Showing papers in "Pharmacological Reviews in 2008"

Pharmacological and Clinical Aspects of Heme Oxygenase

Abstract: This review is intended to stimulate interest in the effect of increased expression of heme oxygenase-1 (HO-1) protein and increased levels of HO activity on normal and pathological states. The HO system includes the heme catabolic pathway, comprising HO and biliverdin reductase, and the products of heme degradation, carbon monoxide (CO), iron, and biliverdin/bilirubin. The role of the HO system in diabetes, inflammation, heart disease, hypertension, neurological disorders, transplantation, endotoxemia and other pathologies is a burgeoning area of research. This review focuses on the clinical potential of increased levels of HO-1 protein and HO activity to ameliorate tissue injury. The use of pharmacological and genetic probes to manipulate HO, leading to new insights into the complex relationship of the HO system with biological and pathological phenomena under investigation, is reviewed. This information is critical in both drug development and the implementation of clinical approaches to moderate and to alleviate the numerous chronic disorders in humans affected by perturbations in the HO system.

International Union of Pharmacology. LXX. Subtypes of γ-Aminobutyric AcidA Receptors: Classification on the Basis of Subunit Composition, Pharmacology, and Function. Update

Abstract: In this review we attempt to summarize experimental evidence on the existence of defined native GABA(A) receptor subtypes and to produce a list of receptors that actually seem to exist according to current knowledge. This will serve to update the most recent classification of GABA(A) receptors (Pharmacol Rev 50:291-313, 1998) approved by the Nomenclature Committee of the International Union of Pharmacology. GABA(A) receptors are chloride channels that mediate the major form of fast inhibitory neurotransmission in the central nervous system. They are members of the Cys-loop pentameric ligand-gated ion channel (LGIC) superfamily and share structural and functional homology with other members of that family. GABA(A) receptors are assembled from a family of 19 homologous subunit gene products and form numerous, mostly hetero-oligomeric, pentamers. Such receptor subtypes with properties that depend on subunit composition vary in topography and ontogeny, in cellular and subcellular localization, in their role in brain circuits and behaviors, in their mechanisms of regulation, and in their pharmacology. We propose several criteria, which can be applied to all the members of the LGIC superfamily, for including a receptor subtype on a list of native hetero-oligomeric subtypes. With these criteria, we develop a working GABA(A) receptor list, which currently includes 26 members, but will undoubtedly be modified and grow as information expands. The list is divided into three categories of native receptor subtypes: "identified," "existence with high probability," and "tentative."

The Role of Incretins in Glucose Homeostasis and Diabetes Treatment

Abstract: Incretins are gut hormones that are secreted from enteroendocrine cells into the blood within minutes after eating. One of their many physiological roles is to regulate the amount of insulin that is secreted after eating. In this manner, as well as others to be described in this review, their final common raison d'etre is to aid in disposal of the products of digestion. There are two incretins, known as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1), that share many common actions in the pancreas but have distinct actions outside of the pancreas. Both incretins are rapidly deactivated by an enzyme called dipeptidyl peptidase 4 (DPP4). A lack of secretion of incretins or an increase in their clearance are not pathogenic factors in diabetes. However, in type 2 diabetes (T2DM), GIP no longer modulates glucose-dependent insulin secretion, even at supraphysiological (pharmacological) plasma levels, and therefore GIP incompetence is detrimental to beta-cell function, especially after eating. GLP-1, on the other hand, is still insulinotropic in T2DM, and this has led to the development of compounds that activate the GLP-1 receptor with a view to improving insulin secretion. Since 2005, two new classes of drugs based on incretin action have been approved for lowering blood glucose levels in T2DM: an incretin mimetic (exenatide, which is a potent long-acting agonist of the GLP-1 receptor) and an incretin enhancer (sitagliptin, which is a DPP4 inhibitor). Exenatide is injected subcutaneously twice daily and its use leads to lower blood glucose and higher insulin levels, especially in the fed state. There is glucose-dependency to its insulin secretory capacity, making it unlikely to cause low blood sugars (hypoglycemia). DPP4 inhibitors are orally active and they increase endogenous blood levels of active incretins, thus leading to prolonged incretin action. The elevated levels of GLP-1 are thought to be the mechanism underlying their blood glucose-lowering effects.

“Inside-Out” Signaling of Sphingosine-1-Phosphate: Therapeutic Targets

Abstract: Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in many critical cellular processes including proliferation, survival, and migration, as well as angiogenesis and allergic responses. S1P levels inside cells are tightly regulated by the balance between its synthesis by sphingosine kinases and degradation. S1P is interconvertible with ceramide, which is a critical mediator of apoptosis. It has been postulated that the ratio between S1P and ceramide determines cell fate. Activation of sphingosine kinase by a variety of agonists increases intracellular S1P, which in turn can function intracellularly as a second messenger or be secreted out of the cell and act extracellularly by binding to and signaling through S1P receptors in autocrine and/or paracrine manners. Recent studies suggest that this “inside-out” signaling by S1P may play a role in many human diseases, including cancer, atherosclerosis, inflammation, and autoimmune disorders such as multiple sclerosis. In this review we summarize metabolism of S1P, mechanisms of sphingosine kinase activation, and S1P receptors and their downstream signaling pathways and examine relationships to multiple disease processes. In particular, we describe recent preclinical and clinical trials of therapies targeting S1P signaling, including 2-amino-2-propane-1,3-diol hydrochloride (FTY720, fingolimod), S1P receptor agonists, sphingosine kinase inhibitors, and anti-S1P monoclonal antibody.

Mitogen-Activated Protein (MAP) Kinase/MAP Kinase Phosphatase Regulation: Roles in Cell Growth, Death, and Cancer

Abstract: Mitogen-activated protein kinase dual-specificity phosphatase-1 (also called MKP-1, DUSP1, ERP, CL100, HVH1, PTPN10, and 3CH134) is a member of the threonine-tyrosine dual-specificity phosphatases, one of more than 100 protein tyrosine phosphatases. It was first identified approximately 20 years ago, and since that time extensive investigations into both mkp-1 mRNA and protein regulation and function in different cells, tissues, and organs have been conducted. However, no general review on the topic of MKP-1 exists. As the subject matter pertaining to MKP-1 encompasses many branches of the biomedical field, we focus on the role of this protein in cancer development and progression, highlighting the potential role of the mitogen-activated protein kinase (MAPK) family. Section II of this article elucidates the MAPK family cross-talk. Section III reviews the structure of the mkp-1 encoding gene, and the known mechanisms regulating the expression and activity of the protein. Section IV is an overview of the MAPK-specific dual-specificity phosphatases and their role in cancer. In sections V and VI, mkp-1 mRNA and protein are examined in relation to cancer biology, therapeutics, and clinical studies, including a discussion of the potential role of the MAPK family. We conclude by proposing an integrated scheme for MKP-1 and MAPK in cancer.

Vascular Actions of Estrogens: Functional Implications

Abstract: The impact of estrogen exposure in preventing or treating cardiovascular disease is controversial. But it is clear that estrogen has important effects on vascular physiology and pathophysiology, with potential therapeutic implications. Therefore, the goal of this review is to summarize, using an integrated approach, current knowledge of the vascular effects of estrogen, both in humans and in experimental animals. Aspects of estrogen synthesis and receptors, as well as general mechanisms of estrogenic action are reviewed with an emphasis on issues particularly relevant to the vascular system. Recent understanding of the impact of estrogen on mitochondrial function suggests that the longer lifespan of women compared with men may depend in part on the ability of estrogen to decrease production of reactive oxygen species in mitochondria. Mechanisms by which estrogen increases endothelial vasodilator function, promotes angiogenesis, and modulates autonomic function are summarized. Key aspects of the relevant pathophysiology of inflammation, atherosclerosis, stroke, migraine, and thrombosis are reviewed concerning current knowledge of estrogenic effects. A number of emerging concepts are addressed throughout. These include the importance of estrogenic formulation and route of administration and the impact of genetic polymorphisms, either in estrogen receptors or in enzymes responsible for estrogen metabolism, on responsiveness to hormone treatment. The importance of local metabolism of estrogenic precursors and the impact of timing for initiation of treatment and its duration are also considered. Although consensus opinions are emphasized, controversial views are presented to stimulate future research.

International Union of Pharmacology. LXVIII. Mammalian Bombesin Receptors: Nomenclature, Distribution, Pharmacology, Signaling, and Functions in Normal and Disease States

Abstract: The mammalian bombesin receptor family comprises three G protein-coupled heptahelical receptors: the neuromedin B (NMB) receptor (BB1), the gastrin-releasing peptide (GRP) receptor (BB2), and the orphan receptor bombesin receptor subtype 3 (BRS-3) (BB3). Each receptor is widely distributed, especially in the gastrointestinal (GI) tract and central nervous system (CNS), and the receptors have a large range of effects in both normal physiology and pathophysiological conditions. The mammalian bombesin peptides, GRP and NMB, demonstrate a broad spectrum of pharmacological/biological responses. GRP stimulates smooth muscle contraction and GI motility, release of numerous GI hormones/neurotransmitters, and secretion and/or hormone release from the pancreas, stomach, colon, and numerous endocrine organs and has potent effects on immune cells, potent growth effects on both normal tissues and tumors, potent CNS effects, including regulation of circadian rhythm, thermoregulation; anxiety/fear responses, food intake, and numerous CNS effects on the GI tract as well as the spinal transmission of chronic pruritus. NMB causes contraction of smooth muscle, has growth effects in various tissues, has CNS effects, including effects on feeding and thermoregulation, regulates thyroid-stimulating hormone release, stimulates various CNS neurons, has behavioral effects, and has effects on spinal sensory transmission. GRP, and to a lesser extent NMB, affects growth and/or differentiation of various human tumors, including colon, prostate, lung, and some gynecologic cancers. Knockout studies show that BB3 has important effects in energy balance, glucose homeostasis, control of body weight, lung development and response to injury, tumor growth, and perhaps GI motility. This review summarizes advances in our understanding of the biology/pharmacology of these receptors, including their classification, structure, pharmacology, physiology, and role in pathophysiological conditions.

Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis

Abstract: Steatosis of the liver may arise from a variety of conditions, but the molecular basis for lipid droplet formation is poorly understood. Although a certain amount of lipid storage may even be hepatoprotective, prolonged lipid storage can result in an activation of inflammatory reactions and loss of metabolic competency. Apart from drug-induced steatosis, certain metabolic disorders associated with obesity, insulin resistance, and hyperlipidemia give also rise to nonalcoholic fatty liver diseases (NAFLD). It is noteworthy that advanced stages of nonalcoholic hepatic steatosis and steatohepatitis (NASH) result ultimately in fibrosis and cirrhosis. In this regard, the lipid droplets (LDs) have been discovered to be metabolically highly active structures that play major roles in lipid transport, sorting, and signaling cascades. In particular, LDs maintain a dynamic communication with the endoplasmic reticulum (ER) and the plasma membrane via sphingolipid-enriched domains of the plasma membrane-the lipid rafts. These microdomains frequently harbor receptor tyrosine kinases and other signaling molecules and connect extracellular events with intracellular signaling cascades. Here, we review recent knowledge on the molecular mechanisms of drug and metabolically induced hepatic steatosis and its progression to steatohepatitis (NASH). The contribution of cytokines and other signaling molecules, as well as activity of nuclear receptors, lipids, transcription factors, and endocrine mediators toward cellular dysfunction and progression of steatotic liver disease to NASH is specifically addressed, as is the cross-talk of different cell types in the pathogenesis of NAFLD. Furthermore, we provide an overview of recent therapeutic approaches in NASH therapy and discuss new as well as putative targets for pharmacological interventions.

Chemistry and Antihypertensive Effects of Tempol and Other Nitroxides

Abstract: Nitroxides can undergo one- or two-electron reduction reactions to hydroxylamines or oxammonium cations, respectively, which themselves are interconvertible, thereby providing redox metabolic actions. 4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol) is the most extensively studied nitroxide. It is a cell membrane-permeable amphilite that dismutates superoxide catalytically, facilitates hydrogen peroxide metabolism by catalase-like actions, and limits formation of toxic hydroxyl radicals produced by Fenton reactions. It is broadly effective in detoxifying these reactive oxygen species in cell and animal studies. When administered intravenously to hypertensive rodent models, tempol caused rapid and reversible dose-dependent reductions in blood pressure in 22 of 26 studies. This was accompanied by vasodilation, increased nitric oxide activity, reduced sympathetic nervous system activity at central and peripheral sites, and enhanced potassium channel conductance in blood vessels and neurons. When administered orally or by infusion over days or weeks to hypertensive rodent models, it reduced blood pressure in 59 of 68 studies. This was accompanied by correction of salt sensitivity and endothelial dysfunction and reduced agonist-evoked oxidative stress and contractility of blood vessels, reduced renal vascular resistance, and increased renal tissue oxygen tension. Thus, tempol is broadly effective in reducing blood pressure, whether given by acute intravenous injection or by prolonged administration, in a wide range of rodent models of hypertension.

Modulation of P-Glycoprotein at the Blood-Brain Barrier: Opportunities to Improve Central Nervous System Pharmacotherapy

Abstract: Pharmacotherapy of central nervous system (CNS) disorders (e.g., neurodegenerative diseases, epilepsy, brain cancer, and neuro-AIDS) is limited by the blood-brain barrier. P-glycoprotein, an ATP-driven, drug efflux transporter, is a critical element of that barrier. High level of expression, luminal membrane location, multispecificity, and high transport potency make P-glycoprotein a selective gatekeeper of the blood-brain barrier and thus a primary obstacle to drug delivery into the brain. As such, P-glycoprotein limits entry into the CNS for a large number of prescribed drugs, contributes to the poor success rate of CNS drug candidates, and probably contributes to patient-to-patient variability in response to CNS pharmacotherapy. Modulating P-glycoprotein could therefore improve drug delivery into the brain. Here we review the current understanding of signaling mechanisms responsible for the modulation of P-glycoprotein activity/expression at the blood-brain barrier with an emphasis on recent studies from our laboratories. Using intact brain capillaries from rats and mice, we have identified multiple extracellular and intracellular signals that regulate this transporter; several signaling pathways have been mapped. Three pathways are triggered by elements of the brain's innate immune response, one by glutamate, one by xenobiotic-nuclear receptor (pregnane X receptor) interactions, and one by elevated beta-amyloid levels. Signaling is complex, with several pathways sharing common signaling elements [tumor necrosis factor (TNF) receptor 1, endothelin (ET) B receptor, protein kinase C, and nitric-oxide synthase), suggesting a regulatory network. Several pathways include autocrine/paracrine elements, involving release of the proinflammatory cytokine, TNF-alpha, and the polypeptide hormone, ET-1. Finally, several steps in signaling are potential therapeutic targets that could be used to modulate P-glycoprotein activity in the clinic.

International Union of Pharmacology. LXXI. Free Fatty Acid Receptors FFA1, -2, and -3: Pharmacology and Pathophysiological Functions

Abstract: Identification of G protein-coupled re- ceptors that are activated by free fatty acids has led to considerable interest in their pharmacology and func- tion because of the wide range of normal physiology and disease states in which fatty acids have been im- plicated. Free fatty acid receptor (FFA) 1 is activated by medium- to long-chain fatty acids and is expressed in the insulin-producing -cells of the pancreas. Acti- vation of FFA1 has been proposed to mediate fatty acid augmentation of glucose-stimulated insulin se- cretion although it is unclear whether the known long- term detrimental effects of -cell exposure to high lev- els of fatty acids are also mediated through this receptor. The related receptors FFA2 and FFA3 are both activated by short-chain fatty acids although they have key differences in the signaling pathways they activate and tissue expression pattern. The aim of this review is to provide a comprehensive overview of the current understanding of the pharmacology and physiological role of these fatty acid receptors.

Sortase as a Target of Anti-Infective Therapy

Abstract: The rise in antibiotic-resistant bacteria is a major concern, in particular because it includes many different species of pathogenic microbes. These "superbugs" are further characterized by high levels of virulence and disease-associated mortality. There seems to be few new antibiotics in the drug discovery pipeline; recent work has sought to define and validate new drug targets. The assembly of surface proteins and pili in the cell wall envelope of Gram-positive bacteria is catalyzed by sortase. Sortase cleaves a conserved C-terminal sequence of these polypeptides to generate an acyl-enzyme intermediate. The acyl-enzyme is next resolved by nucleophilic attack by the amino groups within cell wall cross-bridges or pilin proteins, thereby covalently attaching the polypeptides to the cell wall or the next pilin subunit. Sortase substrates function as adhesins, internalins, blood clotting and immune evasion factors, and transporters for nutrients across the microbial cell wall envelope; without them, most pathogens cannot sustain an infection. Here we review what is known about sortase catalysis and surface protein function, how surface protein anchoring can be inhibited, and what prospects such inhibition may have for anti-infective therapy.

Metabotropic Glutamate 1 Receptor: Current Concepts and Perspectives

Abstract: Almost 25 years after the first report that glutamate can activate receptors coupled to heterotrimeric G-proteins, tremendous progress has been made in the field of metabotropic glutamate receptors. Now, eight members of this family of glutamate receptors, encoded by eight different genes that share distinctive structural features have been identified. The first cloned receptor, the metabotropic glutamate (mGlu) receptor mGlu1 has probably been the most extensively studied mGlu receptor, and in many respects it represents a prototypical subtype for this family of receptors. Its biochemical, anatomical, physiological, and pharmacological characteristics have been intensely investigated. Together with subtype 5, mGlu1 receptors constitute a subgroup of receptors that couple to phospholipase C and mobilize Ca(2+) from intracellular stores. Several alternatively spliced variants of mGlu1 receptors, which differ primarily in the length of their C-terminal domain and anatomical localization, have been reported. Use of a number of genetic approaches and the recent development of selective antagonists have provided a means for clarifying the role played by this receptor in a number of neuronal systems. In this article we discuss recent advancements in the pharmacology and concepts about the intracellular transduction and pathophysiological role of mGlu1 receptors and review earlier data in view of these novel findings. The impact that this new and better understanding of the specific role of these receptors may have on novel treatment strategies for a variety of neurological and psychiatric disorders is considered.

Antipsychotic Drugs: Comparison in Animal Models of Efficacy, Neurotransmitter Regulation, and Neuroprotection

Abstract: Various lines of evidence indicate the presence of progressive pathophysiological processes occurring within the brains of patients with schizophrenia. By modulating chemical neurotransmission, antipsychotic drugs may influence a variety of functions regulating neuronal resilience and viability and have the potential for neuroprotection. This article reviews the current literature describing preclinical and clinical studies that evaluate the efficacy of antipsychotic drugs, their mechanism of action and the potential of first- and second-generation antipsychotic drugs to exert effects on cellular processes that may be neuroprotective in schizophrenia. The evidence to date suggests that although all antipsychotic drugs have the ability to reduce psychotic symptoms via D2 receptor antagonism, some antipsychotics may differ in other pharmacological properties and their capacities to mitigate and possibly reverse cellular processes that may underlie the pathophysiology of schizophrenia.

Anchoring Junctions As Drug Targets: Role in Contraceptive Development

Abstract: In multicellular organisms, cell-cell interactions are mediated in part by cell junctions, which underlie tissue architecture. Throughout spermatogenesis, for instance, preleptotene leptotene spermatocytes residing in the basal compartment of the seminiferous epithelium must traverse the blood-testis barrier to enter the adluminal compartment for continued development. At the same time, germ cells must also remain attached to Sertoli cells, and numerous studies have reported extensive restructuring at the Sertoli-Sertoli and Sertoli-germ cell interface during germ cell movement across the seminiferous epithelium. Furthermore, the proteins and signaling cascades that regulate adhesion between testicular cells have been largely delineated. These findings have unveiled a number of potential “druggable” targets that can be used to induce premature release of germ cells from the seminiferous epithelium, resulting in transient infertility. Herein, we discuss a novel approach with the aim of developing a nonhormonal male contraceptive for future human use, one that involves perturbing adhesion between Sertoli and germ cells in the testis.

Vertebrate Membrane Proteins: Structure, Function, and Insights from Biophysical Approaches

Abstract: Membrane proteins are key targets for pharmacological intervention because they are vital for cellular function. Here, we analyze recent progress made in the understanding of the structure and function of membrane proteins with a focus on rhodopsin and development of atomic force microscopy techniques to study biological membranes. Membrane proteins are compartmentalized to carry out extra- and intracellular processes. Biological membranes are densely populated with membrane proteins that occupy approximately 50% of their volume. In most cases membranes contain lipid rafts, protein patches, or paracrystalline formations that lack the higher-order symmetry that would allow them to be characterized by diffraction methods. Despite many technical difficulties, several crystal structures of membrane proteins that illustrate their internal structural organization have been determined. Moreover, high-resolution atomic force microscopy, near-field scanning optical microscopy, and other lower resolution techniques have been used to investigate these structures. Single-molecule force spectroscopy tracks interactions that stabilize membrane proteins and those that switch their functional state; this spectroscopy can be applied to locate a ligand-binding site. Recent development of this technique also reveals the energy landscape of a membrane protein, defining its folding, reaction pathways, and kinetics. Future development and application of novel approaches during the coming years should provide even greater insights to the understanding of biological membrane organization and function.

International Union of Pharmacology. LXIX. Status of the calcitonin gene-related peptide subtype 2 receptor.

Abstract: Historically, calcitonin gene-related peptide (CGRP) receptors have been divided into two classes, CGRP(1) and CGRP(2). After the cloning of calcitonin receptor-like receptor (CLR) and receptor activity-modifying proteins (RAMPs), it became clear that the CGRP(1) receptor was a complex between CLR and RAMP1. It is now apparent that the CGRP(2) receptor phenotype is the result of CGRP acting at receptors for amylin and adrenomedullin. Accordingly, the term "CGRP(2)" receptor should no longer be used, and the "CGRP(1)" receptor should be known as the "CGRP" receptor.

Pharmacogenomics of G Protein-Coupled Receptor Ligands in Cardiovascular Medicine

Abstract: Agonists and antagonists of G protein-coupled receptors are important drugs for the treatment of cardiovascular disease, but the therapeutic response of any given patient remains difficult to predict because of large interindividual variability. Among the factors potentially contributing to such variability, we have reviewed the evidence for a role of pharmacodynamic pharmacogenetics (i.e., polymorphisms in the cognate receptors for such drugs as well as other proteins potentially modifying their action). Based upon the availability of data and the prevalence of use, we have focused on ligands at adrenergic and angiotensin II receptors (including the indirectly acting angiotensin-converting enzyme inhibitors). The vast majority of gene polymorphisms reviewed here have shown only inconsistent effects on drug action, which does not make these polymorphisms useful genetic markers to predict treatment responses. We conclude that considerable additional research, partly involving other types of study than those available now, will be necessary to allow a definitive judgment whether pharmacodynamic pharmacogenetic markers are useful in an individualized approach to cardiovascular therapy. Moreover, we predict that even such additional research will result in only few cases where the promise of tailored treatment can be fulfilled; however, some of these few cases may be of major clinical relevance.

Cyclic nucleotide phosphodiesterases

Abstract: Cyclic nucleotide phosphodiesterases (PDEs) are a family of enzymes that function to terminate the action of the hormone …