), an animal model of MS. Estrogen levels increase during
pregnancy and basic researches have shown that estrogens have
immunomodulatory effects on immune cells. The importance of
estrogen in pathogenic autoimmune diseases has also been demonstrated
in EAE by altering hormone levels. Mice treated with estrogen
experienced significantly decreased EAE severity and delayed
onset of disease as a result of neuroprotective and anti-inflammatory
effects. Brain atrophy has been detected at the early stages
of MS by using MRI; thus, as a neuoprotective agent, estrogen
might be effective against brain atrophy. Estrogen’s
effects are primarily mediated by the nuclear estrogen receptor
(ER), and recent studies have shown the presence of nuclear
ERs on the cells involved in the immune response. There have
been some reports on genetic polymorphisms of ERs in MS. In
this review paper, we discuss increasing evidence that points
to a link between estrogen and MS. We also analyze the therapeutic
potential of estrogens in MS and review current genetic studies
on ER.
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The Insulin-like Growth Factor-1 Axis and its Potential
as a Therapeutic Target in Central Nervous System (CNS) Disorders
Olivia Bibollet-Bahena, Qiao-Ling Cui and Guillermina
Almazan
The insulin-like growth factor-1 (IGF-1) is a pleiotropic
factor. Many studies have revealed its importance in the development
and maintenance of the central nervous system (CNS). This
review will discuss the IGF-1 axis, from the factor itself
to the signalling pathways it activates, and its tight regulation.
Particular focus will be brought on potential therapeutic
targets of the IGF-1 axis in CNS disorders, including brain
tumours and neurodegenerative diseases affecting neurons and
oligodendrocytes.
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Endogenous Regulation of Neural Stem Cells in the
Adult Mammalian Brain
Valerie Coronas
Tissue-specific stem cells replenish organs by replacing
cells lost due to tears and wears or injury throughout life.
Long considered as an exception to this rule, the adult mammalian
brain has consistently been found to possess stem cells that
ensure neurogenesis. Neural stem cells persist within the
subventricular zone bordering the lateral ventricles of the
brain. Constitutively, neural stem cells proliferate and produce
a continuous supply of new neurons that migrate towards the
olfactory bulb where they ensure turnover of interneurons.
Owing to their potential clinical use for the treatment of
neurodegenerative diseases, the factors that control proliferation,
self-renewal and differentiation of neural stem cells have
received increasing interest. These studies have unraveled
that the cellular dynamic within the subventricular zone is
tightly controlled by astrocytes and endothelial cells that
neighbor neural stem cells. These neighboring cells produce
substrate-bound and soluble factors that make up a specialized
microenvironment named the neurogenic niche. The equilibrium
between neural stem cells activity and quiescence is adjusted
by neurons located in remote brain areas that adapt neuron
production to physiological and pathological constraints.
Brain injury or neurodegenerative diseases affect neural stem
cells proliferation, differentiation and migration suggesting
that neural stem cells are involved in brain self-repair.
Understanding the endogenous mechanisms that regulate neural
stem cells will help to replenish cellular constituents lost
by injury and thereby allow an effective development of neural
stem cells based therapies of brain diseases.
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Biochemistry and Neurobiology of Prosaposin: A Potential
Therapeutic Neuro-Effector
Roberta Misasi, Isao Hozumi, Takashi Inuzuka, Antonella
Capozzi, Vincenzo Mattei, Yukako Kuramoto, Hiroshi Shimeno,
Shinji Soeda, Norihiro Azuma, Toyoaki Yamauchi and
Masao Hiraiwa
Prosaposin, a 66 kDa glycoprotein, was identified initially
as the precursor of the sphingolipid activator proteins, saposins
A-D, which are required for the enzymatic hydrolysis of certain
sphingolipids by lysosomal hydrolases. While mature saposins
are distributed to lysosomes, prosaposin exists in secretory
body fluids and plasma membranes. In addition to its role
as the precursor, prosaposin shows a variety of neurotrophic
and myelinotrophic activities through a receptor-mediated
mechanism. In studies in vivo, prosaposin was demonstrated
to exert a variety of neuro-efficacies capable of preventing
neuro-degeneration following neuro-injury and promoting the
amelioration of allodynia and hyperalgesia in pain models.
Collective findings indicate that prosaposin is not a simple
house-keeping precursor protein; instead, it is a protein
essentially required for the development and maintenance of
the central and peripheral nervous systems. Accumulating evidence
over the last decade has attracted interests in exploring
and developing new therapeutic approaches using prosaposin
for human disorders associated with neuro-degeneration. In
this review we detail the structure characteristics, cell
biological feature, in vivo efficacy, and neuro-therapeutic
potential of prosaposin, thereby providing future prospective
in clinical application of this multifunctional protein.
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Histamine H3-Receptor Inverse Agonists as Novel Antipsychotics
Chihiro Ito
Schizophrenia (SZ) that is resistant to treatment with
dopamine (DA) D2 antagonists may involve changes other than
those in the dopaminergic system. Recently, histamine (HA),
which regulates arousal and cognitive functions, has been
suggested to act as a neurotransmitter in the central nervous
system. Four HA receptors-H1, H2, H3, and H4-have been identified.
Our recent basic and clinical studies revealed that brain
HA improved the symptoms of SZ. The H3 receptor is primarily
localized in the central nervous system, and it acts not only
as a presynaptic autoreceptor that modulates the HA release
but also as a presynaptic heteroreceptor that regulates the
release of other neurotransmitters such as monoamines and
amino acids. H3-receptor inverse agonists have been considered
to improve cognitive functions. Many atypical antipsychotics
are H3-receptor antagonists. Imidazole-containing H3-receptor
inverse agonists inhibit not only cytochrome P450 but also
hERG potassium channels (encoded by the human ether-a-go-go-related
gene). Several imidazole H3-receptor inverse agonists also
have high affinity for H4 receptors, which are expressed at
high levels in mast cells and leukocytes. Clozapine is an
H4-receptor agonist; this agonist activity may be related
to the serious side effect of agranulocytosis caused by clozapine.
Therefore, selective non-imidazole H3-receptor inverse agonists
can be considered as novel antipsychotics that may improve
refractory SZ.
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Therapeutic Strategies in HTLV-I-Associated Myelopathy/Tropical
Spastic Paraparesis (HAM/TSP)
Tatsufumi Nakamura, Yoshihiro Nishiura and Katsumi
Eguchi
Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical
spastic paraparesis (HAM/TSP) is chronic progressive myelopathy
characterized by bilateral pyramidal tracts involvement with
sphincteric disturbances. HTLV-I infects approximately 10-20
million people worldwide. There are large endemic areas in
southern Japan, the Caribbean, Central and South America,
the Middle East, Melanesia, and equatorial regions of Africa.
Since the primary neuropathological feature of HAM/TSP is
chronic inflammation caused by HTLV-I infection in the spinal
cord, various treatments focusing on immunomodulatory or anti-viral
effects were performed for HAM/TSP patients until now. However,
there are still many of problems, such as insufficient effects,
side effects and expensive costs in long-term treatments,
etc., in these treatments. Therefore, an ideal therapeutic
strategy against HAM/TSP is still not established yet. Although
only a small proportion of HTLV-I-infected individuals develops
HAM/TSP, neurological symptoms are certainly progressive once
myelopathy develops, leading to deterioration of the quality
of life. Therefore, we now need the therapeutic regimens to
protect the development, or be able to commence the treatments
as soon as possible after the development safely and inexpensively
even in long-term course or lifelong course of treatment.
As HTLV-I-infected CD4+ T
cells are the first responders in the immunopathogenesis of
HAM/TSP, the ideal treatment is the elimination of HTLV-I-infected
cells from the peripheral blood. In this article, we will
review the therapeutic strategies against HAM/TSP up to now
and will introduce our new therapeutic approach focusing on
the targeting of HTLV-I-infected cells in HAM/TSP patients.
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The Trigeminal System in Birds and Nociception
Jacob Leendert Dubbeldam
Aim of this paper is to give a concise overview of what
is known about the trigeminal nociceptive system in birds.
Several types of nociceptors have been discovered, thermal
nociceptors and polymodal, i.e. mechanothermal and mechanochemical
receptors. Information from these receptors reaches the Laminae
I and II of the caudal subnucleus of the descending trigeminal
system and of the dorsal horn of the rostral spinal cord.
The organization of the afferents to the avian brainstem and
of the primary nociceptive centers is largely the same as
that in mammals. This is also true for a number of histochemical
characteristics of these primary centers.
The comparability of the ascending nociceptive system in birds
and mammals is more problematic. This is due to the differences
in organization of the forebrain in mammals and birds. The
paper concludes with a short discussion on the sense of pain
and the connection with nociception.
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