Current Molecular Pharmacology - Volume 2, Issue 1, 2009

Post-surgical adhesion is a medical challenge, especially following abdominal and pelvic surgeries. This refers to the formation of fibrotic scars that form from connective tissue in the gynecological tract or abdominal cavity. Dysfunctional Adipose Tissue (AT) by surgical injuries and hypoxia increases the risk of post-surgical adhesion through different molecular mechanisms. Damage-Associated Molecular Patterns (DAMPs) and Hypoxia-induced factor 1 alpha (HIF-1α) produced during surgery trauma and hypoxia induce AT dysfunction to promote inflammation, oxidative stress, metabolic alterations, and profibrotic pathways, which contribute to post-surgical adhesions. HIF-1α and DAMPs can be considered therapeutic targets to prevent AT dysfunction and diminish the formation of adhesions in obese patients undergoing abdominal or pelvic surgeries.

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.

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.

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.

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.

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 HIVdriven 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.

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 assessing the efficacy and safety of these drugs should confirm these promising perspectives in the treatment of the metabolic syndrome.

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.

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.

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 dementia. For example, the NMDA receptor antagonist, memantine has been shown to improve cognition, function (activities of daily living, 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.

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.

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 VPAaffected 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.

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 microinsertion/ 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.

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.

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.