Current Molecular Pharmacology
ISSN: 1874-4672
Current Molecular Pharmacology
Volume 2, Number 1, January 2009
Contents
Mechanisms of Non-Opioid Analgesics Beyond Cyclooxygenase
Enzyme Inhibition Pp. 1-14
May Hamza and Raymond A. Dionne
[Abstract] [Full
text article]
Induced Pluripotent Stem Cells, New Tools for Drug
Discovery and New Hope for Stem Cell Therapies Pp.
15-18
Yanhong Shi
[Abstract]
[Full
text article]
Regulation of Transcription Factors by Heterotrimeric
G Proteins Pp. 19-31
M.K.C. Ho, Y. Su, W.W.S. Yeung and
Y.H. Wong
[Abstract] [Full
text article]
Antiviral Strategies: The Present and
Beyond Pp. 32-39
J.D. Burke and E.N. Fish
[Abstract]
[Full
text article]
Immunological Mechanisms of Interleukin-2
(IL-2) Treatment in HIV/AIDS Disease Pp.
40-45
C. Tincati, A. d’Arminio Monforte
and G. Marchetti
[Abstract]
[Full
text article]
Peroxisome Proliferator-Activated Receptor
(PPAR)β/δ:
A New Potential Therapeutic Target for the Treatment of Metabolic
Syndrome Pp. 46-55
Teresa Coll, Ricardo Rodríguez-Calvo,
Emma Barroso, Lucía Serrano, Elena Eyre, Xavier Palomer
and Manuel Vázquez-Carrera
[Abstract]
[Full
text article]
Molecular Basis of Cardioprotection by
Erythropoietin Pp. 56-69
D. Burger, A. Xenocostas and Q.P.
Feng
[Abstract]
[Full
text article]
p75NTR as a Therapeutic Target for Neuropsychiatric
Diseases Pp. 70-76
Takashi Fujii and Hiroshi Kunugi
[Abstract]
[Full
text article]
Altered Glutamate Neurotransmission and Behaviour
in Dementia: Evidence from Studies of Memantine Pp.
77-82
P.T. Francis
[Abstract]
[Full
text article]
Group I Metabotropic Glutamate Receptors:
Involvement in Drug-Seeking and Drug-Induced Plasticity
Pp. 83-94
M.K. Bird and A.J. Lawrence
[Abstract]
[Full
text article]
Biochemical, Molecular and Epigenetic
Mechanisms of Valproic Acid Neuroprotection Pp.
95-109
Barbara Monti, Elisabetta Polazzi and
Antonio Contestabile
[Abstract]
[Full
text article]
Personalised Genetic Intervention for
Duchenne Muscular Dystrophy: Antisense Oligomers and Exon
Skipping Pp. 110-121
Chalermchai Mitrpant, Sue Fletcher and
Steve D. Wilton
[Abstract]
[Full
text article]
Pharmacological Countermeasures for the
Acute Radiation Syndrome Pp. 122-133
Mang Xiao and Mark H. Whitnall
[Abstract]
[Full
text article]
The Role of the Endogenous Cannabinoid
System in Peripheral Analgesia Pp. 134-139
Josée Guindon and Pierre
Beaulieu
[Abstract][Full
text article]
Abstracts
[Back to top]
Mechanisms of Non-Opioid Analgesics Beyond Cyclooxygenase
Enzyme Inhibition
May Hamza and Raymond A. Dionne
[Full
text article]
Non-opioid analgesics including both selective and non-selective
cyclooxygenase (COX) inhibitors and acetaminophen are the
most widely used treatments for pain. Inhibition of COX is
thought to be largely responsible for both the therapeutic
and adverse effects of this class of drugs. Accumulating evidence
over the past two decades has demonstrated effects of non-opioids
beyond the inhibition of COX and prostaglandin synthesis that
might also explain their therapeutic and adverse effects.
These include their interaction with endocannabinoids, nitric
oxide, monoaminergic, and cholinergic systems. Moreover, the
recent development of microarray technology that allows the
study of human gene expression suggests multiple pathways
that may be related to the analgesic and anti-inflammatory
effects of non-opioids. The present review will discuss the
multiple actions of non-opioids and their interactions with
these systems during inflammation and pain, suggesting that
COX inhibition is an incomplete explanation for the actions
of non-opioids and proposes the involvement of multiple selective
targets for their analgesic, as well as, their adverse effects.
[Back to top]
Induced Pluripotent Stem Cells, New Tools for Drug Discovery
and New Hope for Stem Cell Therapies
Yanhong Shi
[Full
text article]
Somatic cell nuclear transfer or therapeutic cloning
has provided great hope for stem cell-based therapies. However,
therapeutic cloning has been experiencing both ethical and
technical difficulties. Recent breakthrough studies using
a combination of four factors to reprogram human somatic cells
into pluripotent stem cells without using embryos or eggs
have led to an important revolution in stem cell research.
Comparative analysis of human induced pluripotent stem cells
and human embryonic stem cells using assays for morphology,
cell surface marker expression, gene expression profiling,
epigenetic status, and differentiation potential have revealed
a remarkable degree of similarity between these two pluripotent
stem cell types. This mini-review summarizes these ground-breaking
studies. These advances in reprogramming will enable the creation
of patient-specific stem cell lines to study various disease
mechanisms. The cellular models created will provide valuable
tools for drug discovery. Furthermore, this reprogramming
system provides great potential to design customized patient-specific
stem cell therapies with economic feasibility.
[Back to top]
Regulation of Transcription Factors by Heterotrimeric G Proteins
M.K.C. Ho, Y. Su, W.W.S. Yeung and
Y.H. Wong
[Full
text article]
Lessons from viral hijacks of cells and cancer biology
suggest that the activation of G protein-coupled receptors
(GPCRs) often results in the modulation of various transcription
factors and cofactors. Since drugs acting on GPCRs represent
a significant portion of therapeutic agents currently in use,
it is important to understand the actions of GPCRs on gene
expression. GPCRs and their associated heterotrimeric G proteins
are known to regulate gene transcription through complex signaling
networks. The G protein-mediated signaling cascades have been
extensively studied and accumulating evidence indicates that
the four subfamilies of G proteins may utilize both common
and unique pathways for transcriptional regulation. This review
aims to provide a contemporary account of our understanding
on the regulation of transcription factors by GPCRs, with
a special emphasis on specific regulations of transcription
factors such as STAT3 and NF-κB
by individual G protein subfamilies. Functional impacts of
the signal integration between different pathways and the
contributions by other GPCR-interacting molecules will also
be briefly discussed.
[Back to top]
Antiviral Strategies: The Present and Beyond
J.D. Burke and E.N. Fish
[Full
text article]
Historically, vaccine strategies have proven to be most
effective at eradicating the targeted virus infections. With
the advent of new or re-emerging altered viruses, some of
which jump species to infect humans, the threat of viral pandemics
exists. The protracted time to develop a vaccine during a
pandemic necessitates using antiviral drugs in the intervening
months prior to vaccine availability. Antiviral drugs that
are pathogen specific, for example Amantidine, Tamiflu®
and Relenza®,
targeted against influenza viruses, are associated with the
emergence of virus strains that are drug resistant. The use
of ribavirin, a more broad spectrum antiviral, in combination
therapies directed against influenza and hepatitis C virus,
has proven effective, albeit to a modest extent. Attention
is focused on the potential use of interferons (IFN)-α/β
as broad spectrum antivirals in acute infections, to invoke
both direct antiviral effects against viruses and activation
of specific immune effector cells.
[Back to top]
Immunological Mechanisms of Interleukin-2 (IL-2) Treatment
in HIV/AIDS Disease
C. Tincati, A. d’Arminio Monforte
and G. Marchetti
[Full
text article]
HIV establishes a chronic infection that is marked by
the progressive depletion of CD4+ T-cells, yet the mechanisms
by which this depletion arises are a matter of controversy.
Evidence is accumulating that T CD4+ depletion is not effected
solely by virus-mediated killing and that mechanisms involving
T-cell dynamics play a major role in the pathogenesis of HIV
infection. Hence antiretroviral therapy, by controlling viral
replication alone, invariably fails to achieve the broadest
immune reconstitution. This issue has strengthened the rationale
to widely explore new adjuvant immunotherapy. Most work has
been performed on IL-2, given its potential to correct HIV-driven
immune defects, possibly translating in a more effective immune
competency.
Important insights stem from the IL-2-mediated immune reconstitution
pattern, with a rise in peripheral turnover and thymopoiesis,
IL-7 synthesis and functional markers, resulting in the correction
of the skewed T-cell immunophenotype and cytokine milieu.
Combined, these findings suggest that IL-2 has a beneficial
effect in correcting the severe disruption in T-cell homeostasis
induced by HIV, through the interaction with T-cells and cytokine
microenvironment. However, whether or not these immunologic
effects translate in an actual immunologic competency and
therefore clinical benefit, still awaits demonstration from
ongoing large, controlled clinical studies.
[Back to top]
Peroxisome Proliferator-Activated Receptor (PPAR)β/δ:
A New Potential Therapeutic Target for the Treatment of Metabolic
Syndrome
Teresa Coll, Ricardo Rodríguez-Calvo,
Emma Barroso, Lucía Serrano, Elena Eyre, Xavier Palomer
and Manuel Vázquez-Carrera
[Full
text article]
Metabolic syndrome is defined as the clustering of multiple
metabolic abnormalities, including abdominal obesity, dyslipidemia
(high serum triglycerides and low serum HDL-cholesterol levels),
glucose intolerance and hypertension. The pathophysiology
underlying metabolic syndrome involves a complex interaction
of crucial factors, but two of these, insulin resistance and
obesity (especially visceral obesity), play a major role.
The nuclear receptors Peroxisome Proliferator-Activated Receptors
(PPAR)α
and PPARγ
are therapeutic targets for hypertriglyceridemia and insulin
resistance, respectively. Evidence is now emerging that the
PPARβ/δ
isotype is a potential pharmacological target for the treatment
of disorders associated with metabolic syndrome. PPARβ/δ
activation increases lipid catabolism in skeletal muscle,
heart and adipose tissue and improves the serum lipid profile
and insulin sensitivity in several animal models. In addition,
PPARβ/δ
ligands prevent weight gain and suppress macrophage-derived
inflammation. These data are promising and indicate that PPARβ/δ
ligands may become a therapeutic option for the treatment
of metabolic syndrome. However, clinical trials in humans
as-sessing the efficacy and safety of these drugs should confirm
these promising perspectives in the treatment of the metabolic
syndrome.
[Back to top]
Molecular Basis of Cardioprotection by Erythropoietin
D. Burger, A. Xenocostas and Q.P.
Feng
[Full
text article]
Erythropoietin (EPO), a glycoprotein essential for red
blood cell production acts on several non-erythropoietic tissues.
The EPO receptor (EPOR) is expressed in a variety of cell
types including neurons, endothelial cells, and cardiomyocytes.
Recently, a number of reports have indicated that EPO preserves
heart function in models of cardiac ischemia-reperfusion (I/R)
injury. A diverse range of cellular/physiological processes
is modulated by EPO and are thought to play a role in the
preservation of heart function. In vivo, reductions
in infarct size, apoptosis, oxidative stress, and inflammation
have been reported. More recently, increases in angiogenesis
and reductions in arrhythmias have been implicated in the
cardioprotective effects of EPO. In vitro, EPO reduces
apoptosis, oxidative stress, and inflammation. These cardioprotective
effects appear to be mediated by a receptor interaction that
is distinct from that responsible for EPO’s erythropoietic
effects. Downstream of receptor interactions, the activation
of phosphatidylinositol-3 kinase (PI3-kinase) and Akt appear
to mediate many of EPO’s cardioprotective effects. However,
there is emerging evidence for Akt-independent mechanisms
of cardioprotection including the inhibition of glycogen synthase
kinase 3β,
as well as the activation of potassium channels, protein kinase
C, and protein kinases such as ERK1/2. This review focuses
on the effects of EPO in the heart and the molecular mechanisms
by which EPO achieves its cardioprotective effects.
[Back to top]
p75NTR as a Therapeutic Target for Neuropsychiatric Diseases
Takashi Fujii and Hiroshi Kunugi
[Full
text article]
The p75 neurotrophin receptor (p75NTR) was originally
identified as a low-affinity receptor for neurotrophins. Recent
studies have revealed that p75NTR can promote cell death or
survival and modulate neurite outgrowth depending on the operative
ligands and co-receptors. Up-regulation and ligand activation
of p75NTR have been shown to be involved in neuronal cell
death in cultured cells and animal models of neurodegenerative
diseases. The levels of proneurotrophins, which bind to p75NTR
to promote neuronal death, have been found to be increased
in postmortem brains of patients with Alzheimer's disease.
Furthermore, there is some evidence for the involvement of
this molecule in psychiatric diseases, such as depression
and schizophrenia. Mice lacking p75NTR have been
shown to have several alterations in central nervous system
and cognitive function. Notably, recent progress in genome-based
drug discovery has enabled the identification of peptides
and non-peptide small molecules targeting p75NTR, which may
be potentially beneficial in the treatment of neuropsychiatric
diseases. In this review, we focus on recent findings on p75NTR
as a therapeutic target for neuropsychiatric diseases.
[Back to top]
Altered Glutamate Neurotransmission and Behaviour
in Dementia: Evidence from Studies of Memantine
P.T. Francis
[Full
text article]
Behavioural symptoms are a significant problem in Alzheimer’s
disease (AD). Symptoms including agitation/aggression and
psychosis reduce patient quality of life, significantly increase
caregiver burden, and often trigger nursing home placement.
Underlying changes in the serotonergic, noradrenergic and
cholinergic systems have been linked to some behavioural problems,
however, the use of antipsychotics in this population has
been associated with significant safety concerns.
A role for the glutamate system in schizophrenia, as well
as in anxiety and depression, has been suggested, and evidence
is emerging for a role for dysfunctional glutamate neurotransmission
(via N-methyl-D-aspartate (NMDA) receptors) in certain
behavioural changes in de-mentia. For example, the NMDA receptor
antagonist, memantine has been shown to improve cognition,
function (activities of daily liv-ing, ADLs) and, more recently,
agitation/aggression, and delusions in AD patients. To date,
little information is available regarding the neurochemical
basis of agitation/aggression. However, the frontal and cingulate
cortices – specifically, the formation of neurofibrillary
tangles in glutamatergic pyramidal neurones of these areas
– are proposed as regional substrates of these behaviours.
Given that memantine displays a favourable tolerability profile,
it is relevant to investigate the underlying mechanism linking
memantine with the behavioural elements of AD. One hypothesis
proposes that memantine corrects dysfunctional glutamatergic
neurotransmission in the frontal and cingulate cortices, thereby
normalising pathways responsible for causing agitation. An
alternative hypothesis is based on the observation that increased
tangle formation is associated with agitation, and on recent
studies where memantine has been shown to reduce tau phosphorylation
via glycogen synthase kinase (GSK)-3 or activation
of protein phosphatase (PP)-2A, which might subsequently lead
to reduced agitation.
[Back to top]
Group I Metabotropic Glutamate Receptors: Involvement in Drug-Seeking
and Drug-Induced Plasticity
M.K. Bird and A.J. Lawrence
[Full
text article]
L-glutamate is the principal excitatory neurotransmitter at
fast synapses in the mammalian central nervous system, and
signals though a number of ionotropic and metabotropic receptors.
Among the latter are the group I metabotropic glutamate (mGlu1
and mGlu5) receptors that upon activation elevate intracellular
calcium levels through activation of the phospholipase C pathway.
The role of glutamatergic transmission in both the development
of addiction and the phenomenon of relapse that may occur
after prolonged abstinence, has come under intense scrutiny
in recent times. While both mGlu1 and mGlu5 receptors have
been implicated in certain aspects of the addictive state,
the exact roles these receptors play in this process is, as
yet, unclear. This review will introduce contemporary theories
on drug addiction, including neural circuitry, before critically
assessing the current body of knowledge on group I metabotropic
glutamate receptors in this regard. This will involve an in-depth
discussion of the distribution of these receptors in the brain,
their presence in neural pathways known or postulated to be
involved in addiction and their involvement in drug-related
behavioral paradigms. The effect of acute and chronic drug
administration on the activity and expression of group I metabotropic
glutamate receptors will be investigated, as will the effect
these receptors have on behavioral and biochemical responses
to drugs of abuse. Finally, there will be a brief discussion
on current and future therapeutic applications using our knowledge
of these receptors, and the direction that future studies
will need to take to close the gaps in our understanding.
[Back to top]
Biochemical, Molecular and Epigenetic Mechanisms of Valproic
Acid Neuroprotection
Barbara Monti, Elisabetta Polazzi and
Antonio Contestabile
[Full
text article]
Valproic acid (VPA, 2-propylpentanoic acid) has been widely
used as an antiepileptic drug and for the therapy of bipolar
disorders for several years. Its mechanism of action was initially
found to be primarily related to neurotransmission and modulation
of intracellular pathways. More recently, it emerged as an
anti-neoplastic agent as well, by acting on cell growth, differentiation
and apoptosis. Here, it mainly exerts its effect by regulating
gene expression at the molecular level, through epigenetic
mechanisms. In particular, it has been demonstrated the effect
of VPA in chromatin remodeling, as VPA directly inhibits histone
deacetylases (HDACs) activity. Interestingly, it has been
observed that these biochemical and molecular pathways are
involved not only in beneficial effect of VPA against epilepsy
and malignancies, but they are also responsible for more general
neuroprotective mechanisms. In particular, it has been demonstrated
that VPA is neuroprotective in several models of neurodegenerative
diseases. Moreover, due to the involvement of the VPA-affected
mechanisms in complex behaviors, VPA is increasingly used
as a psychotherapeutic agent. This review summarizes the more
recent data on VPA neuroprotective mechanisms at the biochemical,
molecular and epigenetic levels, focusing on both in vitro
and in vivo models of neurodegenerative diseases.
In particular, attention is paid to mechanisms by which VPA
affects neuronal survival/apoptosis and proliferation/differentiation
balance, as well as synaptic plasticity, by acting both directly
on neurons and indirectly through glial cells. Perspective
applications of the VPA neuroprotective potential in human
neurodegenerative diseases are discussed, when relevant.
[Back to top]
Personalised Genetic Intervention for
Duchenne Muscular Dystrophy: Antisense Oligomers and Exon
Skipping
Chalermchai Mitrpant, Sue Fletcher and
Steve D. Wilton
[Full
text article]
Duchenne muscular dystrophy (DMD) arises from protein-truncating
mutations in the large dystrophin gene that preclude synthesis
of a functional protein that primarily stabilizes muscle fibre
membranes. The absence of dystrophin leads to this most common
and serious form of childhood muscle-wasting. Since the identification
of the dystrophin gene in 1987, cell and gene repair or replacement
therapies have been evaluated for DMD treatment and one genetic
intervention, exon skipping, is now in clinical trials. Antisense
oligomers have been designed to redirect dystrophin splicing
patterns so that targeted exons may be removed from a defective
dystrophin pre-mRNA to either restore the reading frame of
a deletion, or excise an in-frame exon corrupted by a nonsense
mutation or micro-insertion/deletion. This review discusses
the evolution of oligomer induced exon skipping, including
in vitro applications, evaluation of different oligomer
chemistries, the treatment of animal models and alternative
exon skipping strategies involving viral expression cassettes
and ex vivo manipulation of stem cells. The discussion
culminates with the current clinical trials and the great
challenges that lie ahead. The major obstacle to the implementation
of personalised genetic treatments to address the many different
mutations that can lead to DMD, are considered to be establishing
effective treatments for the different patients and their
mutations. Furthermore, the view of regulatory authorities
in assessing preclinical data on potentially scores of different
but class-specific compounds will be of paramount importance
in expediting the clinical application of exon skipping therapy
for this serious and relentlessly progressive muscle wasting
disease.
[Back to top]
Pharmacological Countermeasures for the Acute Radiation Syndrome
Mang Xiao and Mark H. Whitnall
[Full
text article]
The acute radiation syndrome (ARS) is defined as the signs
and symptoms that occur within several months after exposure
to ionizing radiation (IR). This syndrome develops after total-
or partial-body irradiation at a relatively high dose (above
about 1 Gy in humans) and dose rate. Normal tissue injuries
induced by IR differ depending on the target organ and cell
type. Organs and cells with high sensitivity to radiation
include the skin, the hematopoietic system, the gut, the spermatogenic
cells and the vascular system. Exposure to IR causes damage
to DNA, protein, and lipids in mammalian cells, as well as
increased mitochondria-dependent generation of reactive oxygen
species (ROS), with subsequent cell cycle checkpoint arrest,
apoptosis, and stress-related responses. DNA double strand
breaks (DSBs) are a primary lethal lesion induced by IR. The
cellular response to damage is complex and relies on simultaneous
activation of a number of signaling networks. Among these,
the activation of DNA non-homologous end-joining (NHEJ) and
homologous recombination (HR), and signaling pathways containing
ataxia telangiectasia mutated (ATM), play important roles.
The transcription factor NFκB
has emerged as a pro-survival actor in response to IR in ATM
and p53-induced protein with a death domain (PIDD) cascades.
Although radiation-induced ARS has been well documented at
the clinical level, and mechanistic information is accumulating,
successful prophylaxis and treatment for ARS is problematic,
even with the use of supportive care and growth factors. There
is a pressing need to develop radiation countermeasures that
can be used both in the clinic, for small-scale incidents,
and outside the clinic, in mass casualty scenarios. In this
review we summarize recent information on intracellular and
extracellular signaling pathways relevant to radiation countermeasure
research.
[Back to top]
The Role of the Endogenous Cannabinoid System in Peripheral
Analgesia
Josée Guindon and Pierre
Beaulieu
[Full
text article]
The therapeutic potential of cannabinoids has been studied
and investigated through centuries, although many interesting
discoveries have emerged from this field in the past decades.
Indeed, peripheral analgesic effects of cannabinoids are a
new avenue of treatment since they are avoiding the deleterious
central side effects of systemic administration. Recently,
it has been demonstrated that cannabinoid receptors (more
specifically CB1 and CB2
receptors) and their endogenous ligands are present at the
peripheral level, especially in different layers of skin,
and mostly, in the epidermis and dermis. Those findings are
reinforcing and confirming the efficacy of peripheral administration
of cannabinoids used to alleviate pain in many different animal
models. However, many studies have shown that the endocannabinoid
system interacts with other receptors and pathways to modulate
pain at the peripheral level. Thereof, the main goal of this
review is to explain, in a better way, the different interactions
regarding the cannabinoid system with other cellular components
of its environment, its involvement in the modulation of pain
at the peripheral level and, more precisely, in different
layers of the skin.
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