DOCSLIB.ORG

Clobenpropit Protects Propofol-Induced Neuronal Apoptosis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Clobenpropit Protects Propofol-Induced Neuronal Apoptosis European Review for Medical and Pharmacological Sciences 2018; 22: 8013-8020 Histamine H3 receptor antagonist Clobenpropit protects propofol-induced apoptosis of hippocampal neurons through PI3K/AKT pathway W. HE1, Q.-H. YUAN2, Q. ZHOU3 1Department of Anaesthesiology, Mianyang Central Hospital, Mianyang, China 2Department of Pathology, Mianyang Central Hospital, Mianyang, China 3Department of Anaesthesiology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, China Abstract. – OBJECTIVE: The aim of the study anesthetic effect is mainly achieved by exciting was to explore whether histamine H3 receptor gamma-aminobutyric acid (GABA) or inhibit- antagonist Clobenpropit could protect propo- ing N-methyl-D-aspartate (NMDA)2,3. However, fol-induced neurotoxicity in hippocampal neu- studies have found that anesthetics have toxic rons. MATERIALS AND METHODS: Hippocampal effects on neurons in developmental stage, which neurons were extracted from neonatal rats and may lead to neuronal apoptosis and brain dam- induced with propofol. MTT (3-(4,5-dimethylthi- age4. General anesthesia has been applied for azol-2-yl)-2,5-diphenyl tetrazolium bromide) as- nearly two centuries5. With the increased amount say was performed to detect apoptotic rate of of surgeries, anesthesia complications such as neurons. Western blot was conducted to detect protein levels of cleaved-caspase-3 and Bax/ postoperative cognitive dysfunction have been Bcl2. After LY294002 treatment, the PI3K path- focused on. In particular, the potential influences way antagonist was applied in neurons, protein of anesthetics on learning and memory functions levels of cleaved-caspase-3 and Bax/Bcl2 were of children have been well concerned throughout detected by Western blot as well. the world6,7. Propofol has been clinically applied RESULTS: Propofol treatment remarkably in- for induction and maintenance of anesthesia since duced neuronal apoptosis. Clobenpropit allevi- ated cell apoptosis induced by propofol. Pro- 1989. It has become an extremely useful drug for tein expressions of cleaved-caspase-3 and Bax/ inducing and maintaining general anesthesia due Bcl2 were remarkably downregulated in neurons to its rapid onset and recovery after withdrawal8. treated with Clobenpropit. LY294002 induction The anesthetic effect of propofol mainly relies remarkably reverses the protective role of Clo- on activating the type A receptor of GABA and benpropit in neuronal apoptosis, manifesting as inhibiting the NMDA receptor to some extent2,9. downregulated PI3K and p-AKT after LY294002 treatment. The balance of GABA activation and NMDA CONCLUSIONS: Clobenpropit protects propo- inhibition maintains the survival and apoptosis fol-induced neuronal apoptosis through activat- of neurons10. During the developmental process ing PI3K/AKT pathway. of central nervous system, it is very sensitive Key Words: to the external stimuli and the long-term cogni- Clobenpropit, Propofol, PI3K/AKT, Apoptosis. tive function may be influenced. Propofol exerts relative small side effects on central nervous system in comparison with other anesthetics11. Introduction However, recent investigations12,13 have pointed out that propofol administration may induce neu- With the development of surgical techniques, rotoxicity in both in vivo and in vitro models. the number of infants, children, and pregnant It is reported that administration of propofol women undergoing surgeries have also increased, alone or in combination with other drugs induc- leading to the great concern on the side effects of es neuronal death in the experimental animals, anesthetics, especially on immature brains1. The leading to subsequent learning and memory im- Corresponding Author: Qin Zhou, BM; e-mail: [email protected] 8013 W. He, Q.-H. Yuan, Q. Zhou pairment14. There are many developmental events survival, etc. are regulated by PI3K28. AKT, also during neurogenesis, and propofol administration known as protein kinase B (PKB), is an essential may affect neuronal functions at specific stages. target kinase downstream of PI3K. Phosphory- Propofol may be involved in various cellular lation at the Ser473 site activates AKT, which in processes. Although many studies have found turn activates a series of apoptosis-regulated pro- that propofol induces neurotoxicity in the brains teins (e.g., Bad, Caspase-9, etc.) to inhibit apop- of growing animals, the specific mechanism, tosis and promote cell survival29. This study aims however, has not been well understood. Current to investigate the protective role of histamine H3 studies 15-17 believed that the neurotoxic effects receptor antagonist in propofol-induced neuronal of propofol may involve in neural stem cell sur- apoptosis, and the potential mechanism of PI3K/ vival and neurogenesis, mitochondrial damage, AKT pathway. Our results provide a reference for calcium signal abnormalities, microRNAs-me- anesthesia medication in infants. diated mechanisms, BDNF dysregulation and inflammatory factors. In-depth studies are still required for fully investigations. Histamine is an Materials and Methods important neurotransmitter or neuromodulator in the brain. There are four histamine receptors that Extraction of Hippocampal have been already discovered, namely H1, H2, Neurons in Rats H3, and H4. Among them, H1 mainly presents This study was approved by the Animal Ethics in the postsynaptic membrane, whereas H3 re- Committee of Mianyang Central Hospital Animal ceptor mainly presents in the presynaptic mem- Center. The neonatal rats with 18-day-old were brane18-20. H3 receptors can negatively regulate sacrificed by decapitation. After immersing in 75% the synthesis and release of histamine, while H4 alcohol for at least 2 min, the head skin was cut to receptors are currently reported to be involved expose the bilateral cerebral hemispheres. The in the immune response21, 22. Histamine exerts cerebral hemispheres were placed in D-Hank’s various neuromodulation effects on sleep, wake- buffer on ice for harvesting hippocampal tissues. fulness, learning, memory and feeding through The remaining meninges, blood vessels and other its different receptors23. Histamine H3 receptor tissues on the hippocampus were removed and antagonist can promote the synthesis and release washed with cold D-Hank’s. The hippocampus of histamine. Many studies24 have shown that H3 tissues were gently cut and the D-Hank’s contain- receptor antagonist is a very promising therapeu- ing hippocampus tissues were transferred into a tic drug in the treatment of neurological diseases, centrifuge tube. The mixture was centrifuged at such as epilepsy, sleep disorders and memory dis- 900 rpm/min for 5 min. The supernatant was dis- orders. For example, Pitolisant was the first clini- carded and the centrifugation was repeated once cally used H3 receptor antagonist in the treatment with the same procedure. After the supernatant of sleep disorders, showing a good therapeutic was discarded, 3-time volume of membrane pro- effect. Histamine H3 receptor antagonists can tease was added into the hippocampus tissues, fol- reduce neuronal apoptosis and cerebral infarction lowed by digestion for 15 to 20 min. The mixture volume after ischemia25. The histamine receptor was shaken every 5 min. DMED containing 10% antagonist Clobenpropit protects NMDA-induced FBS was added to terminate the digestion. The neuronal excitatory damage by elevating GABA filtered cells were collected into a centrifuge tube concentration26. So far, the effects and mecha- and centrifuged at 900 rpm/min for 5 min. The nisms of histamine H3 receptor and its antagonist supernatant was discarded and the cell suspension on propofol-induced neuronal apoptosis are rarely was prepared by blowing. The cell suspension reported. Phosphatidylinositol 3-kinase (P13K) is was transferred to a culture flask and placed in an an important cellular signal transduction mole- incubator for different adherent culture conditions. cule27. P13K can be activated by stimulation with Non-adherent neurons were harvested subsequent- extracellular signals, such as growth factors, cyto- ly and the glial cells were isolated due to a faster kines, and hormones. Activation of P13K produc- adherence speed. es 3,4-diphosphophosphatidylinositol (PIP2) and 3,4,5-trisphosphonylphosphatidylinositol (PIP3). Extraction of Total Protein PIP3 subsequently activates multiple target pro- From Neurons teins in cells as a second messenger. Finally, the The medium containing neurons was dis- processes of cell proliferation, differentiation, carded and dried with absorbent paper. Pre- 8014 Clobenpropit protects propofol-induced neuronal apoptosis cooled phosphate-buffered saline (PBS) was Results added in each well for cell wash for a total of three times, with 1 min each time. Neurons Effects of Propofol on were lysed on ice for 30 min and shaken every Neuronal Apoptosis 3-5 min. After complete lysis, lysate and cell MTT assay was conducted after neurons were debris were collected in a centrifuge tube, fol- exposed to different concentrations of propofol lowed by centrifugation at 4°C, 12000 rpm/min for detecting apoptotic rate. The data showed for 5 min. The supernatant was collected and that the apoptotic rate of neurons remarkably preserved in -80°C. increased in a concentration-dependent manner (Figure 1). Specifically, neurons were induced MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- with 0.1 μM, 1 μM, 10 μM, 100 μM and 1000 Diphenyl Tetrazolium Bromide) Assay μM propofol for 24 hours. Neuronal apopto-
Load more

Recommended publications
  • In Vitro Pharmacology of Clinically Used Central Nervous System-Active Drugs As Inverse H1 Receptor Agonists
    0022-3565/07/3221-172–179$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 322, No. 1 Copyright © 2007 by The American Society for Pharmacology and Experimental Therapeutics 118869/3215703 JPET 322:172–179, 2007 Printed in U.S.A. In Vitro Pharmacology of Clinically Used Central Nervous System-Active Drugs as Inverse H1 Receptor Agonists R. A. Bakker,1 M. W. Nicholas,2 T. T. Smith, E. S. Burstein, U. Hacksell, H. Timmerman, R. Leurs, M. R. Brann, and D. M. Weiner Department of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (R.A.B., H.T., R.L.); ACADIA Pharmaceuticals Inc., San Diego, California (R.A.B., M.W.N., T.T.S., E.S.B., U.H., M.R.B., D.M.W.); and Departments of Pharmacology (M.R.B.), Neurosciences (D.M.W.), and Psychiatry (D.M.W.), University of California, San Diego, California Received January 2, 2007; accepted March 30, 2007 Downloaded from ABSTRACT The human histamine H1 receptor (H1R) is a prototypical G on this screen, we have reported on the identification of 8R- protein-coupled receptor and an important, well characterized lisuride as a potent stereospecific partial H1R agonist (Mol target for the development of antagonists to treat allergic con- Pharmacol 65:538–549, 2004). In contrast, herein we report on jpet.aspetjournals.org ditions. Many neuropsychiatric drugs are also known to po- a large number of varied clinical and chemical classes of drugs tently antagonize this receptor, underlying aspects of their side that are active in the central nervous system that display potent effect profiles.
    [Show full text]
  • G Protein-Coupled Receptors
    S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. British Journal of Pharmacology (2015) 172, 5744–5869 THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: G protein-coupled receptors Stephen PH Alexander1, Anthony P Davenport2, Eamonn Kelly3, Neil Marrion3, John A Peters4, Helen E Benson5, Elena Faccenda5, Adam J Pawson5, Joanna L Sharman5, Christopher Southan5, Jamie A Davies5 and CGTP Collaborators 1School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK, 2Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK, 3School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK, 4Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK, 5Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/ 10.1111/bph.13348/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading.
    [Show full text]
  • International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors
    1521-0081/67/3/601–655$25.00 http://dx.doi.org/10.1124/pr.114.010249 PHARMACOLOGICAL REVIEWS Pharmacol Rev 67:601–655, July 2015 Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics ASSOCIATE EDITOR: ELIOT H. OHLSTEIN International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors Pertti Panula, Paul L. Chazot, Marlon Cowart, Ralf Gutzmer, Rob Leurs, Wai L. S. Liu, Holger Stark, Robin L. Thurmond, and Helmut L. Haas Department of Anatomy, and Neuroscience Center, University of Helsinki, Finland (P.P.); School of Biological and Biomedical Sciences, University of Durham, United Kingdom (P.L.C.); AbbVie, Inc. North Chicago, Illinois (M.C.); Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany (R.G.); Department of Medicinal Chemistry, Amsterdam Institute of Molecules, Medicines and Systems, VU University Amsterdam, The Netherlands (R.L.); Ziarco Pharma Limited, Canterbury, United Kingdom (W.L.S.L.); Institute of Pharmaceutical and Medical Chemistry (H.S.) and Institute of Neurophysiology, Medical Faculty (H.L.H.), Heinrich-Heine-University Duesseldorf, Germany; and Janssen Research & Development, LLC, San Diego, California (R.L.T.) Abstract ....................................................................................602 Downloaded from I. Introduction and Historical Perspective .....................................................602 II. Histamine H1 Receptor . ..................................................................604 A. Receptor Structure
    [Show full text]
  • Neuroscience Products
    Neuroscience Products CATALOG CATALOG NUMBER U.S. $ NUMBER U.S. $ -A- 3-(N-ACETYLAMINO)-5-(N-DECYL-N- 1 mg 27.50 159549 METHYLAMINO)BENZYL ALCOHOL 5 mg 89.40 o A23187 0-5 C [103955-90-4] (ADMB) See: Antibiotic A23187 A Protein Kinase C activator. Ref.: Proc. Nat. Acad. Sci. USA, 83, 4214 AA-861 20 mg 72.70 (1986). 159061 Purity: 95% 100 mg 326.40 C20H34N2O2 MW 334.5 0oC Orally active, specific and potent inhibitor of 5-lipoxygenase. N-ACETYL-ASP-GLU 25 mg 45.00 153036 [3106-85-2] 100 mg 156.00 Ref.: 1. Yoshimoto, T., et.al., Biochim. o Biophys. Acta, 713, 470 (1982). 2. Ashida, -20-0 C An endogenous neuropeptide with high 250 mg 303.65 Y., et.al., Prostaglandins, 26, 955 (1983). 3. affinity for a brain "Glutamate" receptor. Ancill, R.J., et.al., J. Int. Med. Res., 18, 75 Ref: Zaczek, R., et al., Proc. Natl. Acad. (1990). Sci. (USA), 80, 1116 (1983). C21H26O3 MW 326.4 C11H16N2O8 MW 304.3 ABL PROTEIN TYROSINE KINASE 250 U 47.25 N-ACETYL-2-BENZYLTRYPTAMINE 195876 (v-abl) 1 KU 162.75 See: Luzindole -70oC Recombinant Expressed in E. coli ACETYL-DL-CARNITINE 250 mg 60.00 A truncated form of the v-abl protein 154690 [2504-11-2] 1 g 214.00 tyrosine kinase which contains the 0oC Hydrochloride minimum region needed for kinase activity Crystalline and fibroblast transformation. Suppresses C9H17NO4 • HCl MW 239.7 apoptosis and induces resistance to anti-cancer compounds. O-ACETYL-L-CARNITINE CHLORIDE 500 mg 11.45 Activity: 100 KU/ml 159062 [5080-50-2] 1 g 20.65 Unit Definition: one unit is the amount of 0-5oC (R-(-)-2-Acetyloxy-3-carboxy-N,N,N-trimethyl 5 g 97.45 enzyme which catalyzes the transfer of 1 -1-propanaminium chloride) pmol of phosphate to EAIYAAPFAKKK per Purity: >88% minute at 30°C, pH 7.5.
    [Show full text]
  • WO 2014/085719 Al 5 June 2014 (05.06.2014) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2014/085719 Al 5 June 2014 (05.06.2014) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61M 15/00 (2006.01) A24F 47/00 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (21) International Application Number: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, PCT/US20 13/072426 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 27 November 2013 (27.1 1.2013) KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (25) Filing Language: English OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (26) Publication Language: English SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (30) Priority Data: ZW. 61/730,738 28 November 2012 (28. 11.2012) US 61/794,601 15 March 2013 (15.03.2013) US (84) Designated States (unless otherwise indicated, for every 61/83 1,992 6 June 2013 (06.06.2013) us kind of regional protection available): ARIPO (BW, GH, 61/887,045 4 October 201 3 (04.
    [Show full text]
  • 2 12/ 35 74Al
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 22 March 2012 (22.03.2012) 2 12/ 35 74 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 9/16 (2006.01) A61K 9/51 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 9/14 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (21) International Application Number: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/EP201 1/065959 HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (22) International Filing Date: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 14 September 201 1 (14.09.201 1) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, (25) Filing Language: English RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, (26) Publication Language: English TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/382,653 14 September 2010 (14.09.2010) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, NANOLOGICA AB [SE/SE]; P.O Box 8182, S-104 20 ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, Stockholm (SE).
    [Show full text]
  • Histamine H3 Receptor Antagonists Potentiate Methamphetamine Self-Administration and Methamphetamine-Induced Accumbal Dopamine Release
    Neuropsychopharmacology (2004) 29, 705–717 & 2004 Nature Publishing Group All rights reserved 0893-133X/04 $25.00 www.neuropsychopharmacology.org Histamine H3 Receptor Antagonists Potentiate Methamphetamine Self-Administration and Methamphetamine-Induced Accumbal Dopamine Release 1,3,4 2,4 1,4 ,1 Patrik Munzar , Gianluigi Tanda , Zuzana Justinova and Steven R Goldberg* 1Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, NIDA, NIH, Department of Health 2 and Human Services, Baltimore, MD, USA; Psychobiology Section, Medications Discovery Research Branch, Intramural Research Program, NIDA, NIH, Department of Health and Human Services, Baltimore, MD, USA Methamphetamine administration increases brain levels of histamine and neuronal histamine attenuates several of methamphetamine’s behavioral effects. The role of different subtypes of histamine receptors in this negative feedback, however, remains unclear. There is some evidence on possible involvement of histamine H3 receptors in these actions of methamphetamine. The aim of the present study was to evaluate the effects of two histamine H3 receptor antagonists, clobenpropit and thioperamide, on rewarding and neurochemical effects of methamphetamine utilizing three in vivo methodologies, drug self-administration, drug discrimination, and microdialysis in Sprague–Dawley rats. In rats self-administering methamphetamine intravenously under a fixed-ratio schedule, presession treatment with thioperamide (1.0–3.0 mg/kg, subcutaneous, s.c.) or clobenpropit (1.0–3.0 mg/kg, s.c.) potentiated the reinforcing effects of methamphetamine, as indicated by a dose-dependent increase in responding for a low 0.03 mg/kg dose of methamphetamine, that by itself failed to maintain responding above saline substitution levels, and a decrease in responding for a higher 0.06 mg/kg training dose of methamphetamine.
    [Show full text]
  • Histamine, Histamine Receptors, and Their Role in Immunomodulation: an Updated Systematic Review
    The Open Immunology Journal, 2009, 2, 9-41 9 Open Access Histamine, Histamine Receptors, and their Role in Immunomodulation: An Updated Systematic Review Mohammad Shahid*,1, Trivendra Tripathi2, Farrukh Sobia1, Shagufta Moin2, Mashiatullah Siddiqui2 and Rahat Ali Khan3 1Section of Immunology and Molecular Biology, Department of Microbiology, 2Department of Biochemistry, and 3Department of Pharmacology, Faculty of Medicine, Jawaharlal Nehru Medical College & Hospital, Aligarh Muslim University, Aligarh-202002, U.P., India Abstract: Histamine, a biological amine, is considered as a principle mediator of many pathological processes regulating several essential events in allergies and autoimmune diseases. It stimulates different biological activities through differen- tial expression of four types of histamine receptors (H1R, H2R, H3R and H4R) on secretion by effector cells (mast cells and basophils) through various immunological or non-immunological stimuli. Since H4R has been discovered very re- cently and there is paucity of comprehensive literature covering new histamine receptors, their antagonists/agonists, and role in immune regulation and immunomodulation, we tried to update the current aspects and fill the gap in existing litera- ture. This review will highlight the biological and pharmacological characterization of histamine, histamine receptors, their antagonists/agonists, and implications in immune regulation and immunomodulation. Keywords: Histamine, histamine receptors, H4-receptor, antagonists, agonists, immunomodulation. I.
    [Show full text]
  • Hippocampal-Dependent Antidepressant Action of the H
    International Journal of Neuropsychopharmacology, 2015, 1–11 doi:10.1093/ijnp/pyv032 Research Article research article Hippocampal-Dependent Antidepressant Action of the H3 Receptor Antagonist Clobenpropit in a Rat Model of Depression Teresa Femenía, PhD*; Salvatore Magara, MD*; Caitlin M. DuPont, BS; Maria Lindskog, PhD Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden (Drs Femenía, Magara, and Lindskog, and Ms DuPont). *These authors contributed equally to this work. Correspondence: Maria Lindskog, PhD, Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden ([email protected]). Abstract Background: Histamine is a modulatory neurotransmitter regulating neuronal activity. Antidepressant drugs target modulatory neurotransmitters, thus ultimately regulating glutamatergic transmission and plasticity. Histamine H3 receptor (H3R) antagonists have both pro-cognitive and antidepressant effects; however, the mechanism by which they modulate glutamate transmission is not clear. We measured the effects of the H3R antagonist clobenpropit in the Flinders Sensitive Line (FSL), a rat model of depression with impaired memory and altered glutamatergic transmission. Methods: Behavioral tests included the forced swim test, memory tasks (passive avoidance, novel object recognition tests), and anxiety-related paradigms (novelty suppressed feeding, social interaction, light/dark box tests). Hippocampal protein levels were detected by Western blot. Hippocampal plasticity was studied by in slice field recording of CA3-CA1 long-term synaptic potentiation (LTP), and glutamatergic transmission by whole-cell patch clamp recording of excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons. Results: Clobenpropit, administered systemically or directly into the hippocampus, decreased immobility during the forced swim test; systemic injections reversed memory deficits and increased hippocampal GluN2A protein levels. FSL rats displayed anxiety-related behaviors not affected by clobenpropit treatment.
    [Show full text]
  • Molecular Tools for G-Protein Coupled Receptors: Synthesis
    Molecular Tools for G-Protein Coupled Receptors: Synthesis, Pharmacological Characterization and [3H]-Labeling of Subtype-selective Ligands for Histamine H4 and NPY Y2 Receptors Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) an der Fakultät für Chemie und Pharmazie der Universität Regensburg vorgelegt von Paul Baumeister aus Zinzenzell 2014 Die vorliegende Arbeit entstand in der Zeit von April 2010 bis April 2014 unter der Anleitung von Herrn Prof. Dr. Armin Buschauer am Institut für Pharmazie der Naturwissenschaftlichen Fakultät IV – Chemie und Pharmazie – der Universität Regensburg. Das Promotionsgesuch wurde eingereicht im Juni 2014. Tag der mündlichen Prüfung: 18.07.2014 Prüfungsausschuss: Prof. Dr. J. Heilmann (Vorsitzender) Prof. Dr. A. Buschauer (Erstgutachter) Prof. Dr. S. Elz (Zweitgutachter) Prof. Dr. J. Wegener (Drittprüfer) „If you don’t turn your life into a story, you just become a part of someone else’s story.“ Terry Pratchett I Danksagung An dieser Stelle möchte mich ganz herzlich bei allen bedanken, die zum Gelingen dieser Arbeit beigetragen haben und mich während der Promotionszeit begleitet haben. Besonders möchte ich danken: Meinem Doktorvater Herrn Prof. Dr. Armin Buschauer für das Vertrauen und die Möglichkeit dieses interessante und herausfordernde Projekt zu verwirklichen, seine wissenschaftlichen Anregungen, für die mir gewährte forscherische Freiheit, seine konstruktive Kritik bei der Durchsicht der Arbeit, sein stets offenes Ohr, sowie die Mentorenschaft in der Emil-Fischer-Graduiertenschule; Herrn Prof. Dr. Günther Bernhardt für seine stete Hilfsbereitschaft und sein Interesse am Fortschritt der Arbeit, sein Fachwissen, die Durchsicht der Arbeit, die Co-Mentorenschaft in der Emil-Fischer- Graduiertenschule, sowie für hervorragenden Sommerfeste; Herrn Prof. Dr.
    [Show full text]
  • ( 12 ) United States Patent
    US010493080B2 (12 ) United States Patent (10 ) Patent No.: US 10,493,080 B2 Schultz et al. (45 ) Date of Patent : Dec. 3 , 2019 ( 54 ) DIRECTED DIFFERENTIATION OF (56 ) References Cited OLIGODENDROCYTE PRECURSOR CELLS TO A MYELINATING CELL FATE U.S. PATENT DOCUMENTS 7,301,071 B2 11/2007 Zheng (71 ) Applicants : The Scripps Research Institute , La 7,304,071 B2 12/2007 Cochran et al. Jolla , CA (US ) ; Novartis AG , Basel 9,592,288 B2 3/2017 Schultz et al. 2003/0225072 A1 12/2003 Welsh et al. ( CH ) 2006/0258735 Al 11/2006 Meng et al. 2009/0155207 Al 6/2009 Hariri et al . (72 ) Inventors : Peter Schultz , La Jolla , CA (US ) ; Luke 2010/0189698 A1 7/2010 Willis Lairson , San Diego , CA (US ) ; Vishal 2012/0264719 Al 10/2012 Boulton Deshmukh , La Jolla , CA (US ) ; Costas 2016/0166687 Al 6/2016 Schultz et al. Lyssiotis , Boston , MA (US ) FOREIGN PATENT DOCUMENTS (73 ) Assignees : The Scripps Research Institute , La JP 10-218867 8/1998 Jolla , CA (US ) ; Novartis AG , Basel JP 2008-518896 5/2008 (CH ) JP 2010-533656 A 10/2010 WO 2008/143913 A1 11/2008 WO 2009/068668 Al 6/2009 ( * ) Notice : Subject to any disclaimer , the term of this WO 2009/153291 A1 12/2009 patent is extended or adjusted under 35 WO 2010/075239 Al 7/2010 U.S.C. 154 ( b ) by 0 days . (21 ) Appl. No .: 15 /418,572 OTHER PUBLICATIONS Molin - Holgado et al . “ Regulation of muscarinic receptor function in ( 22 ) Filed : Jan. 27 , 2017 developing oligodendrocytes by agonist exposure ” British Journal of Pharmacology, 2003 , 138 , pp .
    [Show full text]
  • Novel Modulation of Adenylyl Cyclase Type 2 Jason Michael Conley Purdue University
    Purdue University Purdue e-Pubs Open Access Dissertations Theses and Dissertations Fall 2013 Novel Modulation of Adenylyl Cyclase Type 2 Jason Michael Conley Purdue University Follow this and additional works at: https://docs.lib.purdue.edu/open_access_dissertations Part of the Medicinal-Pharmaceutical Chemistry Commons Recommended Citation Conley, Jason Michael, "Novel Modulation of Adenylyl Cyclase Type 2" (2013). Open Access Dissertations. 211. https://docs.lib.purdue.edu/open_access_dissertations/211 This document has been made available through Purdue e-Pubs, a service of the Purdue University Libraries. Please contact [email protected] for additional information. Graduate School ETD Form 9 (Revised 12/07) PURDUE UNIVERSITY GRADUATE SCHOOL Thesis/Dissertation Acceptance This is to certify that the thesis/dissertation prepared By Jason Michael Conley Entitled NOVEL MODULATION OF ADENYLYL CYCLASE TYPE 2 Doctor of Philosophy For the degree of Is approved by the final examining committee: Val Watts Chair Gregory Hockerman Ryan Drenan Donald Ready To the best of my knowledge and as understood by the student in the Research Integrity and Copyright Disclaimer (Graduate School Form 20), this thesis/dissertation adheres to the provisions of Purdue University’s “Policy on Integrity in Research” and the use of copyrighted material. Approved by Major Professor(s): ____________________________________Val Watts ____________________________________ Approved by: Jean-Christophe Rochet 08/16/2013 Head of the Graduate Program Date i NOVEL MODULATION OF ADENYLYL CYCLASE TYPE 2 A Dissertation Submitted to the Faculty of Purdue University by Jason Michael Conley In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy December 2013 Purdue University West Lafayette, Indiana ii For my parents iii ACKNOWLEDGEMENTS I am very grateful for the mentorship of Dr.
    [Show full text]