Annual Review Of Pharmacology Research Articles

Development of Potent and Selective Negative Allosteric Modulators of the Metabotropic Glutamate Receptor 2 for the Potential Treatment of Alzheimer’s Disease

AbstractBackgroundThe metabotropic glutamate receptor 2 (mGluR2) is a group II mGluR that binds glutamate and utilizes Gi/o signaling within the central nervous system (CNS) to modulate synaptic transmission and neuronal excitation.1 The alteration of basal glutamate signaling has been implicated in a variety of neurodegenerative diseases including Alzheimer’s disease (AD).2 mGluR2 has been found to be overexpressed in the hippocampal neurons of AD patients and receptor overactivation has been shown to induce plaque formation in in vitro AD models.3, 4 Thus, the utilization of a mGluR2 negative allosteric modulator (NAM) may prevent neurodegeneration. The utility of mGluR2 NAMs for neurodegenerative diseases remains unclear due to the lack of mGluR selectivity of historical compounds.1. Niswender, C.M. and P.J. Conn, Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annual review of pharmacology and toxicology, 2010. 50: p. 295‐322.2. Li, S.H., K.S. Abd‐Elrahman, and S.S.G. Ferguson, Targeting mGluR2/3 for treatment of neurodegenerative and neuropsychiatric diseases. Pharmacology & Therapeutics, 2022. 239: p. 108275.3. Lee, H.‐g., et al., Aberrant expression of metabotropic glutamate receptor 2 in the vulnerable neurons of Alzheimer’s disease. Acta Neuropathologica, 2004. 107(4): p. 365‐371.4. Caraci, F., et al., Targeting group II metabotropic glutamate (mGlu) receptors for the treatment of psychosis associated with Alzheimer’s disease: selective activation of mGlu2 receptors amplifies beta‐amyloid toxicity in cultured neurons, whereas dual activation of mGlu2 and mGlu3 receptors is neuroprotective. Mol Pharmacol, 2011. 79(3): p. 618‐26.MethodNovel mGluR2 NAMs were synthesized using an iterative library synthetic approach to improve potency, selectivity, and provide an overall sufficient drug metabolism/pharmacokinetics (DMPK) profile. Compound potency (IC50) and selectivity were evaluated in an in vitro GIRK cell‐based T1 flux assay expressing mGluR2 or mGluR3 receptors. Lead compounds were tested in in vitro plasma protein binding assays and rat in vitro and in vivo clearance values were obtained.ResultThe successful discovery and development of a potent and selective mGluR2 NAM as an in vivo tool compound to elucidate the biological effects associated with mGluR2 antagonism was achieved.ConclusionmGluR2 NAMs may be useful therapeutic agents for the potential treatment of AD and other neurodegenerative diseases.

Introduction to the Theme "New Therapeutic Targets".

"New Therapeutic Targets" is the theme of articles in the Annual Review of Pharmacology and Toxicology, Volume 59. Reviews in this volume discuss targets for a variety of conditions in need of new therapies, including type 2 diabetes, heart failure with preserved ejection fraction, obesity, thyroid-associated ophthalmopathy, tinnitus, multiple sclerosis, Parkinson's disease and other neurodegenerative diseases, pain, depression, post-traumatic stress disorder, muscle wasting diseases, cancer, and anemia associated with chronic renal disease. Numerous articles in this volume focus on the identification, validation, and utility of novel therapeutic targets, in particular, ones that involve new or unexpected molecular entities. This theme complements several previous themes, including "New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development," "Precision Medicine and Prediction in Pharmacology," and "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology."

Addiction Circuitry in the Human Brain

A major challenge in understanding substance-use disorders lies in uncovering why some individuals become addicted when exposed to drugs, whereas others do not. Although genetic, developmental, and environmental factors are recognized as major contributors to a person’s risk of becoming addicted, the neurobiological processes that underlie this vulnerability are still poorly understood. Imaging studies suggest that individual variations in key dopamine-modulated brain circuits, including circuits involved in reward, memory, executive function, and motivation, contribute to some of the differences in addiction vulnerability. A better understanding of the main circuits affected by chronic drug use and the influence of social stressors, developmental trajectories, and genetic background on these circuits is bound to lead to a better understanding of addiction and to more effective strategies for the prevention and treatment of substance-use disorders. Reprinted with permission from the Annual Review of Pharmacology and Toxicology 2012; 52:321–336

TNF-alpha, IL-4 and IL-10 cytokines induces changes in HO-1 and HDC expression in cervical cancer cells

Event Abstract Back to Event TNF-alpha, IL-4 and IL-10 cytokines induces changes in HO-1 and HDC expression in cervical cancer cells Paulina Gomez-Lomeli1, Pablo C. Ortiz-Lazareno1*, Alejandro Bravo-Cuellar1, Georgina Hernandez-Flores1, Jorge R. Dominguez-Rodriguez1, Luis F. Jave-Suarez1 and Adriana Aguilar-Lemarroy1 1 Instituto Mexicano del Seguro Social, Mexico Background Chronic infection with human papilloma virus (HPV) has been associated as an important factor in generating cancer. E6 and E7 viral proteins are involved in cell transformation. Likewise tumor cells generate escape mechanisms as the expression of molecules that regulate the immune response. HDC and HO-1 exert anti-apoptotic functions. These enzymes may represent another mechanism of resistance in cervical cancer cells. Objectives. We analyzed the gene and protein expression of heme oxygenase (HO-1) and histidine decarboxylase (HDC) enzymes in HPV+ HeLa and SiHa cervical cancer cell lines and HPV- C33A cancer cells treated with TNF-α, I-4 and IL-10 cytokines. Methods HeLa, SiHa and C33A cervical cancer cells were treated with pro and anti-inflammatory cytokines; mRNA was extracted and analyzed expression of HO1 and HDC by real-time PCR. Protein expression was assessed by flow cytometry. Results Cytokines treatment induces a downregulation in HDC gene expression in HPV+ cancer cells in comparison with untreated tumor cells. In HeLa and SiHa cells this gene is downregulated whereas in C33A cancer cells we observed upregulation of HDC gene. In general HDC and HO-1 protein expression was reduced in cancer cells treated with pro and anti-inflammatory cytokines. Conclusions HDC and HO-1 protein expression is modified when the cells were treated with cytokines. In HeLa, SiHa and C33 cancer cells the expression of these enzymes is similar, however at the gene level the behavior is different between cancer cell lines, and this could be due to the presence of HPV infection in some cancer cells. References Moody, C. A. and L. A. Laimins (2010). "Human papillomavirus oncoproteins: pathways to transformation." Nat Rev Cancer 10(8): 550-560. Kareva, I. and P. Hahnfeldt (2013). "The Emerging "Hallmarks" of Metabolic Reprogramming and Immune Evasion: Distinct or Linked?" Cancer Res Gozzelino, R., et al. (2010). "Mechanisms of Cell Protection by Heme Oxygenase-1." Annual Review of Pharmacology and Toxicology 50(1): 323-354. Ichikawa, A., et al. (2010). "Molecular biology of histidine decarboxylase and prostaglandin receptors." Proceedings of the Japan Academy, Series B 86(8): 848-866. Keywords: Heme-oxynenase 1, Histidine Decarboxylase, Cervical cancer cells, tNF-alpha, Anti-inflammatory cytokines Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Adaptive Immunity Citation: Gomez-Lomeli P, Ortiz-Lazareno PC, Bravo-Cuellar A, Hernandez-Flores G, Dominguez-Rodriguez JR, Jave-Suarez LF and Aguilar-Lemarroy A (2013). TNF-alpha, IL-4 and IL-10 cytokines induces changes in HO-1 and HDC expression in cervical cancer cells. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00634 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 11 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Pablo C Ortiz-Lazareno, Instituto Mexicano del Seguro Social, Guadalajara, Mexico, pablolazareno@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Paulina Gomez-Lomeli Pablo C Ortiz-Lazareno Alejandro Bravo-Cuellar Georgina Hernandez-Flores Jorge R Dominguez-Rodriguez Luis F Jave-Suarez Adriana Aguilar-Lemarroy Google Paulina Gomez-Lomeli Pablo C Ortiz-Lazareno Alejandro Bravo-Cuellar Georgina Hernandez-Flores Jorge R Dominguez-Rodriguez Luis F Jave-Suarez Adriana Aguilar-Lemarroy Google Scholar Paulina Gomez-Lomeli Pablo C Ortiz-Lazareno Alejandro Bravo-Cuellar Georgina Hernandez-Flores Jorge R Dominguez-Rodriguez Luis F Jave-Suarez Adriana Aguilar-Lemarroy PubMed Paulina Gomez-Lomeli Pablo C Ortiz-Lazareno Alejandro Bravo-Cuellar Georgina Hernandez-Flores Jorge R Dominguez-Rodriguez Luis F Jave-Suarez Adriana Aguilar-Lemarroy Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

NIEHS's New Strategic Plan

I am pleased to present “our” new strategic plan for the National Institute of Environmental Health Sciences (NIEHS 2012). I say that it’s “our” plan because the entire document reflects tremendous thought, discussion, and sharing of ideas by hundreds of scientists and community stakeholders, and it speaks to the entire field of environmental health research. This plan is about what we will strive to accomplish together as we devote ourselves to research that, in my opinion, has the greatest chance for preventing disease and for improving health throughout the world. As reflected in the new strategic plan (NIEHS 2012), the NIEHS has a fresh vision, not because our values have changed but because our research has been so successful—and many of you have made a huge contribution to that progress. New technologies and increasing knowledge bring exciting new opportunities each and every year. The NIEHS’s new strategic plan builds upon the accomplishments and vision that came before. The NIEHS has come a long way in making environmental health research responsive to the needs and concerns of the American people— to make environmental health part of the public health debate. This continues to be a source of motivation and purpose for NIEHS staff and our research partners. Environmental justice is an everlasting core value for NIEHS research. In the past few years, we at the NIEHS have made some important progress in exposure science, supporting new technologies for sensor devices and bioinformatics. We have been embracing new science such as epigenetics and exposure phenotyping, focusing on interdisciplinary research and translational research. In addition, our clinical research unit is now up and running. As the NIEHS moves forward, our overall goal is to make the institute, including the National Toxicology Program (NTP), the foremost trusted source of environmental health knowledge, leading the field in innovation and the application of research to solve health problems. Our new vision statement (NIEHS 2012) captures our collective dreams and aspirations, and reflects our strong commitment to making a real difference: The vision of the National Institute of Environmental Health Sciences is to provide global leadership for innovative research that improves public health by preventing disease and disability from our environment. What this means in practical terms is that we are pursuing some of the “big influences” that have been understudied, all of which interact with traditional environmental exposures: the microbiome, for example, and inflammation pathways, immunological pathways, nutrition, and epigenetic processes. We also want to lead the process of defining the “exposome,” which is the totality of exposure encountered by humans. We have elevated the NTP to the divisional level within the NIEHS. And we will continue to integrate our toxicology research with our excellent basic and translational science programs, not because I am a toxicologist but because the NTP is a problem-solving program—a truly translational component of the NIEHS. For example, the NTP is part of our consortium on bisphenol A, contributing to the scientific deliberations, right along with our intramural scientists and our grantees. The NTP is leading the Tox21 initiative along with the National Institute of Health’s National Center for Comparative Genomics, the U.S. Environmental Protection Agency, and the Food and Drug Administration. This high throughput testing program shows great promise not only as a new and faster method but also for moving toxicology into a predictive science. The NTP is moving beyond the traditional approaches of testing one chemical at a time and are taking on the significant challenge of evaluating mixtures. We are also looking at the effects of exposures throughout the life span, expanding our research and testing to include prenatal exposures and how they may link to adult disease. It is clear that there are multiple windows of susceptibility and that exposures early in life may have long-lasting consequences to both health and disease. Finally, the antiquated idea that the dose makes the poison is overly simplistic. The newest research clearly shows that biology is affected by low doses of chemicals, often within the range of general population exposure, and that these biological changes can be harmful, especially during periods of development. Therefore, low-dose research must go hand in hand with our life-span approach. The NIEHS’s job doesn’t stop with the publication of scientific results. We also have an obligation to help translate the nation’s research investment into public health intervention, new policy, and preventive clinical practice. To be successful, we at the NIEHS need to conduct and support the best science, whether it is led by an individual researcher or a multidisiplinary team, and this means working together with all of our partners. We thank everyone who joined us in our strategic planning process. We appreciate your commitment and support.

Aldosterone Promotes Thrombosis Formation After Arterial Injury in Mice

To the Editor: The renin/angiotensin/aldosterone system (RAAS) has been broadly implicated in the pathogenesis of cardiovascular disease.1 Angiotensin converting enzyme (ACE) inhibitors have been shown to be beneficial in reducing cardiovascular events.2 The specific role of aldosterone in promoting ischemic cardiovascular disease is unclear. Recent evidence suggests that subjects with primary aldosteronism are at increased risk of cardiovascular events compared with subjects with essential hypertension,3 suggesting a potential direct role of aldosterone in mediating ischemic events. Human studies have demonstrated that pharmacological blockade of aldosterone with spironolactone in congestive heart failure patients leads to reduced cardiovascular mortality, even in the presence of ACE inhibition.4 Because many cardiovascular events are attributable to thrombosis in the setting of atherosclerosis, we used an animal model to directly determine the effect of elevated aldosterone on atherosclerosis as well as arterial thrombus formation after …

It’s Renin in the Brain

Since the first description of renin, angiotensinogen and angiotensin as well as converting enzyme and angiotensin receptors in the brain exactly 30 years ago,1–5⇓⇓⇓⇓ there was a heated debate, whether an endogenous intrinsic brain renin- angiotensin system (RAS) exists or not.6,7⇓ For a long time, the “believers” of local angiotensin II generation by the brain RAS were in a minority. Even at a symposium 1981, celebrating the 10-year anniversary of the discovery of the brain RAS, there was skepticism and the question whether the “renin-like” enzyme in brain was identical with cathepsins, tonin, or other proteases was a matter of debate. Historically, it is interesting that the presence in the brain of other classically peripheral peptides such as insulin, glucagon, and substance P was accepted without identification of the local synthetic pathway and less controversial than angiotensin as neuropeptide. Open letters, public debates, and personal accusations nourished sometimes emotional controversy whether angiotensin could be generated locally in tissue. The brain was a model for angiotensin generating pathways in other extrarenal tissues because the blood-brain barrier, which is impermeable for proteins and peptides, made it more unlikely that the RAS components measured in the brain were contaminations from the plasma. Angiotensin has extremely powerful effects on the brain that synergistically increase blood volume and blood pressure, eg, by stimulation of water intake and salt appetite, release of various pituitary hormones, increase of sympathetic tone, and decrease of baroreceptor reflex.7 The local generation of angiotensin II in the brain by an endogenous intrinsic RAS could therefore be extremely important for cardiovascular control and beyond. With the advent of transgenic technology, novel approaches to study the mechanistic and functional aspects of the brain RAS became available. Renin and angiotensinogen could be overexpressed or ablated …

Nitric oxide in plants: the history is just beginning

ABSTRACTNitric oxide (NO) is a bioactive molecule that exerts a number of diverse activities in phylogenetically distant species, as well as opposing effects in related biological systems. It was firstly described in mammals as a major messenger in the cardiovascular, immune and nervous system, in which it plays regulatory, signalling, cytoprotective and cytotoxic effects (Ignarro, Annual Review of Pharmacology and Toxicology 30, 535–560, 1990; Anbar, Experientia 51, 545–550, 1995). This versatility is mainly achieved through interactions with targets via either a redox or an additive chemistry (Stamler, Cell 78, 931–936, 1994). For this reason, metal‐ and thiol‐containing proteins serve as major target sites for NO: these include signalling proteins, receptors, enzymes, transcription factors and DNA, among others. Furthermore, NO is a small, highly diffusible molecule. It rapidly crosses biological membranes and triggers various different processes in a short period of time. In this context, NO can co‐ordinate and regulate cellular functions of microsomes and organelles such as mitochondria. The ubiquity of NO reactions, as well as the finding that the biochemical and molecular mechanisms underlying many physiological processes are well conserved between diverse species, have opened the exploration of NO chemistry in different organisms. Among these, plants were not the exception. The research in plants has been focused on three main fields: (i) the search for NO or any source of NO generation; (ii) the examination of the effects of NO upon exogenous treatments; and (iii) the search for the same molecules involved in NO‐sensitive transduction pathways as in animals (e.g. cGMP, Ca2+, calmodulin). As it is evident from this review, recent progress on NO functionality in plants has been impressive. With the use of biochemistry, molecular genetics and structural biology, together with classical physiological approaches, an explosion of new discoveries will surely begin. It is certainly a good time for plant biologists.

Presynaptic inhibitory action of a metabotropic glutamate receptor agonist on excitatory transmission in visual cortical neurons.

A family of metabotropic glutamate receptors (mGluRs) has been elucidated by molecular cloning. To study the possible modulatory role of mGluRs in synaptic transmission, we tested the effect of a mGluR agonist, (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD), on the excitatory post-synaptic currents (EPSCS) recorded from neurons in thin slices of rat visual cortex, by using the whole-cell patch-clamp method. We found that trans-ACPD markedly suppressed the evoked EPSCS without affecting the mean amplitude of spontaneous miniature EPSCS. This effect on the evoked EPSCS was blocked by a potassium channel blocker, 4-aminopyridine (4-AP) in a dose-dependent manner. We suggest that trans-ACPD presynaptically inhibits EPSCS by a mechanism involving the 4-AP-sensitive channels.

Closure of potassium M-channels by muscarinic acetylcholine-receptor stimulants requires a diffusible messenger.

The M-current (IK(M)) is a slow voltage-gated K+ current which can be inhibited by muscarinic acetylcholine-receptor (mAChR) agonists. In the present experiments we have tested whether this inhibition results from a local (membrane-delimited) interaction between the receptor and adjacent channels, or whether channel closure is mediated by a diffusible messenger. To do this, single KM(+)-channel currents were recorded from membrane patches in dissociated rat superior cervical sympathetic neurons by using cell-attached patch electrodes. Channel activity was inhibited when muscarine was applied to the cell membrane outside the patch but persisted when channels were exposed to muscarine added to the pipette solution. We conclude that a diffusible molecule (or molecules) is (are) required to induce intrapatch channel closure following activation of extra-patch receptors.

Behavioural analysis of addiction: what future does it have?

British Journal of AddictionVolume 83, Issue 9 p. 991-993 Free Access Behavioural Anylisis of Addiction: what future does it have? Ian Stolerman PH.D., Ian Stolerman PH.D. Institute of Psychiatry, De Crespigny Park, London SE5 8AF, United KingdomSearch for more papers by this author Ian Stolerman PH.D., Ian Stolerman PH.D. Institute of Psychiatry, De Crespigny Park, London SE5 8AF, United KingdomSearch for more papers by this author First published: September 1988 https://doi.org/10.1111/j.1360-0443.1988.tb00521.xCitations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References 1 Schuster, C. R. & Thompson, T. (1969) Self-administration of and behavioral dependence on drugs, Annual Review of Pharmacology, 9, pp. 483– 502. 2 S. R. Goldberg & I. P. Stolerman, (Eds) (1986) Behavioral analysis of drug dependence ( New York , Academic Press). 3 Yanagrra, T. & Takahashi, S. (1973) Dependence liability of several sedative-hypnotic agents evaluated in monkeys. Journal of Pharmacology and Experimental Therapeutics, 185, pp. 307– 316. 4 Wlklbr, A. (1971) Present status of the concept of drug dependence. Psychological Medicine, 1, pp. 377– 380. 5 De Wit, H. & Stewart, J. (1983) Drug reinstatement of heroin-reinforced responding in the rat, Psychopharmacology, 79, pp. 29– 31. 6 Koob, G. F. & Goeders, N. E. (1988) Neuroanatomical basis of drug self-administration, Oxford Reviews in Psychopharmacology, Vol. 1: Neuropharmacological Basis of Reward, pp. 214– 263 ( Oxford , Clarendon Press). 7 Schuster, C. R. & Johanson, C. E. (1985) Efficacy, dependence potential and neurotoxicity of anorectic drugs, in: L. S. Sbiden & R. L. Balster, (Eds) Behavioral Pharmacology: the present status, pp. 263– 279 ( New York , Alan R. Liss). Citing Literature Volume83, Issue9September 1988Pages 991-993 ReferencesRelatedInformation

Annual review of pharmacology and toxicology, Volume 23. Edited by Robert George, Ronald Okun, and Arthur K. Cho. Annual Reviews Inc., 4139 El Camino Way, Palo Alto, CA 94306. 1983. 713 pp. 15 × 22 cm. Price $27.00

Annual review of pharmacology and toxicology, Volume 23. Edited by Robert George, Ronald Okun, and Arthur K. Cho. Annual Reviews Inc., 4139 El Camino Way, Palo Alto, CA 94306. 1983. 713 pp. 15 × 22 cm. Price $27.00

Annual Review of Pharmacology and Toxicology. Vol. 22

Annual Review of Pharmacology and Toxicology. Vol. 22

Annual Review of Pharmacology and Toxicology

Annual Review of Pharmacology and Toxicology

Annual Review of Pharmacology and Toxicology

Annual Review of Pharmacology and Toxicology

Annual Review of Pharmacology,

This book represents another valuable volume in a series that has been dedicated to presenting the most current information available in various areas of pharmacology. A record 31 articles reflect the many facets of pharmacology, ranging from a chapter entitled Rudolf Buchheim and the Beginning of Pharmacology As a Science to a consideration of the Application of Quantum Chemistry to Drugs and Their Interactions. Unlike many review articles that are written so that only those actively working in the area can decipher the myriad of information presented, the various chapters in this volume are, in general, very readable and can be enjoyed by those unfamiliar with the particular topic. This reviewer also found the presence of two or more articles on related topics contribute to the comprehensive nature of the volume. Articles on the factors involved in the teratogenicity of drugs, perinatal pharmacology, and mechanisms of drug toxicity compliment each

Annual Review of Pharmacology

Annual Review of Pharmacology

Annual Review of Pharmacology

Annual Review of Pharmacology

Cyclic AMP and Cyclic GMP

A chapter on Cyclic AMP and Drug Action has already been published in Annual Review of Pharmacology (1). In spite of its restrictive title, this paper covered most of the knowledge about the biochemical and biological effects of cAMP that was available in 1969. During the last four years, investigations of cAMP and cGMP have continued at an accelerated rate. Due to the restriction in the number of pages, the present review had to be selective and not exhaustive. We wanted to avoid a mere compilation of bibliographic references. The bibliography is therefore incomplete and only certain areas, which seemed to the author of special interest, have been described.

Annual Review of Pharmacology

Annual Review of Pharmacology