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CNS
& Neurological Disorders -Drug Targets
ISSN: 1871-5273
OPEN ACCESS PLUS
Contents
Prolyl Oligopeptidase, Inositol Phosphate Signalling
and Lithium Sensitivity, 2011, 10, 333-339
Adrian J. Harwood
[Abstract] [Full
Text Article]
Drosophila melanogaster in the Study of Human
Neurodegeneration, 2010, 9, 504-523
Frank Hirth
[Abstract] [Full
Text Article]
TRPC Channels and their Implications for Neurological Diseases,
2010, 9, 94-104
Senthil Selvaraj, Yuyang Sun and Brij B. Singh
[Abstract] [Full
Text Article]
NF-κB, a Potential Therapeutic Target for the
Treatment of Multiple Sclerosis, 2008, 7, 536-557
J. Yan and J.M. Greer
[Abstract] [Full
Text Article]
GABAA Receptors, Anesthetics and Anticonvulsants in
Brain Development, 2008, 7, 211-224
Oliver Henschel, Keith E. Gipson and Angelique
Bordey
[Abstract] [Full
Text Article]
The Role of Neurogenesis in Neurodegenerative Diseases
and its Implications for Therapeutic Development,
2008, 7, 187-210
Andrea Abdipranoto, Sara Wu, Sandy Stayte and
Bryce Vissel
[Abstract] [Full
Text Article]
Phenotypic Screening Strategies for Neurodegenerative
Diseases: A Pathway to Discover Novel Drug Candidates and
Potential Disease Targets or Mechanisms, 2010,
9, 693-700
R.M. Pruss
[Abstract] [Full
Text Article]
Abstracts
[Back to top]
Prolyl Oligopeptidase, Inositol Phosphate Signalling
and Lithium Sensitivity
Adrian J. Harwood
[Full
Text Article]
Inhibition of prolyl oligopeptidase (PO) elevates inositol
phosphate (IP) signalling and reduces cell sensitivity to
lithium (Li+). This review discusses recent evidence
that shows PO acts via the multiple inositol polyphosphate
phosphatase (MIPP) to regulate gene expression. As a consequence,
PO inhibition causes both a transient, rapid increase in I(1,4,5)P3
and a long-term elevation of IP signalling. This pathway is
evolutionary conserved, being present in both the social amoeba
Dictyostelium and human cell systems, and has potential
implications for mental health.
[Back to top]
Drosophila melanogaster in the Study of Human
Neurodegeneration
Frank Hirth
[Full
Text Article]
Human neurodegenerative diseases are devastating illnesses
that predominantly affect elderly people. The majority of
the diseases are associated with pathogenic oligomers from
misfolded proteins, eventually causing the formation of aggregates
and the progressive loss of neurons in the brain and nervous
system. Several of these proteinopathies are sporadic and
the cause of pathogenesis remains elusive. Heritable forms
are associated with genetic defects, suggesting that the affected
protein is causally related to disease formation and/or progression.
The limitations of human genetics, however, make it necessary
to use model systems to analyse affected genes and pathways
in more detail. During the last two decades, research using
the genetically amenable fruitfly has established Drosophila
melanogaster as a valuable model system in the study
of human neurodegeneration. These studies offer reliable models
for Alzheimer’s, Parkinson’s, and motor neuron
diseases, as well as models for trinucleotide repeat expansion
diseases, including ataxias and Huntington’s disease.
As a result of these studies, several signalling pathways
including phosphatidylinositol 3-kinase (PI3K)/Akt and target
of rapamycin (TOR), c-Jun N-terminal kinase (JNK) and bone
morphogenetic protein (BMP) signalling, have been shown to
be deregulated in models of proteinopathies, suggesting that
two or more initiating events may trigger disease formation
in an age-related manner. Moreover, these studies also demonstrate
that the fruitfly can be used to screen chemical compounds
for their potential to prevent or ameliorate the disease,
which in turn can directly guide clinical research and the
development of novel therapeutic strategies for the treatment
of human neurodegenerative diseases.
[Back to top]
TRPC Channels and their Implications for Neurological
Diseases
Senthil Selvaraj, Yuyang Sun and Brij B. Singh
[Full
Text Article]
Calcium is an essential intracellular messenger and serves
critical cellular functions in both excitable and non-excitable
cells. Most of the physiological functions in these cells
are uniquely regulated by changes in cytosolic Cas2+
levels ([Ca2+]i), which are achieved via various
mechanisms. One of these mechanism(s) is activated by the
release of Ca2+ from the endoplasmic reticulum
(ER), followed by Ca2+ influx across the plasma
membrane (PM). Activation of PM Ca2+ channels is
essential for not only refilling of the ER Ca2+
stores, but is also critical for maintaining [Ca2+]i
that regulates biological functions, such as neurosecretion,
sensation, long term potentiation, synaptic plasticity, gene
regulation, as well as cellular growth and differentiation.
Alterations in Ca2+ homeostasis have been suggested
in the onset/progression of neurological diseases, such as
Parkinson’s, Alzheimer’s, bipolar disorder, and
Huntington’s diseases. Available data on transient receptor
potential conical (TRPC) protein indicate that these proteins
initiate Ca2+ entry pathways and are essential
in maintaining cytosolic, ER, and mitochondrial Ca2+
levels. A number of biological functions have been assigned
to these TRPC proteins. Silencing of TRPC1 and TRPC3 has been
shown to inhibit neuronal proliferation and loss of TRPC1
is implicated in neurodegeneration. Thus, TRPC channels not
only contribute towards normal physiological processes, but
are also implicated in several human pathological conditions.
Overall, it is suggested that these channels could be used
as potential therapeutic targets for many of these neurological
diseases. Thus, in this review we have focused on the functional
implication of TRPC channels in neuronal cells along with
the elucidation of their role in neurodegeneration.
[Back to top]
NF-κB, a Potential Therapeutic Target for the
Treatment of Multiple Sclerosis
J. Yan and J.M. Greer
[Full
Text Article]
Multiple sclerosis (MS) is a chronic inflammatory autoimmune
disease of the central nervous system (CNS) that afflicts
over 2 million people worldwide. On the basis of the temporal
course of disease, MS can be subdivided into three clinical
groups: relapsing remitting MS (RR-MS), secondary progressive
MS and primary progressive MS. There is a high degree of clinical
diversity within these subgroups. The pathogenesis of MS in
most patients is likely to result from autoreactive, activated
CD4+ T cells moving from the periphery across the
blood brain barrier into the CNS. Most therapeutic agents
used in MS (e.g. immunosuppressive and immunomodulatory drugs
and cell cycle interruption drugs) are only used for RR-MS.
These treatments show some efficiency in lessening the relapse
rate in RR-MS and time to progression, but cannot cure MS.
Thus, there is a need for new efficient treatments for all
types of MS. An increasing number of studies indicate that
nuclear factor-κB plays an important role in controlling
expression of genes relevant to the pathogenesis of autoimmunity.
Genetic factors related to NF-κB may also be determinants
of MS susceptibility, as polymorphisms in the molecules involved
in regulation of the NF-κB signal transduction pathway
differ between RR-MS and progressive MS. Herein, the role
of NF-κB in MS will be reviewed and its potential as
a new therapeutic target in MS will be considered and compared
with existing treatments.
[Back to top]
GABAA Receptors, Anesthetics and Anticonvulsants in Brain
Development
Oliver Henschel, Keith E. Gipson and Angelique
Bordey
[Full
Text Article]
GABA, acting via GABAA receptors, is well-accepted
as the main inhibitory neurotransmitter of the mature brain,
where it dampens neuronal excitability. The receptor’s
properties have been studied extensively, yielding important
information about its structure, pharmacology, and regulation
that are summarized in this review. Several GABAergic drugs
have been commonly used as anesthetics, sedatives, and anticonvulsants
for decades. However, findings that GABA has critical functions
in brain development, in particular during the late embryonic
and neonatal period, raise worthwhile questions regarding
the side effects of GABAergic drugs that may lead to long-term
cognitive deficits. Here, we will review some of these drugs
in parallel with the control of CNS development that GABA
exerts via activation of GABAA receptors. This review
aims to provide a basic science and clinical perspective on
the function of GABA and related pharmaceuticals acting at
GABAA receptors.
[Back to top]
The Role of Neurogenesis in Neurodegenerative Diseases and
its Implications for Therapeutic Development
Andrea Abdipranoto, Sara Wu, Sandy Stayte and
Bryce Vissel
[Full
Text Article]
Neurodegenerative diseases are characterised by a net
loss of neurons from specific regions of the central nervous
system (CNS). Until recently, research has focused on identifying
mechanisms that lead to neurodegeneration, while therapeutic
approaches have been primarily targeted to prevent neuronal
loss. This has had limited success and marketed pharmaceuticals
do not have dramatic benefits. Here we suggest that the future
success of therapeutic strategies will depend on consideration
and understanding of the role of neurogenesis in the adult
CNS. We summarize evidence suggesting that neurogenesis is
impaired in neurodegenerative diseases such as Parkinson's,
Alzheimer's and Amyotrophic Lateral Sclerosis, while it is
enhanced in stroke. We review studies where stimulation of
neurogenesis is associated with restored function in animal
models of these diseases, suggesting that neurogenesis is
functionally important. We show that many current therapeutics,
developed to block degeneration or to provide symptomatic
relief, serendipitously stimulate neurogenesis or, at least,
do not interfere with it. Importantly, many receptors, ion
channels and ligand-gated channels implicated in neurodegeneration,
such as NMDA, AMPA, GABA and nicotinic acetylcholine receptors,
also play an important role in neurogenesis and regeneration.
Therefore, new therapeutics targeted to block degeneration
by antagonizing these channels may have limited benefit as
they may also block regeneration. Our conclusion is that future
drug development must consider neurogenesis. It appears unlikely
that drugs being developed to treat neurodegenerative diseases
will be beneficial if they impair neurogenesis. And, most
tantalizing, therapeutic approaches that stimulate neurogenesis
might stimulate repair and even recovery from these devastating
diseases.
[Back to top]
Phenotypic Screening Strategies for Neurodegenerative
Diseases: A Pathway to Discover Novel Drug Candidates and
Potential Disease Targets or Mechanisms
R.M. Pruss
[Full Text Article]
Target-directed drug design, although a conceptually rational
approach, is only one strategy for drug discovery. In the
case of neurodegenerative diseases where molecular targets
and disease mechanisms are unknown, even when specific genes
are known to trigger the disease, phenotypic screening offers
another approach. This review describes the establishment
of phenotypic screening assays using primary neurons subjected
to a disease-relevant pathophysiological stress and measuring
the most important functional outcome, survival. Although
a challenge both to screening teams to reproducibly produce
the cells and chemists to interpret structure-activity relationships,
such systems have historically identified or produced effective
drugs. The primary screening assay is only the start; once
hits are validated, they must be characterized using traditional
target-directed or mechanism-based secondary assays to establish
their selectivity, lack of side-effect liability, and eventually
be shown to produce the desired effects in a preclinical animal
model of the disease. These compounds then provide valuable
pharmacological tools to identify neurodegenerative disease
targets and mechanisms, whether or not they have all the properties
required of a drug candidate.
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