Amnestic Concentrations of Sevoflurane Inhibit Synaptic
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Picrotoxin-Like Channel Blockers of GABAA Receptors
COMMENTARY Picrotoxin-like channel blockers of GABAA receptors Richard W. Olsen* Department of Molecular and Medical Pharmacology, Geffen School of Medicine, University of California, Los Angeles, CA 90095-1735 icrotoxin (PTX) is the prototypic vous system. Instead of an acetylcholine antagonist of GABAA receptors (ACh) target, the cage convulsants are (GABARs), the primary media- noncompetitive GABAR antagonists act- tors of inhibitory neurotransmis- ing at the PTX site: they inhibit GABAR Psion (rapid and tonic) in the nervous currents and synapses in mammalian neu- system. Picrotoxinin (Fig. 1A), the active rons and inhibit [3H]dihydropicrotoxinin ingredient in this plant convulsant, struc- binding to GABAR sites in brain mem- turally does not resemble GABA, a sim- branes (7, 9). A potent example, t-butyl ple, small amino acid, but it is a polycylic bicyclophosphorothionate, is a major re- compound with no nitrogen atom. The search tool used to assay GABARs by compound somehow prevents ion flow radio-ligand binding (10). through the chloride channel activated by This drug target appears to be the site GABA in the GABAR, a member of the of action of the experimental convulsant cys-loop, ligand-gated ion channel super- pentylenetetrazol (1, 4) and numerous family. Unlike the competitive GABAR polychlorinated hydrocarbon insecticides, antagonist bicuculline, PTX is clearly a including dieldrin, lindane, and fipronil, noncompetitive antagonist (NCA), acting compounds that have been applied in not at the GABA recognition site but per- huge amounts to the environment with haps within the ion channel. Thus PTX major agricultural economic impact (2). ͞ appears to be an excellent example of al- Some of the other potent toxicants insec- losteric modulation, which is extremely ticides were also radiolabeled and used to important in protein function in general characterize receptor action, allowing and especially for GABAR (1). -
GABA Receptors
D Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews Review No.7 / 1-2011 GABA receptors Wolfgang Froestl , CNS & Chemistry Expert, AC Immune SA, PSE Building B - EPFL, CH-1015 Lausanne, Phone: +41 21 693 91 43, FAX: +41 21 693 91 20, E-mail: [email protected] GABA Activation of the GABA A receptor leads to an influx of chloride GABA ( -aminobutyric acid; Figure 1) is the most important and ions and to a hyperpolarization of the membrane. 16 subunits with γ most abundant inhibitory neurotransmitter in the mammalian molecular weights between 50 and 65 kD have been identified brain 1,2 , where it was first discovered in 1950 3-5 . It is a small achiral so far, 6 subunits, 3 subunits, 3 subunits, and the , , α β γ δ ε θ molecule with molecular weight of 103 g/mol and high water solu - and subunits 8,9 . π bility. At 25°C one gram of water can dissolve 1.3 grams of GABA. 2 Such a hydrophilic molecule (log P = -2.13, PSA = 63.3 Å ) cannot In the meantime all GABA A receptor binding sites have been eluci - cross the blood brain barrier. It is produced in the brain by decarb- dated in great detail. The GABA site is located at the interface oxylation of L-glutamic acid by the enzyme glutamic acid decarb- between and subunits. Benzodiazepines interact with subunit α β oxylase (GAD, EC 4.1.1.15). It is a neutral amino acid with pK = combinations ( ) ( ) , which is the most abundant combi - 1 α1 2 β2 2 γ2 4.23 and pK = 10.43. -
Exploring the Activity of an Inhibitory Neurosteroid at GABAA Receptors
1 Exploring the activity of an inhibitory neurosteroid at GABAA receptors Sandra Seljeset A thesis submitted to University College London for the Degree of Doctor of Philosophy November 2016 Department of Neuroscience, Physiology and Pharmacology University College London Gower Street WC1E 6BT 2 Declaration I, Sandra Seljeset, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I can confirm that this has been indicated in the thesis. 3 Abstract The GABAA receptor is the main mediator of inhibitory neurotransmission in the central nervous system. Its activity is regulated by various endogenous molecules that act either by directly modulating the receptor or by affecting the presynaptic release of GABA. Neurosteroids are an important class of endogenous modulators, and can either potentiate or inhibit GABAA receptor function. Whereas the binding site and physiological roles of the potentiating neurosteroids are well characterised, less is known about the role of inhibitory neurosteroids in modulating GABAA receptors. Using hippocampal cultures and recombinant GABAA receptors expressed in HEK cells, the binding and functional profile of the inhibitory neurosteroid pregnenolone sulphate (PS) were studied using whole-cell patch-clamp recordings. In HEK cells, PS inhibited steady-state GABA currents more than peak currents. Receptor subtype selectivity was minimal, except that the ρ1 receptor was largely insensitive. PS showed state-dependence but little voltage-sensitivity and did not compete with the open-channel blocker picrotoxinin for binding, suggesting that the channel pore is an unlikely binding site. By using ρ1-α1/β2/γ2L receptor chimeras and point mutations, the binding site for PS was probed. -
Characterization of Strychnine Binding Sites in the Rodent
CHARACTERIZATION OF STRYCHNINE BINDING SITES IN THE RODENT SPINAL CORD BY VINCENT MAURICE O’CONNOR UNIVERSITY COLLEGE LONDON A thesis submitted for the degree of Doctor of Philosophy from the University of London, 1992. I ProQuest Number: 10608898 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 10608898 Published by ProQuest LLC(2017). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 This thesis is dedicated to the select band o f people, including the most recent arrivals and the sorely missed departed, that I hold closest in my affections. "At the end of the day" they make It all worthwhile. Remember, in the words of the famous actor whose name at present escapes me; "Nobody said it would be easy". Although my own feeling is that Nobody was probably wrong. II Thesis abstract The convulsant alkaloid strychnine is a selective and highly potent antagonist at postsynaptic receptor for the inhibitory neurotransmitter glycine . These properties have led to the extensive use of strychnine as a ligand to probe the postsynaptic glycine receptor. Despite the recent increased understanding of the molecular structure of this receptor protein there is still much dispute as to the nature of the interaction between glycine and strychnine. -
Chronic Social Isolation Reduces 5-HT Neuronal Activity Via Upregulated SK3 Calcium-Activated Potassium Channels Derya Sargin1, David K Oliver1, Evelyn K Lambe1,2,3*
SHORT REPORT Chronic social isolation reduces 5-HT neuronal activity via upregulated SK3 calcium-activated potassium channels Derya Sargin1, David K Oliver1, Evelyn K Lambe1,2,3* 1Department of Physiology, University of Toronto, Toronto, Canada; 2Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Canada; 3Department of Psychiatry, University of Toronto, Toronto, Canada Abstract The activity of serotonin (5-HT) neurons is critical for mood regulation. In a mouse model of chronic social isolation, a known risk factor for depressive illness, we show that 5-HT neurons in the dorsal raphe nucleus are less responsive to stimulation. Probing the responsible cellular mechanisms pinpoints a disturbance in the expression and function of small-conductance Ca2+-activated K+ (SK) channels and reveals an important role for both SK2 and SK3 channels in normal regulation of 5-HT neuronal excitability. Chronic social isolation renders 5-HT neurons insensitive to SK2 blockade, however inhibition of the upregulated SK3 channels restores normal excitability. In vivo, we demonstrate that inhibiting SK channels normalizes chronic social isolation- induced anxiety/depressive-like behaviors. Our experiments reveal a causal link for the first time between SK channel dysregulation and 5-HT neuron activity in a lifelong stress paradigm, suggesting these channels as targets for the development of novel therapies for mood disorders. DOI: 10.7554/eLife.21416.001 Introduction *For correspondence: evelyn. Major depression is a prevalent and debilitating disease for which standard treatments remain inef- [email protected] fective. Social isolation has long been implicated as a risk factor for depression in humans Competing interests: The (Cacioppo et al., 2002,2006; Holt-Lunstad et al., 2010) and induces anxiety- and depressive-like authors declare that no behaviors in rodents (Koike et al., 2009; Wallace et al., 2009; Dang et al., 2015; Shimizu et al., competing interests exist. -
Toxicological and Pharmacological Profile of Amanita Muscaria (L.) Lam
Pharmacia 67(4): 317–323 DOI 10.3897/pharmacia.67.e56112 Review Article Toxicological and pharmacological profile of Amanita muscaria (L.) Lam. – a new rising opportunity for biomedicine Maria Voynova1, Aleksandar Shkondrov2, Magdalena Kondeva-Burdina1, Ilina Krasteva2 1 Laboratory of Drug metabolism and drug toxicity, Department “Pharmacology, Pharmacotherapy and Toxicology”, Faculty of Pharmacy, Medical University of Sofia, Bulgaria 2 Department of Pharmacognosy, Faculty of Pharmacy, Medical University of Sofia, Bulgaria Corresponding author: Magdalena Kondeva-Burdina ([email protected]) Received 2 July 2020 ♦ Accepted 19 August 2020 ♦ Published 26 November 2020 Citation: Voynova M, Shkondrov A, Kondeva-Burdina M, Krasteva I (2020) Toxicological and pharmacological profile of Amanita muscaria (L.) Lam. – a new rising opportunity for biomedicine. Pharmacia 67(4): 317–323. https://doi.org/10.3897/pharmacia.67. e56112 Abstract Amanita muscaria, commonly known as fly agaric, is a basidiomycete. Its main psychoactive constituents are ibotenic acid and mus- cimol, both involved in ‘pantherina-muscaria’ poisoning syndrome. The rising pharmacological and toxicological interest based on lots of contradictive opinions concerning the use of Amanita muscaria extracts’ neuroprotective role against some neurodegenerative diseases such as Parkinson’s and Alzheimer’s, its potent role in the treatment of cerebral ischaemia and other socially significant health conditions gave the basis for this review. Facts about Amanita muscaria’s morphology, chemical content, toxicological and pharmacological characteristics and usage from ancient times to present-day’s opportunities in modern medicine are presented. Keywords Amanita muscaria, muscimol, ibotenic acid Introduction rica, the genus had an ancestral origin in the Siberian-Be- ringian region in the Tertiary period (Geml et al. -
Bicuculline and Gabazine Are Allosteric Inhibitors of Channel Opening of the GABAA Receptor
The Journal of Neuroscience, January 15, 1997, 17(2):625–634 Bicuculline and Gabazine Are Allosteric Inhibitors of Channel Opening of the GABAA Receptor Shinya Ueno,1 John Bracamontes,1 Chuck Zorumski,2 David S. Weiss,3 and Joe Henry Steinbach1 Departments of 1Anesthesiology and 2Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, and 3University of Alabama at Birmingham, Neurobiology Research Center and Department of Physiology and Biophysics, Birmingham, Alabama 35294-0021 Anesthetic drugs are known to interact with GABAA receptors, bicuculline only partially blocked responses to pentobarbital. both to potentiate the effects of low concentrations of GABA and These observations indicate that the blockers do not compete to directly gate open the ion channel in the absence of GABA; with alphaxalone or pentobarbital for a single class of sites on the however, the site(s) involved in direct gating by these drugs is not GABAA receptor. Finally, at receptors containing a1b2(Y157S)g2L known. We have studied the ability of alphaxalone (an anesthetic subunits, both bicuculline and gabazine showed weak agonist steroid) and pentobarbital (an anesthetic barbiturate) to directly activity and actually potentiated responses to alphaxalone. These activate recombinant GABAA receptors containing the a1, b2, and observations indicate that the blocking drugs can produce allo- g2L subunits. Steroid gating was not affected when either of two steric changes in GABAA receptors, at least those containing this mutated b2 subunits [b2(Y157S) and b2(Y205S)] are incorporated mutated b2 subunit. We conclude that the sites for binding ste- into the receptors, although these subunits greatly reduce the roids and barbiturates do not overlap with the GABA-binding site. -
Increased NMDA Receptor Inhibition at an Increased Sevoflurane MAC Robert J Brosnan* and Roberto Thiesen
Brosnan and Thiesen BMC Anesthesiology 2012, 12:9 http://www.biomedcentral.com/1471-2253/12/9 RESEARCH ARTICLE Open Access Increased NMDA receptor inhibition at an increased Sevoflurane MAC Robert J Brosnan* and Roberto Thiesen Abstract Background: Sevoflurane potently enhances glycine receptor currents and more modestly decreases NMDA receptor currents, each of which may contribute to immobility. This modest NMDA receptor antagonism by sevoflurane at a minimum alveolar concentration (MAC) could be reciprocally related to large potentiation of other inhibitory ion channels. If so, then reduced glycine receptor potency should increase NMDA receptor antagonism by sevoflurane at MAC. Methods: Indwelling lumbar subarachnoid catheters were surgically placed in 14 anesthetized rats. Rats were anesthetized with sevoflurane the next day, and a pre-infusion sevoflurane MAC was measured in duplicate using a tail clamp method. Artificial CSF (aCSF) containing either 0 or 4 mg/mL strychnine was then infused intrathecally at 4 μL/min, and the post-infusion baseline sevoflurane MAC was measured. Finally, aCSF containing strychnine (either 0 or 4 mg/mL) plus 0.4 mg/mL dizocilpine (MK-801) was administered intrathecally at 4 μL/min, and the post- dizocilpine sevoflurane MAC was measured. Results: Pre-infusion sevoflurane MAC was 2.26%. Intrathecal aCSF alone did not affect MAC, but intrathecal strychnine significantly increased sevoflurane requirement. Addition of dizocilpine significantly decreased MAC in all rats, but this decrease was two times larger in rats without intrathecal strychnine compared to rats with intrathecal strychnine, a statistically significant (P < 0.005) difference that is consistent with increased NMDA receptor antagonism by sevoflurane in rats receiving strychnine. -
The Protective Effect of Nicardipine on Iron-Induced Purkinje
Fırat Tıp Dergisi 2008;13(3): 167-170 Experimental Research www.firattipdergisi.com The Protective Effect of Nicardipine on Iron-Induced Purkinje Cell Loss in Rat Cerebellum: A Stereological Study Ramazan KOZAN a1 , M. Ömer BOSTANCI 2, Fatih SEFĐL 2, Faruk BAĞIRICI 2 1 Mustafa Kemal University, Faculty of Medicine, Department of Physiology, HATAY 2 Ondokuz Mayis University, Faculty of Medicine, Department of Physiology, SAMSUN ABSTRACT Objective: The aim of the present study is to investigate the effect of nicardipine, a calcium channel blocker, on the neurotoxicity induced by intracerebroventricular (i.c.v.) iron injection in rats. Materials and Methods: Animals were divided into three groups; control, iron and iron+nicardipine groups. Rats in iron and iron+nicardipine groups received i.c.v. FeCl 3, while rats in control group received the same volume of saline. All animals were kept alive for ten days following the operation and animals in iron+nicardipine group were injected intraperitoneally nicardipine (10 mg/kg/day) once a day during this period. After ten days, all rats were perfused intracardially and cerebellar tissues were stained with Cresyl violet. Means of total Purkinje cells numbers in the cerebellum were estimated using the optical fractionator counting method. Results: Means of total Purkinje cells numbers in the cerebellum as follows: 317182±9667, 209002±7836 and 265659±8291 in the control, iron and iron+nicardipine groups, respectively. Total number of Purkinje cells in iron and iron+nicardipine groups were significantly lower than control animals (p< 0.05). However, comparison between iron and iron+nicardipine groups revealed that nicardipine significantly attenuates the iron-induced Purkinje cell loss (p<0.05). -
Waste Disposal Guide
Waste Disposal Guide How to Properly Dispose of Waste Materials Generated at Michigan State University Environmental Health & Safety (EHS) / Office of Radiation, Chemical & Biological Safety (ORCBS) C124 Research Complex‐Engineering East Lansing, MI 48824‐1326 Revised April 2009 CONTACT INFORMATION Campus Emergency: 911 ORCBS Phone Number: (517) 355-0153 ORCBS Fax Number: (517) 353-4871 ORCBS E-mail Address: [email protected] ORCBS Web Address: http://www.orcbs.msu.edu TABLE OF CONTENTS Sections Introduction ................................................................................................................... 4 Hazardous Waste Defined ............................................................................................ 5 Requirements for Chemical Waste ............................................................................... 6 Classification of Chemical Waste .................................................................................. 7 Containers ..................................................................................................................... 8 Container Label ............................................................................................................. 9 General Labeling & Packaging Procedures .................................................................. 9 Specific Labeling & Packaging Procedures ............................................................. 9-15 Scheduling a Chemical Waste Pick-up ...................................................................... -
AMANITA MUSCARIA: Mycopharmacological Outline and Personal Experiences
• -_._----------------------- .....•.----:: AMANITA MUSCARIA: Mycopharmacological Outline and Personal Experiences by Francesco Festi and Antonio Bianchi Amanita muscaria, also known as Fly Agaric, is a yellow-to-orange capped wild mushroom. It grows in symbir-, is with arboreal trees such as Birch, Pine or Fir, in both Europe and the Americas. Its his- tory has it associated with both shamanic and magical practices for at least the last 2,000 years, and it is probably the Soma intoxicant spoken of in the Indian Rig-Vedas. The following piece details both the generic as well as the esoteric history and pharmacological pro- files of the Amanita muscaria. It also introduces research which J shows that psychoactivity related to this species is seasonally- determinant. This determinant can mean the difference between poi- soning and pleasant, healing applications, which include psychedelic experiences. Connections between the physiology of sleep and the plant's inner chemistry is also outlined. if" This study is divided into two parts, reflecting two comple- l"" ~ ,j. mentary but different approaches to the same topic. The first (" "~l>;,;,~ ~ study, presented by Francesco Festi, presents a critical over- .~ view of the ~-:<'-.:=l.=';i.:31. ethnobotanical, chemical and phar- macological d~:.:: -.c. ~_~.::-_ .:::e :-efe:-::-e j to the Amanita muscaria (through 198'5 In :he se.:,='~_·: :;-.r:. also Italian author and mycologist Antc nio Bianchi reports on personal experiences with the Amar.i:a muscaria taken from European samples. The following experimental data - far from constituting any final answers - are only a proposal and (hopefully) an excitement for further investigations. -
Molecular Changes in Opioid Addiction: the Role of Adenylyl Cyclase and Camp/PKA System 205
CHAPTER SEVEN Molecular Changes in Opioid Addiction: The Role of Adenylyl Cyclase and cAMP/PKA System ,1 † Patrick Chan* , Kabirullah Lutfy * Department of Pharmacy and Pharmacy Administration, Western University of Health Sciences, College of Pharmacy, Pomona, California, USA † Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, California, USA 1 Corresponding author: e-mail address: [email protected]. Contents 1. Introduction 204 2. The Adenylyl Cyclase Pathway 205 2.1 Adenylyl Cyclase 205 2.2 Protein Kinase A 207 3. Opioid Effect on cAMP-Responsive Element-Binding Protein 209 4. Molecular Changes in Brain Regions That May Underlie Opiate Dependence 211 4.1 Molecular Changes in the Locus Coeruleus 211 4.2 Molecular Changes in the Amygdala 214 4.3 Molecular Changes in the Periaqueductal Gray 216 5. Molecular Changes in the Ventral Tegmental Area 217 6. Molecular Changes in Other CNS Regions 218 7. Conclusions 219 References 219 Abstract For centuries, opiate analgesics have had a considerable presence in the treatment of moderate to severe pain. While effective in providing analgesia, opiates are notorious in exerting many undesirable adverse reactions. The receptor targets and the intra- cellular effectors of opioids have largely been identified. Furthermore, much of the mechanisms underlying the development of tolerance, dependence, and withdrawal have been delineated. Thus, there is a focus on developing novel compounds or strategies in mitigating or avoiding the development of tolerance, dependence, and withdrawal. This review focuses on the adenylyl cyclase and cyclic adenosine 3,5-monophosphate (cAMP)/protein kinase A (AC/cAMP/PKA) system as the central player in mediating the acute and chronic effects of opioids.