DOCSLIB.ORG

Monoacylglycerol Lipase Inhibition by Organophosphorus Compounds Leads to Elevation of Brain 2-Arachidonoylglycerol and the Associated Hypomotility in Mice

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Monoacylglycerol Lipase Inhibition by Organophosphorus Compounds Leads to Elevation of Brain 2-Arachidonoylglycerol and the Associated Hypomotility in Mice Toxicology and Applied Pharmacology 211 (2006) 78–83 www.elsevier.com/locate/ytaap Monoacylglycerol lipase inhibition by organophosphorus compounds leads to elevation of brain 2-arachidonoylglycerol and the associated hypomotility in mice Gary B. Quistad, Rebecka Klintenberg, Pierluigi Caboni, Shannon N. Liang, John E. Casida ⁎ Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, 115 Wellman Hall, Berkeley, CA 94720-3112, USA Received 27 September 2005; revised 24 October 2005; accepted 24 October 2005 Available online 28 November 2005 Abstract Three components of the cannabinoid system are sensitive to selected organophosphorus (OP) compounds: monoacylglycerol (MAG) lipase that hydrolyzes the major endogenous agonist 2-arachidonoylglycerol (2-AG); fatty acid amide hydrolase (FAAH) that cleaves the agonist anandamide present in smaller amounts; the CB1 receptor itself. This investigation considers which component of the cannabinoid system is the most likely contributor to OP-induced hypomotility in mice. Structure–activity studies by our laboratory and others rule against major involvement of a direct toxicant–CB1 receptor interaction for selected OPs. Attention was therefore focused on the OP sensitivities of MAG lipase and FAAH, assaying 19 structurally diverse OP chemicals (pesticides, their metabolites and designer compounds) for in vitro inhibition of both enzymes. Remarkably high potency and low selectivity is observed with three O-alkyl (C1,C2,C3) alkylphosphonofluoridates (C8,C12) (IC50 0.60–3.0 nM), five S-alkyl (C5,C7, C9) and alkyl (C10,C12) benzodioxaphosphorin oxides (IC50 0.15–5.7 nM) and one OP insecticide metabolite (chlorpyrifos oxon, IC50 34–40 nM). In ip-treated mice, the OPs at 1–30 mg/kg more potently inhibit brain FAAH than MAG lipase, but FAAH inhibition is not correlated with hypomotility. However, the alkylphosphonofluoridate-treated mice show dose-dependent increases in severity of hypomotility, inhibition of MAG lipase activity and elevation of 2-AG. Moderate to severe hypomotility is accompanied by 64 to 86% MAG lipase inhibition and about 6-fold elevation of brain 2-AG level. It therefore appears that OP-induced MAG lipase inhibition leads to elevated 2-AG and the associated hypomotility. © 2005 Elsevier Inc. All rights reserved. Keywords: 2-arachidonoylglycerol; Cannabinoid system; Fatty acid amide hydrolase; Hypomotility; Monoacylglycerol lipase; Organophosphorus Introduction endogenous agonists are 2-arachidonoylglycerol (2-AG) and anandamide, and their levels are regulated by monoacylglycerol Organophosphorus (OP) compounds interact with several (MAG) lipase and fatty acid amide hydrolase (FAAH), components of the cannabinoid system (Fig. 1). The principal respectively (Sugiura and Waku, 2000). MAG lipase and FAAH are very sensitive to methyl arachidonylfluorophos- phonate (MAFP) with 50% inhibition at 0.1 to 2 nM (Quistad et Abbreviations: AChE, acetylcholinesterase; 2-AG, 2-arachidonoylglycerol; al., 2001; Saario et al., 2004). Several OPs inhibit agonist BDPO, benzodioxaphosphorin oxide; CB1, cannabinoid receptor; CPO, chlorpyrifos oxon; DFP, diisopropyl fluorophosphate; DMSO, dimethyl binding at the cannabinoid (CB1) receptor, but the site(s) sulfoxide; EOPF, ethyl octylphosphonofluoridate; FAAH, fatty acid amide involved and significance are not known (Martin et al., 2000; hydrolase; IC50, concentration inhibiting 50% of enzyme activity; IDFP, Casida and Quistad, 2004). Most alkylphosphonofluoridates not isopropyl dodecylfluorophosphonate; MAFP, methyl arachidonylfluoropho- only prevent binding at CB1 but also inhibit FAAH to give the sphonate; MAG, monoacylglycerol; MOPF, methyl octylphosphonofluoridate; usual cannabinoid responses in rats (Martin et al., 2000). An NTE-LysoPLA, neuropathy target esterase-lysophospholipase; OG, 1(3)- oleoylglycerol; OP, organophosphorus. exception is methyl octylphosphonofluoridate [n-C8H17P(O) ⁎ Corresponding author. Fax: +1 510 642 6497. (OCH3)F, MOPF], fully potent for cannabinoid pharmacological E-mail address: [email protected] (J.E. Casida). signs but not binding to CB1. The physiological responses to 0041-008X/$ - see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.taap.2005.10.007 G.B. Quistad et al. / Toxicology and Applied Pharmacology 211 (2006) 78–83 79 Fig. 1. Some components of the cannabinoid system. MOPF are unexplained but suggested due to alternate receptor cides, their metabolites and designer compounds) elevates 2- subtypes or another mechanism (Martin et al., 2000). AG in brain, thereby resulting in OP-induced hypomotility MAG lipase is increasingly viewed as a major factor in the in a mouse model. cannabinoid system (Hohmann et al., 2005), along with FAAH (McKinney and Cravatt, 2005). MAG lipase is unique Materials and methods among the lipases in using only monoacylglycerols as substrates (Karlsson et al., 2000), and the highest levels of Chemicals. Caution: some of the compounds have high acute toxicity, and MAG lipase mRNA occur in brain regions where CB1 others are delayed neurotoxicants (Casida and Quistad, 2004; Wu and receptor is expressed (Dinh et al., 2002). MAG lipase occurs Casida, 1996). They were used under careful containment conditions. The in both cytosol and cellular membranes. Rat brain MAG OPs examined were of diverse chemical structures represented by lipase is a 33-kDa protein with 92% amino acid sequence alkylphosphonofluoridates, benzodioxaphosphorin oxide (BDPO) analogs, commercial pesticides and activated metabolites. Sources for the pesticides, identity compared to mouse adipocyte MAG lipase and is their metabolites and other candidate inhibitors (N95% purity) were as related to esterases, lysophospholipases and haloperoxidases follows: 2-AG and diisopropyl fluorophosphate (DFP) from Sigma Chemical (Dinh et al., 2002; Karlsson et al., 1997). (St. Louis, MO); chlorpyrifos oxon (CPO), paraoxon, dichlorvos, chlorpyr- Cannabinoid pharmacological effects include hypomotility, ifos and tribufos from Chem Service (West Chester, PA); profenofos from also induced by injection of 2-AG and anandamide (Mechoulam Syngenta (Greensboro, NC). The other OPs were synthesized in this laboratory: isopropyl dodecylfluorophosphonate (IDFP) and decanesulfonyl et al., 1995; Quistad et al., 2001; Sulcova et al., 1998). The fluoride (Segall et al., 2003a); ethyl octylphosphonofluoridate (EOPF) (Wu relative contribution for MAG lipase and 2-AG compared to and Casida, 1995); octanesulfonyl fluoride (Wu and Casida, 1996); stearyl- FAAH and anandamide is of considerable current interest. MAG BDPO and diazoxon (Quistad et al., 2001); other BDPOs (Wu and Casida, lipase plays the major role in vivo in modulating the 1992, 1994). MOPF was prepared by our previous method for its ethyl pharmacological activity of 2-AG as shown with FAAH- analog EOPF (Wu and Casida, 1995). Glycerol coupled via carbodiimide to [14C]oleic acid (PerkinElmer Life Sciences, Boston, MA) gave 1(3)-[14C] deficient mice which hydrolyze 2-AG at the same rate as wild- oleoylglycerol (OG) and reacted with heptadecanoyl chloride (Sigma) gave type mice (Lichtman et al., 2002). RNA interference-mediated 1(3)-heptadecanoylglycerol. silencing of MAG lipase also suggests a primary role for its degradation of 2-AG (Dinh et al., 2004). 2-AG is considered to Mouse studies. Male albino Swiss–Webster mice (27–30 g) from Harlan be the more important natural ligand at CB1 since, although 24- Laboratories (Indianapolis, IN) were maintained under standard conditions with fold less potent, it is 800-fold more abundant than anandamide in access to food and water ad libitum. The studies were carried out in accordance brain (Sugiura and Waku, 2000). 2-AG also induces a stronger with the Guiding Principles in the Use of Animals in Toxicology as adopted by 2+ the Society of Toxicology in 1989. Mice were treated ip with the test compounds rapid, transient elevation of intracellular free Ca in in dimethyl sulfoxide (DMSO) (30 μl) or DMSO alone as a control and neuroblastoma × glioma hybrid cells expressing CB1 (Sugiura maintained for 4 h. OP treatments were in a 0.3, 1, 3, 10 and 30 mg/kg series for and Waku, 2000). Increased 2-AG in brain is the fast component comparison of specific compounds at the same dose. The following of stress-induced analgesia accompanied by slower formation of hypomotility rating scheme was used to record increasingly severe signs: 0, anandamide (Hohmann et al., 2005), and 2-AG is neuroprotec- normal spontaneous motor activity; 1, reduced spontaneous motor activity with mild hindleg rigidity; 2, bradykinesia with moderate hindleg rigidity; 3, akinesia tive after brain injury (Panikashvili et al., 2001). Rapid elevation with severe hindleg rigidity. After the animal was sacrificed by cervical of 2-AG levels in brain is associated with several stress factors, dislocation while under isoflurane anesthesia, the brain was immediately including foot shock (Hohmann et al., 2005), closed-head removed and frozen (−20 °C for enzyme assays) or immediately placed in trauma (Panikashvili et al., 2001), decapitation (Sugiura et al., powdered dry ice and held at −80 °C (for 2-AG analysis). In vitro inhibition – 2001) and convulsant action (Sugiura et al., 2000). studies used Swiss Webster mouse brains from Pel-Freez (Rogers, AR). This investigation tests the hypothesis that inhibition of Enzyme assays. MAG lipase activity was determined as the release of MAG lipase
Load more

Recommended publications
  • 615 Neuroscience-Cayman-Bertin
    Thomas G. Brock, Ph.D. Introduction to Neuroscience In our first Biology classes, we learned that lipids form the membranes around cells. For many students, interests quickly moved to the intracellular constituents ‘that really matter’, or to how cells or systems work in health and disease. If there was further thought about lipids, it might have been limited to more personal issues, like an expanding waistline. It was easy to forget about lipids in the complexities of, say, Alzheimer’s Disease, where tau protein is hyperphosphorylated by a host of kinases before forming neurofibrillary tangles and amyloid precursor protein is processed by assorted secretases, ultimately aggregating to form neurodegenerating plaques. What possible role could lipids have in all this? After all, lipids just form the membranes around cells. Fortunately, neuroscientists study complex systems. Whether working at the molecular, cellular, or organismal level, the research focus always returns to the intricately interconnected bigger picture. Perhaps surprisingly, lipids keep emerging as part of the bigger picture. At least, the smaller lipids do. Many of the smaller lipids, including the cannabinoids and eicosanoids, act as paracrine hormones, modulating cell functions in a receptor-mediated fashion. In this sense, they are rather like the peptide hormones in their diversity and actions. In the neurosystem, this means that these signaling lipids determine if synapses fire or not, when cells differentiate or die, and whether tissues remain healthy or become inflamed. Returning to the question posed above about lipids in Alzheimer’s, these mediators have roles at many levels in the course of the disease, as presented in an article on page 42 of this catalog.
    [Show full text]
  • Targeting the Endocannabinoid System to Reduce Nociception
    Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2011 Targeting the endocannabinoid system to reduce nociception Lamont Booker Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Medical Pharmacology Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/2419 This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. Targeting the Endocannabinoid System to Reduce Nociception A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. By Lamont Booker Bachelor’s of Science, Fayetteville State University 2003 Master’s of Toxicology, North Carolina State University 2005 Director: Dr. Aron H. Lichtman, Professor, Pharmacology & Toxicology Virginia Commonwealth University Richmond, Virginia April 2011 Acknowledgements The author wishes to thank several people. I like to thank my advisor Dr. Aron Lichtman for taking a chance and allowing me to work under his guidance. He has been a great influence not only with project and research direction, but as an excellent example of what a mentor should be (always willing to listen, understanding the needs of each student/technician, and willing to provide a hand when available). Additionally, I like to thank all of my committee members (Drs. Galya Abdrakmanova, Francine Cabral, Sandra Welch, Mike Grotewiel) for your patience and willingness to participate as a member. Our term together has truly been memorable! I owe a special thanks to Sheryol Cox, and Dr.
    [Show full text]
  • Harnessing the Endocannabinoid 2-Arachidonoylglycerol to Lower Intraocular Pressure in a Murine Model
    Glaucoma Harnessing the Endocannabinoid 2-Arachidonoylglycerol to Lower Intraocular Pressure in a Murine Model Sally Miller,1 Emma Leishman,1 Sherry Shujung Hu,2 Alhasan Elghouche,1 Laura Daily,1 Natalia Murataeva,1 Heather Bradshaw,1 and Alex Straiker1 1Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States 2Department of Psychology, National Cheng Kung University, Tainan, Taiwan Correspondence: Alex Straiker, De- PURPOSE. Cannabinoids, such as D9-THC, act through an endogenous signaling system in the partment of Psychological and Brain vertebrate eye that reduces IOP via CB1 receptors. Endogenous cannabinoid (eCB) ligand, 2- Sciences, Indiana University, Bloom- arachidonoyl glycerol (2-AG), likewise activates CB1 and is metabolized by monoacylglycerol ington, IN 47405, USA; lipase (MAGL). We investigated ocular 2-AG and its regulation by MAGL and the therapeutic [email protected]. potential of harnessing eCBs to lower IOP. Submitted: February 16, 2016 Accepted: May 16, 2016 METHODS. We tested the effect of topical application of 2-AG and MAGL blockers in normotensive mice and examined changes in eCB-related lipid species in the eyes and spinal Citation: Miller S, Leishman E, Hu SS, cord of MAGL knockout (MAGLÀ/À) mice using high performance liquid chromatography/ et al. Harnessing the endocannabinoid tandem mass spectrometry (HPLC/MS/MS). We also examined the protein distribution of 2-arachidonoylglycerol to lower intra- ocular pressure in a murine model. MAGL in the mouse anterior chamber. Invest Ophthalmol Vis Sci. RESULTS. 2-Arachidonoyl glycerol reliably lowered IOP in a CB1- and concentration-dependent 2016;57:3287–3296. DOI:10.1167/ manner. Monoacylglycerol lipase is expressed prominently in nonpigmented ciliary iovs.16-19356 epithelium.
    [Show full text]
  • 1. Endocannabinoid System (ECS)
    UNIVERSITÀ DI PISA Dipartimento di Farmacia Corso di Laurea Specialistica in Chimica e Tecnologia Farmaceutiche Tesi di Laurea: DESIGN AND SYNTHESIS OF HETEROCYCLIC DERIVATIVES AS POTENTIAL MAGL INHIBITORS Relatori: Prof. Marco Macchia Candidato: Glenda Tarchi Prof.ssa Clementina Manera (matricola N° 445314) Dott.ssa Chiara Arena Settore Scientifico Disciplinare: CHIM-08 ANNO ACCADEMICO 2013–2014 INDEX Sommario INDEX ......................................................................................... 3 1. Endocannabinoid system (ECS) ......................................... 6 1.1 Endocannabinoid receptors ........................................................... 7 1.2 Mechanism of endocannabinoid neuronal signaling ..................... 9 1.3 Endocannabinoids biosynthesis ................................................... 11 1.4 Enzymes involved in endocannabinoids degradation ................. 16 1.4.1 FAAH ........................................................................................................ 16 1.4.2 MAGL ....................................................................................................... 18 1.4.3 ABHD6 ..................................................................................................... 20 1.4.4 ABDH12 ................................................................................................... 21 2. MAGL like pharmacological target ................................ 23 2.1 The role of MAGL in pain and inflammation ............................. 24 2.1.1 Relation between
    [Show full text]
  • Control of Analgesic and Anti-Inflammatory Pathways by Fatty Acid Amide Hydrolase Long, James Harry
    Control of analgesic and anti-inflammatory pathways by fatty acid amide hydrolase Long, James Harry The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author For additional information about this publication click this link. http://qmro.qmul.ac.uk/jspui/handle/123456789/3124 Information about this research object was correct at the time of download; we occasionally make corrections to records, please therefore check the published record when citing. For more information contact [email protected] Control of analgesic and anti-inflammatory pathways by fatty acid amide hydrolase James Harry Long Thesis submitted for the degree of Doctor of Philosophy to the University of London Translational Medicine and Therapeutics William Harvey Research Institute Charterhouse Square, London, EC1M 6BQ Table of contents Table of Contents Declaration VIII Acknowledgements IX Abstract X Abbreviations XI Chapter 1 – Introduction 1 1.1. Pain and analgesia 2 1.1.1. Nociception 2 1.1.2. Inflammatory pain 5 1.1.3. Neuropathic pain 10 1.1.4. Analgesia 10 1.1.5. COX inhibitors 11 1.1.6. Opioid receptor agonists 12 1.1.7. Glucocorticoids 13 1.1.8. Anaesthetics 13 1.1.9. Antidepressants 14 1.1.10. Anticonvulsants 14 1.1.11. Muscle relaxants 15 1.1.12. An alternative analgesic pathway 15 1.2. Endocannabinoid system 16 1.2.1. Cannabinoid receptors 16 1.2.2. Endocannabinoids 18 1.2.3. Endocannabinoid biosynthesis 21 1.2.4. Endocannabinoid metabolism 21 1.2.5.
    [Show full text]
  • Application of High Resolution Mass Spectrometry for the Screening and Confirmation of Novel Psychoactive Substances Joshua Zolton Seither [email protected]
    Florida International University FIU Digital Commons FIU Electronic Theses and Dissertations University Graduate School 4-25-2018 Application of High Resolution Mass Spectrometry for the Screening and Confirmation of Novel Psychoactive Substances Joshua Zolton Seither [email protected] DOI: 10.25148/etd.FIDC006565 Follow this and additional works at: https://digitalcommons.fiu.edu/etd Part of the Chemistry Commons Recommended Citation Seither, Joshua Zolton, "Application of High Resolution Mass Spectrometry for the Screening and Confirmation of Novel Psychoactive Substances" (2018). FIU Electronic Theses and Dissertations. 3823. https://digitalcommons.fiu.edu/etd/3823 This work is brought to you for free and open access by the University Graduate School at FIU Digital Commons. It has been accepted for inclusion in FIU Electronic Theses and Dissertations by an authorized administrator of FIU Digital Commons. For more information, please contact [email protected]. FLORIDA INTERNATIONAL UNIVERSITY Miami, Florida APPLICATION OF HIGH RESOLUTION MASS SPECTROMETRY FOR THE SCREENING AND CONFIRMATION OF NOVEL PSYCHOACTIVE SUBSTANCES A dissertation submitted in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in CHEMISTRY by Joshua Zolton Seither 2018 To: Dean Michael R. Heithaus College of Arts, Sciences and Education This dissertation, written by Joshua Zolton Seither, and entitled Application of High- Resolution Mass Spectrometry for the Screening and Confirmation of Novel Psychoactive Substances, having been approved in respect to style and intellectual content, is referred to you for judgment. We have read this dissertation and recommend that it be approved. _______________________________________ Piero Gardinali _______________________________________ Bruce McCord _______________________________________ DeEtta Mills _______________________________________ Stanislaw Wnuk _______________________________________ Anthony DeCaprio, Major Professor Date of Defense: April 25, 2018 The dissertation of Joshua Zolton Seither is approved.
    [Show full text]
  • Overactive Endocannabinoid Signaling Impairs Apolipoprotein E-Mediated Clearance of Triglyceride-Rich Lipoproteins
    Overactive endocannabinoid signaling impairs apolipoprotein E-mediated clearance of triglyceride-rich lipoproteins Maxwell A. Ruby*, Daniel K. Nomura†, Carolyn S. S. Hudak†, Lara M. Mangravite*, Sally Chiu*, John E. Casida†‡, and Ronald M. Krauss*‡ *Children’s Hospital Oakland Research Institute, Oakland, CA 94609; and †Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, CA 94720-3112 Contributed by John E. Casida, University of California, Berkeley, CA, July 25, 2008 (sent for review June 9, 2008) The endocannabinoid (EC) system regulates food intake and en- The EC system consists of the cannabinoid receptors, the ergy metabolism. Cannabinoid receptor type 1 (CB1) antagonists endocannabinoids (ECs), and the enzymes responsible for their show promise in the treatment of obesity and its metabolic synthesis and breakdown (14, 15). CB1 is a G protein-coupled consequences. Although the reduction in adiposity resulting from membrane receptor that transmits its response via Gi/o protein- therapy with CB1 antagonists may not account fully for the mediated reduction in adenylate cyclase activity (14). The ECs concomitant improvements in dyslipidemia, direct effects of over- anandamide and 2-arachidonoylglycerol (2-AG) are produced active EC signaling on plasma lipoprotein metabolism have not locally by N-acyl phosphatidylethanolamine phospholipase D been documented. The present study used a chemical approach to and by diacylglycerol lipase, respectively (14, 15). Signaling is evaluate the direct effects of increased EC signaling in mice by terminated primarily by enzymatic breakdown of anandamide by inducing acute elevations of endogenously produced cannabinoids fatty acid amide hydrolase (FAAH) and of 2-AG by monoacyl- through pharmacological inhibition of their enzymatic hydrolysis glycerol lipase (MAGL) (14–18).
    [Show full text]
  • Cannabinoids for the Control of Experimental Multiple Sclerosis Pryce, Gareth
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Queen Mary Research Online Cannabinoids for the control of experimental multiple sclerosis Pryce, Gareth The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author For additional information about this publication click this link. https://qmro.qmul.ac.uk/jspui/handle/123456789/673 Information about this research object was correct at the time of download; we occasionally make corrections to records, please therefore check the published record when citing. For more information contact [email protected] 1 Cannabinoids for the control of experimental multiple sclerosis GARETH PRYCE Neuroimmunology Unit, Neuroscience & Trauma Barts and the London School of Medicine and Dentistry Queen Mary University of London UK 2 This thesis is dedicated in memory of my Dad, Glyn Pryce (1927-2010), with love and thanks. 3 ACKNOWLEDGEMENTS I wouldlike to thank DavidBaker andGavin Giovannoni for their supervision and providingme with the opportunity to undertake this thesis. I wouldlike to thank J.Ludovic Croxford, Sam Jackson, Sarah Al-Izki from the lab past and present; Ana Cabranes (RIP) and the Javier Fernadez-Ruiz laboratory in Madrid, Spain; the Vincenzo Di Marzio Laboratory Naples, Italy; the Andy Irving Laboratory, Dundee; the laboratories of Elga De Vries andSandra Amor at the Free University Amsterdam, The Netherlands and the laboratories of Ruth Ross and Roger Pertwee in Aberdeen and Alison Hardcastle University College London for providing me with supportive data and particularly Cristina Visintin and David Selwoodof University College London andCanbex for providingdata from contract Research organizations.
    [Show full text]
  • Laws, Rules, and Regulations
    LAWS, RULES, AND REGULATIONS August 2020 Asa Hutchinson, Governor John Clay Kirtley, Pharm.D. Executive Director Arkansas Department of Health Arkansas State Board of Pharmacy 322 South Main Street, Suite 600 Little Rock, AR 72201 Phone: 501.682.0190 Fax: 501.682.0195 [email protected] www.pharmacyboard.arkansas.gov 10/8/2020 Arkansas State Board of Pharmacy Members Lenora Newsome, P.D. President, Smackover Rebecca Mitchell, Pharm.D. Vice President/Secretary, Greenbrier Deborah Mack, P.D. Member, Bentonville Lynn Crouse, Pharm.D. Member, Lake Village Brian Jolly, Pharm.D. Member, Beebe Carol Rader, RN Public Member, Fort Smith Amy Fore, MHSA, FACMPE, FACHE Public Member, Fort Smith 10/8/2020 Board of Pharmacy Law Book - Acts Table of Contents Pharmacy Practice Act A 17-92-101 Definitions……………………………………………………… 1-4 17-92-102 Exemptions…………………………………………………….. 4-5 17-92-103 Pharmacy laws unaffected……………………………………... 5 17-92-104 Privilege tax unaffected……………………………………….. 5 17-92-105 Prohibited acts – Penalties……………………………………... 6 17-92-106 Injunctions……………………………………………………… 6 17-92-107 Prosecutions – Disposition of fines……………………………. 6 17-92-108 Fees…………………………………………………………….. 6-10 17-92-109 Prescriptions for optometrists………………………………….. 10 17-92-110 Prescriptive authority of advance practice nurses……………… 10 17-92-111 Construction of Acts 1997, No. 1204………………………….. 10 17-92-112 Prescriptions for physician assistants…………………………. 10 17-92-201 Members – Qualifications……………………………………… 11 17-92-202 Members – Oath……………………………………………… 11 17-92-203 Members – Compensation…………………………………….. 11 17-92-204 Organization and proceedings…………………………………. 12 17-92-205 Rules and regulations – Enforcement………………………….. 12-13 17-92-206 Issuance of bulletins – Annual Reports………………………... 14 17-92-207 Maintenance of office………………………………………….
    [Show full text]
  • Functional Selectivity at the Cannabinoid Receptor Both Endogenously and Exogenously Expressed in a Variety of Cell Lines and Tissues
    A Study of Functional Selectivity at the Cannabinoid Type 1 Receptor Richard Priestley, BSc (Hons) Thesis submitted to the University of Nottingham for the degree of Doctor of Philosophy July 2015 1 Abstract The cannabinoid CB1 receptor is a G protein-coupled receptor (GPCR) which is important in the regulation of neuronal function, predominately via coupling to heterotrimeric Gi/o proteins. The receptor has also been shown to interact with a variety of other intracellular signalling mediators, including other G proteins, several members of the mitogen activated kinase (MAP) superfamily and β- arrestins. The CB1 receptor is recognised by an array of structurally distinct endogenous and exogenous ligands and a growing body of evidence indicates that ligands acting at GPCRs are able to differently activate specific signalling pathways, a phenomenon known as functional selectivity or biased agonism. This is important in future drug development as it may be possible to produce drugs which selectively activate signalling pathways linked to therapeutic benefits, while minimising activation of those associated with unwanted side effects. The main aim of this thesis, therefore, was to investigate ligand-selective functional selectivity at the cannabinoid CB1 receptor both endogenously and exogenously expressed in a variety of cell lines. Chinese hamster ovary (CHO) and human embryonic kidney (HEK 293) cells stably transfected with the human recombinant CB1 receptor and untransfected murine Neuro 2a (N2a) cells, were exposed to a number of cannabinoid
    [Show full text]
  • Metabolic Regulation by Lipid Activated Receptors by Maxwell A
    Metabolic Regulation by Lipid Activated Receptors By Maxwell A Ruby A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy In Molecular & Biochemical Nutrition In the Graduate Division Of the University of California, Berkeley Committee in charge: Professor Marc K. Hellerstein, Chair Professor Ronald M. Krauss Professor George A. Brooks Professor Andreas Stahl Fall 2010 Abstract Metabolic Regulation by Lipid Activated Receptors By Maxwell Alexander Ruby Doctor of Philosophy in Molecular & Biochemical Nutrition University of California, Berkeley Professor Marc K. Hellerstein, Chair Obesity and related metabolic disorders have reached epidemic levels with dire public health consequences. Efforts to stem the tide focus on behavioral and pharmacological interventions. Several hypolipidemic pharmaceutical agents target endogenous lipid receptors, including the peroxisomal proliferator activated receptor α (PPAR α) and cannabinoid receptor 1 (CB1). To further the understanding of these clinically relevant receptors, we elucidated the biochemical basis of PPAR α activation by lipoprotein lipolysis products and the metabolic and transcriptional responses to elevated endocannabinoid signaling. PPAR α is activated by fatty acids and their derivatives in vitro. While several specific pathways have been implicated in the generation of PPAR α ligands, we focused on lipoprotein lipase mediated lipolysis of triglyceride rich lipoproteins. Fatty acids activated PPAR α similarly to VLDL lipolytic products. Unbound fatty acid concentration determined the extent of PPAR α activation. Lipolysis of VLDL, but not physiological unbound fatty acid concentrations, created the fatty acid uptake necessary to stimulate PPAR α. Consistent with a role for vascular lipases in the activation of PPAR α, administration of a lipase inhibitor (p-407) prevented PPAR α dependent induction of target genes in fasted mice.
    [Show full text]
  • Light-Induction of Endocannabinoids and Activation of Drosophila TRPC
    bioRxiv preprint doi: https://doi.org/10.1101/2021.06.17.448894; this version posted June 17, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 1 2 Light-induction of endocannabinoids and 3 activation of Drosophila TRPC channels 4 5 Takaaki Sokabe1,2,3,*, Heather B. Bradshaw4, Makoto Tominaga2,3, 6 Emma Leishman4, and Craig Montell1,* 7 8 1Department of Molecular, Cellular, and Developmental Biology and the Neuroscience 9 Research Institute, University of California, Santa Barbara, California 93106, USA 10 2Division of Cell Signaling, National Institute for Physiological Sciences, and Thermal 11 Biology Group, Exploratory Research Center on Life and Living Systems (ExCELLS), 12 National Institutes of Natural Sciences, Okazaki, Aichi, 444-8787, Japan 13 3Department of Physiological Sciences, SOKENDAI, Okazaki, Aichi, Japan 14 4Department of Psychological and Brain Sciences, 15 Indiana University, Bloomington, Illinois, 47405, USA 16 *Correspondence: T.S. ([email protected]) or C.M. ([email protected]) 17 18 Running title: Endocannabinoids and phototransduction 19 Character count (including spaces): 63,181 20 ORCID: CM, 0000-0001-5637-1482; TS, 0000-0003-1280-9424 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.17.448894; this version posted June 17, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 2 21 Abstract 22 Drosophila phototransduction represents a classical model for signaling cascades 23 that culminate with activation of TRP channels.
    [Show full text]