| CNS
& Neurological Disorders - Drug Targets
ISSN: 1871-5273
Current Drug Targets - CNS
& Neurological Disorders
Volume 4, Number 1, February 2005
Contents
Neurodegenerative Diseases
Guest Editor: Santosh R. D'Mello
Editorial
Santosh R. D'Mello
[Full
text article]
Treating Neurodegenerative Conditions Through
the Understanding of Neuronal Apoptosis Pp.3-23
Santosh R. D'Mello and Paul C. Chin
[Abstract] [Full
text article]
Regulation of Neuronal Cell Death and Neurodegeneration
by Members of the Bcl-2 Family: Therapeutic Implications Pp.25-39
John J. Shacka and Kevin A. Roth
[Abstract] [Full
text article]
Remodeling Chromatin and Stress Resistance in
the Central Nervous System: Histone Deacetylase Inhibitors
as Novel and Broadly Effective Neuroprotective Agents Pp.41-50
Brett Langley, JoAnn M. Gensert, M. Flint Beal and Rajiv
R. Ratan
[Abstract] [Full
text article]
Caspase Function in Neuronal Death: Delineation
of the Role of Caspases in Ischemia Pp.51-61
Giselle F. Prunell, Valerie A. Arboleda and Carol M. Troy
[Abstract] [Full
text article]
Targeting the JNK Signaling Pathway for Stroke
and Parkinson’s Diseases Therapy Pp.63-67
Chia-Yi Kuan and Robert E. Burke
[Abstract] [Full
text article]
Mitochondria Play a Central Role in Estrogen-Induced
Neuroprotection Pp.69-83
James W. Simpkins, Jian Wang, Xiaofei Wang, Evelyn Perez,
Laszlo Prokai and James A. Dykens
[Abstract] [Full
text article]
Targeting Hypoxia-Inducible Factor (HIF) as a
Therapeutic Strategy for CNS Disorders Pp.85-92
Robert S. Freeman and Maria Cecilia Barone
[Abstract] [Full
text article]
Abstracts
[Back to top]
Editorial
Santosh R. D'Mello
[Full
text article]
Neurodegenerative diseases such as Alzheimer's, Parkinson's
and Huntington's disease and neurodegenerative conditions
such as stroke and traumatic brain injury are leading causes
of death in the Western world. Although displaying a diverse
range of linical symptoms, these neuropathologies have a commonality:
the abnormal loss of neurons. While current treatments can
reduce the symptoms associated with some of these pathologies,
they do not stop the loss of neurons and hence do not slow
down disease progression. Thus, there is an urgent need for
the development of therapeutic drugs that will stop or reduce
the loss of neurons in these diseases. Essential to this process
of drug development is the identification of disease-related
molecules that can be targeted by small molecule compounds
and biomolecules. Compelling evidence gathered over the past
decade has indicated that pathological neurodegeneration occurs
as a result of an inappropriate activation of apoptosis, a
cell suicide program. Intensive research has identified a
large number of molecules and signal transduction pathways
that promote or inhibit apoptosis. Inhibition of many of the
molecules that promote apoptosis or stimulation of the activity
of molecules that promote cell survival has been found to
protect neurons in cell culture and in animal models of neurodegenerative
disorders. Understanding the molecular mechanisms underlying
apoptosis therefore offers promise of benefit to people suffering
from neurodegenerative conditions.
The overall aim of the reviews in this issue is to describe
the latest and most exciting information on the identification
of intracellular molecular targets involved in neurodegenerative
conditions, and the development of potential neuroprotective
drugs that act on them. D'Mello and Chin provide a description
of the molecular mechanisms underlying apoptosis in neurons.
A section of the review covers neuroprotective compounds that
modulate the activity of specific signaling molecules involved
in the regulation of apoptosis. It is well established that
caspases, a family of cysteine proteases, play a pivotal role
in the apoptotic process in both neurons and non-neuronal
cell types. Prunell et al. review the current information
on caspases. Focus is placed on ischemic stroke and the role
of caspases in this neurological condition. Another family
of proteins consisting of both anti- and pro-apoptotic members
are the Bcl-2 proteins. Shacka and Roth provide a description
of the Bcl-2 proteins. Their involvement in the development
of the nervous system and in various neurodegenerative diseases
has been reviewed. A separate section covers neuroprotective
strategies targeting Bcl-2 proteins. A number of small molecule
activators and inhibitors of individual Bcl-2 proteins have
recently been identified. The efficacy of some of these small
molecule modulators in preventing death of cultured neurons
and in animal models of neurodegenerative diseases is described
in the review. Among the biological factors that stimulate
the activity of anti-apoptotic proteins are estrogens. A separate
review by Simpkins et al. describes the neuroprotective effects
of estrogen. The protective effect of estrogens is likely
to be mediated by supporting mitochondrial function. Compelling
evidence for oxidative stress, bioenergetic impairment and
mitochondrial failure in the etiology of neurodegenerative
diseases has been presented in this review. Besides mitochondrial
dysfunction, acetylation and deacetylation of histones within
chromatin and of other nuclear and cytoplasmic signaling proteins
has been found to regulate neuronal survival. Langley et
al. review the evidence that misregulation of histone
acetylase transferases and/or histone deacetylases are involved
in certain neurological syndromes and in neurodegenerative
diseases such as Huntington's disease, Alzheimer's disease
and amyotropic lateral sclerosis. The promise of histone deacetylase
inhibition by small molecule compounds in the treatment of
central nervous system disorders has also been discussed.
Another target that is being explored for the treatment of
neurodegenerative conditions is the c-Jun N-terminal kinase
signaling pathway. CEP-1347, a compound that inhibits this
pathway is already in a multi-center phase II/III clinical
trial for the treatment of Parkinson's disease. Kuan and Burke
review JNK signaling as a therapeutic target. Finally, Freeman
and Barone describe the role of the hypoxia-inducible transcription
factor (HIF) in neuroprotection. As described in the review,
HIF is activated in response to stimuli such as hypoxia leading
to the stimulation of cell survival genes. Several compounds
which increase HIF activity have been developed and the utility
of such compounds in the treatment of neurological disorders
associated with hypoxia is being seriously considered.
[Back to top]
Treating Neurodegenerative Conditions Through the Understanding
of Neuronal Apoptosis
Santosh R. D'Mello and Paul C. Chin
[Full
text article]
Neurological diseases disrupt the quality of the lives of
patients and often leads to their premature deaths. A common
feature of most neurological diseases is the degeneration
of neurons. It is generally accepted that neuronal loss, in
these diseases, occurs by the inappropriate activation of
a cell-suicide process called apoptosis. Drugs that inhibit
neuronal apoptosis could thus be candidates for therapeutic
intervention in neurodegenerative disorders. In this review
we describe advances made in recent years on the molecules
and signal transduction pathways that regulate neuronal apoptosis
either positively or negatively. Emphasis is on molecules
that are being targeted for the potential treatment of neurodegenerative
conditions in humans. Furthermore, we will summarize results
from studies performed using small-molecule neuroprotective
drugs that target specific signaling molecules known to regulate
neuronal apoptosis.
[Back to top]
Regulation of Neuronal Cell Death and Neurodegeneration
by Members of the Bcl-2 Family: Therapeutic Implications
John J. Shacka and Kevin A. Roth
[Full
text article]
The Bcl-2 family of proteins contains both anti and pro-apoptotic
members that have been shown to regulate neuronal cell death
during development and in many models of acute and chronic
neurodegeneration. This family of proteins can be divided
into three distinct classes based on structure and function:
the antiapoptotic sub-group; the pro-apoptotic, multi-domain
sub-group; and the pro-apoptotic, BH3 domain-only sub-group.
Alterations in the expression of Bcl-2 family members occur
in several animal and human neurodegenerative diseases including
Alzheimer’s, Huntington’s and Parkinson’s
diseases and Amyotrophic Lateral Sclerosis. Similar changes
are seen in in vivo and in vitro models
of acute neurodegeneration, including stroke and traumatic
brain injury. Methods to increase the overall expression and/or
function of anti-apoptotic Bcl-2 family members, and thus
promote neuron survival, have been studied extensively in
these models. Most treatment efforts focus on either the targeted
delivery via viral vectors of anti-apoptotic members
of Bcl-2 family members into the affected brain regions of
interest, the generation of direct interactions of small molecule
inhibitors with Bcl-2 family members, or the induced expression
of Bcl-2 family members secondary to pharmacological manipulation.
Although many challenges exist in the design of safe and efficacious
Bcl-2 family mimetics for the treatment of neurodegeneration,
such strategies offer great promise for preserving neuron
viability, and hopefully function, in a variety of human neurological
diseases.
[Back to top]
Remodeling Chromatin and Stress Resistance in the
Central Nervous System: Histone Deacetylase Inhibitors as
Novel and Broadly Effective Neuroprotective Agents
Brett Langley, JoAnn M. Gensert, M. Flint Beal
and Rajiv R. Ratan
[Full
text article]
Acetylation and deacetylation of histone protein plays a
critical role in regulating gene expression in a host of biological
processes including cellular proliferation, development, and
differentiation. Accordingly, aberrant acetylation and deacetylation
resulting from the misregulation of histone acetyltransferases
(HATs) and/or histone deacetylases (HDACs) has been linked
to clinical disorders such as Rubinstein-Taybi syndrome, fragile
X syndrome, leukemia, and various cancers. Of significant
import has been the development of small molecule HDAC inhibitors
that permit pharmacological manipulation of histone acetylation
levels and treatment of some of these diseases including cancer.
In this Review we discuss evidence that aberrant HAT and HDAC
activity may also be a common underlying mechanism contributing
to neurodegeneration during acute and chronic neurological
diseases, including stroke, Huntington’s disease Amyotrophic
Lateral Sclerosis and Alzheimer’s disease. With this
in mind, a number of studies examining the use of HDAC inhibitors
as therapy for restoring histone acetylation and transcriptional
activation in in vitro and in vivo neurodegenerative
models are discussed. These studies demonstrate that pharmacological
HDAC inhibition is a promising therapeutic approach for the
treatment of a range of central nervous system disorders.
[Back to top]
Caspase Function in Neuronal Death: Delineation of
the Role of Caspases in Ischemia
Giselle F. Prunell, Valerie A. Arboleda and Carol
M. Troy
[Full
text article]
Cerebral ischemia is one of the major causes of morbidity
and mortality in the Western world. Despite extensive research,
adequate therapies are still elusive. Neuronal degeneration
and death are hallmarks of stroke/ischemia. Understanding
how the death machinery executes neuronal death in ischemia
will provide therapeutic targets. Key to the death machinery
are caspases: the family of cell death proteases. While much
data has been published regarding caspase involvement in models
of ischemia, the pathways have not been thoroughly defined.
The specification of the caspases critical for death has been
hampered by the use of nonspecific reagents. Thus many conclusions
about specificity are unwarranted. In this review we discuss
how caspases can be measured and review the existing knowledge
of the roles of specific caspases in ischemia. We also discuss
approaches to determining the molecules that execute ischemic
death.
[Back to top]
Targeting the JNK Signaling Pathway for Stroke and
Parkinson’s Diseases Therapy
Chia-Yi Kuan and Robert E. Burke
[Full
text article]
The c-Jun NH2-terminal Kinase (JNK) signaling pathway is
frequently induced by cellular stress and correlated with
neuronal death. This unique property makes JNK signaling a
promising target for developing pharmacological intervention.
Among several neurological disorders, JNK signaling is particularly
implicated in ischemic stroke and Parkinson’s disease.
The inhibitors of the JNK signaling pathway include upstream
kinase inhibitors (for example, CEP-1347), small chemical
inhibitors of JNK (SP600125 and AS601245), and peptide inhibitors
of the interaction between JNK and its substrates (D-JNKI
and I-JIP). The mechanisms by which JNK signaling induces
apoptosis and evidence of cytoprotective effects of these
JNK inhibitors are summarized in the present review.
[Back to top]
Mitochondria Play a Central Role in Estrogen-Induced Neuroprotection
James W. Simpkins, Jian Wang, Xiaofei Wang, Evelyn
Perez, Laszlo Prokai and James A. Dykens
[Full
text article]
Oxidative stress, bioenergetic impairment and mitochondrial
failure have all been implicated in the etiology of neurodegenerative
diseases such as Alzheimer’s disease (AD), Parkinson’s
disease (PD) and Huntington’s disease (HD), as well
as retinal degeneration in glaucoma and retinitis pigmentosa.
Moreover, at least 75 debilitating, and often lethal, diseases
are directly attributable to deletions or mutations in mitochondrial
DNA, or in nuclear-encoded proteins destined for delivery
to the mitochondria. Such widespread mitochondrial involvement
in disease reflects the regulatory position mitochondrial
failure plays in both acute necrotic cell death, and in the
less catastrophic process of apoptosis. The potent feminizing
hormone, 17 β-estradiol
(E2), has shown cytoprotective activities in a host of cell
and animal models of stroke, myocardial infarct and neurodegenerative
diseases. The discovery that 17·α-estradiol,
an isomer of E2, is equally as cytoprotective as E2 yet is
>200-fold less active as a hormone, has permitted development
of novel, more potent analogs where cytoprotection is independent
of hormonal potency. Studies of structure-activityrelationships,
glutathione interactions and mitochondrial function have led
to a mechanistic model in which these steroidal phenols intercalate
into cell membranes where they block lipid peroxidation reactions,
and are in turn recycled via glutathione. Such a mechanism
would be particularly germane in mitochondria where function
is directly dependent on the impermeability of the inner membrane,
and where glutathione levels are maintained at extraordinarily
high 8-10mM concentrations. Indeed, the parental estrogens
and novel analogs stabilize mitochondria under Ca2+ loading
otherwise sufficient to collapse membrane potential. The cytoprotective
and mitoprotective potencies for 14 of these analogs are significantly
correlated, suggesting that these compounds prevent cell death
in large measure by maintaining functionally intact mitochondria.
This therapeutic strategy is germane not only to sudden mitochondrial
failure in acute circumstances, such as during a stroke or
myocardial infarction, but also to gradual mitochondrial dysfunction
associated with chronic degenerative disorders such as AD,
PD and HD.
[Back to top]
Targeting Hypoxia-Inducible Factor (HIF) as a Therapeutic
Strategy for CNS Disorders
Robert S. Freeman and Maria Cecilia Barone
[Full
text article]
Hypoxia occurs when oxygen availability drops below the levels
necessary to maintain normal rates of metabolism. Because
of its high metabolic activity, the brain is highly sensitive
to hypoxia. Severe or prolonged oxygen deprivation in the
brain contributes to the damage associated with stroke and
a variety of other neuronal disorders. Conversely, the extreme
hypoxic environment found in the core of many brain tumors
supports the growth of the tumor and the survival of tumor
cells. Normal cells exposed to transient or moderate hypoxia
are generally able to adapt to the hypoxic conditions largely
through activation of the hypoxia-inducible transcription
factor HIF. HIF-regulated genes encode proteins involved in
energy metabolism, cell survival, erythropoiesis, angiogenesis,
and vasomotor regulation. In many instances of hypoxia or
hypoxia and ischemia, the induction of HIF target genes may
be beneficial. When these same insults occur in tissues that
are normally poorly vascularized, such as the retina and the
core of solid tumors, induction of the same HIF target genes
can promote disease. Major new insights into the molecular
mechanisms that regulate the oxygen-sensitivity of HIF, and
in the development of compounds with which to manipulate HIF
activity, are forcing serious consideration of HIF as a therapeutic
target for diverse CNS disorders associated with hypoxia.
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