Central
Nervous System Agents in Medicinal Chemistry
ISSN: 1871-5249
Current Medicinal Chemistry
- Central Nervous System Agents
Volume 5, Number 1, March 2005
Contents
Approaches to Alzheimer’s Disease and Other
Chronic
Degenerative Disorders
Guest Editor: H. Uri Saragovi
Editorial
Gregory S. Hamilton
[Editorial
In PDF]
Introduction: Strategies, Molecular Targets and
Animal Models Useful for Developing Therapies for Alzheimer’s
Disease Pp. 1-3
H. Uri Saragovi
[Abstract] [Full
text article]
Diagnosis and Treatment of Alzheimer’s Disease
Pp. 5-13
Myriam Monczor
[Abstract] [Full
text article]
Strategies to Diminish the Aβ Load in Alzheimer’s
Disease Pp. 15-28
A.C. Cuello and K.F.S. Bell
[Abstract] [Full
text article]
Neurotrophin Small Molecule Mimetics: Candidate
Therapeutic Agents for Neurological Disorders Pp.
29-41
Frank M. Longo, Youmei Xie and Stephen M. Massa
[Abstract] [Full
text article]
Glaucoma: Validated and Facile In Vivo
Experimental Models of a Chronic Neurodegenerative Disease
for Drug Development Pp. 43-49
Marcelo Rudzinski and H. Uri Saragovi
[Abstract] [Full
tex tarticle]
Alzheimer’s Disease and Oxidative Stress:
The Old Problem Remains Unsolved Pp. 51-62
Paula I. Moreira, Kazuhiro Honda, Quan Liu, Gjumrakch
Aliev, Catarina R. Oliveira, Maria S. Santos, Xiongwei Zhu,
Mark A. Smith and George Perry
[Abstract] [Full
text article]
General Articles
Role of the 5-HT2C Receptor in Atypical Antipsychotics: Hero
or Villain? Pp. 63-66
Martyn Wood
[Abstract] [Full
text article]
Pharmacological Manipulation of Neural Progenitor
Pathways In Situ: Possibilities for Neural Restoration
in the Injured Adult Brain Pp. 67-81
Carla B. Mellough, Andrew Wood and Stefan A. Przyborski
[Abstract] [Full
text article]
Abstracts
[Back to top]
Editorial
Gregory S. Hamilton
[Editorial
In PDF]
The year 2005 began in the wake of the most catastrophic
natural disaster of modern times: the destructive tsunami
which has devastated much of coastal Southeast Asia and resulted
in enormous loss of life and human suffering. I’m sure
many readers donated generously to the various relief efforts
following this tragedy. To be faced with human suffering on
such a scale is feel at times overwhelmed by the enormity
of the task of helping the victims of such a disaster. The
alleviation of suffering from the degenerative disorders of
the nervous system is a long-sought goal for medicinal and
pharmaceutical scientists, and the slow progress and severity
of the diseases can likewise wear at the dedicated researcher.
But progress is being made, surely if more slowly than we
would like.
It is the intention of Current Medicinal Chemistry-Central
Nervous System Agents to pursue the topic of therapeutic approaches
to chronic degenerative disorders of the nervous system is
several Hot Topic issues. This month, Professor Uri Saragovi
of McGill University has guest-edited a collection of articles
focused on this topic. The topic of Alzheimer’s Disease,
discussed in two of these articles, will be reprised in a
later Hot Topic issue.
The present issue is rounded out by two exceptionally interesting
articles: One by Prof. Martyn Wood on 5-HT2c receptors in
the action of atypical antipsychotics, and a sweeping review
by Prof. Stefan Przyborski and colleagues on the manipulation
of neural progenitor pathways as an approach to neural restoration.
It is hoped this issue’s articles, and those of the
future, provide a basis for readers’ continued ruminations
on how to apply their intellectual gifts and physical energy
to bringing hope to those who currently have none.
[Back to top]
Introduction: Strategies, Molecular Targets and Animal Models
Useful for Developing Therapies for Alzheimer’s Disease
H. Uri Saragovi
[Full text
article]
[Back to top]
Diagnosis and Treatment of Alzheimer’s Disease
Myriam Monczor
[Full
text article]
Alzheimer´s disease (AD) is the most common dementia.
Its frequency has increased dramatically in the last years
due to the extended length of life. It presents cognitive
symptoms inherent to the dementias, and a progressive and
insidious deterioration. Aside from the cognitive deficits
there are psychiatric symptoms related to the neurodegeneration
of the different cerebral zones, with alteration of the neurotransmission.
The etiologic hypotheses of the Alzheimer´s Disease
are complex; it is considered that the appearance of the disease
is a consequence of the interrelation of genetic and neurobiological
processes like colinergic hypothesis, amyloid hypothesis,
glutamatergic hypothesis, oxidative hypothesis and inflammatory
hypothesis. The diagnosis of the Alzheimer´s Disease
is by exclusion due to the fact that there are no accurate
diagnostic methods in the life of the patient. However, the
criteria of the diagnosis by exclusion should be relative
considering the AD is one of the most frequent dementia, and
we have now some possible orientators. The Mild Cognitive
Impairment (MCI) is an entity definy because of the memory
impairment without another deficit, and a normal global function.
However, some studies had demostrated the MCI has an evolution
to Alzheimer’s disease 12% per year. The pharmacological
treatment in early stages of the disease is useful to improve
the cognitive disorders to slow down the advance of the deficits,
and to diminish the psychiatric symptoms such as agitation,
depression and the psychosis. The colinesterase inhibitors
are the most studied for the treatment of the AD: tacrine,
rivastigmine, donepezil,and galantamine. Vitamin E, estrogens,
antiinfamatory drugs, ginkgo biloba and another strategies
has been utilized with different efficacy. The future will
show new horizons in relationship with neuronal growth factor,
antiamyloid therapies and genetic therapies.
[Back to top]
Strategies to Diminish the Aβ Load in Alzheimer’s
Disease
A.C. Cuello and K.F.S. Bell
[Full
text article]
Striking advances have been made in recent years toward potential
therapies for Alzheimer’s disease. Alzheimer’s
disease, which is the leading cause of dementia in the elderly,
is pathologically defined by the presence of amyloid plaques,
composed of the amyloid-beta protein, and neurofibrillary
tangles. The amyloid pathology has been associated with decreased
synaptic plasticity and neurodegeneration, thereby explaining
the visibly decreased cognitive function and evident dementia.
Subsequently, a large number of studies have been launched,
which attempt to disrupt the progression from Aβ aggregation
to plaque formation. These studies have involved the use of
beta-sheet breakers, secretase inhibition, immunotherapy and
anti-inflammatories, the most notable findings of which are
discussed in this review.
[Back to top]
Neurotrophin Small Molecule Mimetics: Candidate Therapeutic
Agents for Neurological Disorders
Frank M. Longo, Youmei Xie and Stephen M. Massa
[Full
text article]
Neurotrophin proteins bind to p75NTR and Trk receptors
to trigger potent biological effects including modulation
of neuronal survival, promotion and maintenance of neurite
networks, upregulation of neural function and modulation of
synaptic plasticity. Factors limiting clinical application
include poor stability, restricted nervous system penetration
and a wide array of biological activities that may lead to
adverse effects. A potential approach for addressing these
limitations is the development of synthetic, small molecule,
neurotrophin mimetics with favorable profiles of stability,
tissue penetration and targeted biological actions. Neurotrophin
mimetic strategies include development of agents that act
at neurotrophin receptors as agonists, partial agonists, inverse
agonists or antagonists to promote, inhibit or modify neurotrophin-related
signal transduction. The existence of a two-receptor system
for neurotrophins, suggests the possibility that small molecules
mimicking p75NTR versus Trk-interacting neurotrophin
domains might differentially promote selected neurotrophin
functions. Moreover, the principle of differential receptor
activation predicts that different mimetics acting at a given
neurotrophin receptor might elicit differential signaling
patterns and biological effects. For example, prevention of
neuronal death in the absence of the neurotrophin effects
of upregulation of pain transduction or inflammation might
constitute a desired activity profile. Synthesis of active
peptide mimetics corresponding to specific neurotrophin domains
has established the proof-of-principle that neurotrophin domain
mimetics can be created that exhibit antagonist or agonist
features and points to the possibility of creating non-peptide,
small molecule mimetics with favorable medicinal properties
and targeted neurotrophin activities.
[Back to top]
Glaucoma: Validated and Facile In Vivo Experimental
Models of a Chronic Neurodegenerative Disease for Drug Development
Marcelo Rudzinski and H. Uri Saragovi
[Full
text article]
Glaucoma is a neurodegenerative disorder that affects the
optic nerve and the inner layers of the retina. Increased
intraocular pressure is a major risk factor in the disease.
Chronic elevation of intraocular pressure specifically induces
the death of retinal ganglion cells. By developing animal
models of the disease, the scientific community has been able
to make progress in understanding the mechanisms leading to
the death of retinal ganglion cells, the molecular mechanisms
of the pathology, and developing new pharmacological interventions.
In this report, we review and compare animal models of glaucoma.
We find that the episcleral cauterization model offers many
advantages over other in vivo models. Its feasibility
and lack of frequent complications make it the most extensively
used animal model of glaucoma. Furthermore, we discuss features
related to the pathogenesis of the disease and compare it
with other models of retinal ganglion cell damage (e.g.
optic nerve axotomy and excitotoxicity). In the last section,
we focus on drug candidates for neuroprotective treatment
of glaucoma, and discuss their likely mechanisms of action.
[Back to top]
Alzheimer’s Disease and Oxidative Stress: The Old Problem
Remains Unsolved
Paula I. Moreira, Kazuhiro Honda, Quan Liu, Gjumrakch
Aliev, Catarina R. Oliveira, Maria S. Santos, Xiongwei Zhu,
Mark A. Smith and George Perry
[Full
text article]
Despite the controversial discussion about amyloid-β as a
cause or consequence of Alzheimer disease pathophysiology,
one of the most devastating neurodegenerative disorders, all
researchers working in this field agree that oxidative stress
is intimately associated with Alzheimer disease. This review
will focus primarily on oxidative stress associated to disturbances
in energy metabolism, with special emphasis on the role of
mitochondrial dysfunction and the overproduction of reactive
oxygen and nitrogen species. These free radical species attack
neuronal lipids, proteins and nucleic acids inevitably leading
to neuronal dysfunction. These neuronal alterations can be
measured using several markers such as protein carbonyls and
3-nitrotyrosine (protein oxidation markers), malondialdehyde,
thiobarbituric acid-reactive substances, 4-hydroxynonenal
and acrolein (lipid oxidation markers), 8-hydroxyguanosine
and 8-hydroxy-2’-deoxyguanosine (nucleic acid oxidation
markers) and advanced glycation end products (glyco-oxidation
marker). The prompt identification of early signs of oxidative
stress and its potential neuronal targets can open a window
for the development of new therapeutic strategies envisaged
to prevent or, at least, ameliorate the symptoms of Alzheimer
disease. In this line, and since oxidative damage occurs due
to an imbalance between reactive species production and cell
antioxidant defenses, we will discuss in brief the use of
antioxidant-based therapies and their effects in the fight
against the oxidative stress occurring in Alzheimer disease.
[Back to top]
Role of the 5-HT2C Receptor in Atypical Antipsychotics:
Hero or Villain?
Martyn Wood
[Full
text article]
The atypical antipsychotic drugs (APD) are characterised
by an interaction with the 5-hydroxytryptamine (5-HT)2
receptor. Following the identification of the 5-HT2A,
5-HT2B and 5-HT2C receptor subtypes
and the development of more selective compounds for these
receptors, the role of these receptors in the pharmacological
profile of APD has been studied. Although initial interest
focussed on the 5-HT2A receptor, recent evidence
has suggested that an interaction with the 5-HT2C
could be more important. This has been limited by suggestions
that 5-HT2C receptor antagonism in APD may be associated
with the severe side-effect of weight gain. This review highlights
the evidence suggesting that 5-HT2C receptor antagonism
could have important benefits in APD profile and that 5-HT2C
receptor antagonism does not directly contribute to weight
gain.
[Back to top]
Pharmacological Manipulation of Neural Progenitor Pathways
In Situ: Possibilities for Neural Restoration in the
Injured Adult Brain
Carla B. Mellough, Andrew Wood and Stefan A.
Przyborski
[Full
text article]
Progress over the last decade has confirmed the occurrence
of de novo neurogenesis within discrete regions of
the adult brain. It has been demonstrated that under certain
conditions neurogenesis can be stimulated above basal levels
in the adult, and that resident pools of adult progenitors
can be manipulated to generate new neurons in situ.
Undoubtedly, these reports prelude possibilities for applications
in regenerative medicine. Much attention is now being focused
on the elucidation of the discrete mechanisms that are involved
in the induction of the neurogenic response in the adult brain
and whether these pathways can be pharmacologically manipulated
to endogenously replace lost cells and alleviate neuropathy.
There is evidence that the re-expression of many key molecular
components of the various pathways controlling cellular proliferation,
migration and differentiation during development can be re-induced
within the mature brain. Recent reports show that the expression
of a number of these developmentally-associated molecules
occurs in close association with adult progenitor proliferation
and neurogenesis, signifying an additional role for these
systems in eliciting the adult neurogenic response. Here we
review the literature regarding this phenomenon, with reference
to the main candidate pathways involved including bone morphogenetic
protein, sonic hedgehog and Wnt signalling pathways, and discuss
the progress which has been made in the use of small molecules
to manipulate these pathways and affect adult neurogenesis
in situ.
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