DOCSLIB.ORG

Pharmacological Approaches to the Treatment of Ischaemic Neuronal Damage

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Pharmacological Approaches to the Treatment of Ischaemic Neuronal Damage Ey e (1991) 5, 193-197 Pharmacological Approaches to the Treatment of Ischaemic Neuronal Damage L. L. IVERSEN Harlow Summary Retina is particularly susceptible to ischaemic damage following exposure to anoxia or hypoglycaemia. In animal models the neuronal damage following ischaemia resembles that caused by exposure to glutamate or other excitotoxic agents which act on excitatory amino acid receptors. There are a number of pharmacological approaches designed to limit neuronal damage following ischaemia. These include free radical scavenging agents, calcium channel blockers, kappa opiate agonists and excitatory amino acid antagonists. Recent studies with antagonists acting at both NMDA and non-NMDA receptors for glutamate show that such compounds can pro­ tect against ischaemic damage, and are effective even when administered several hours after the ischaemic insult. Retinal neurones, like those in other regions systemic administration of L-glutamate or of CNS, are highly dependent on the oxida­ aspartate in very large doses (2-4 g/kg s.cut) tive metabolism of glucose for their energy lead to profound neurodegenerative changes requirements, and are susceptible to damage in retinal neurones of albino mice. These under conditions of ischaemia or hypoglycae­ changes were seen mainly in ganglion cells in mia. There has been an increased research adult animals, but in immature animals all ret­ effort in recent years devoted to the develop­ inal cells were affected. Olney and colleagues ment of pharmacological agents which might more than a decade later noted that system­ protect neural tissue against such damage. A ically administered L-glutamate caused neu­ wide variety of differentscientific approaches rode generative changes in basal has been used, and new compounds in hypothalamus and circumventricular regions development as potential 'neuroprotectives' of immature rat brain, and Olney was the first include amino steroids and other free radical to formulate the hypothesis that L-glutamate scavengers, calcium channel blockers, kappa and other neurotoxins which act to excite opiate agonists, and excitatory amino acid nerve cells owe their toxicity to their excitant antagonists (for reviews see 1-3). This short properties.5,6 It is now generally recognised review will focus on the latter category of new that L-glutamate and L-aspartate are widely used excitatory neurotransmitters in mamma­ drugs, where considerable scientific progress lian CNS.b,7 In retina they are the principal has been made recently. transmitters used by excitatory inter-neu­ The Excitoxic Hypothesis rones (bipolar cells, some amacrine cells and The neurotoxic effects of L-glutamate and probably most ganglion cells). L-aspartate were firstdescribed by Lucas and A further extension of the excitotoxin Newhouse4 33 years ago. They found that hypothesis suggests that neural damage fol- Correspondence to: L. L. Iversen, Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. 194 L. L. IVERSEN Selective agonists b;nate N-methyl-D-a&partate (NMDA) Endogenous agonists (cooe )'-cooe .N� L-glutamate L-aspartate Antagonists o lie < HO-P-O NH IIIIIC009 y-o-glutamylglycine D-2-amino-S-phosphonovalerate (DOG) (o-2-am;no-S-phosphonopentaDoate (APV, APS) Fig. 3. Structures of the putative excitatory amino acid neurotransmitters L -glutamate and L -aspartate and some analogues which have been used to define the subtypes of excitatory amino acid receptor. Fig. 1. Structures of excitatory amino acid neurotransmitters and some analogues which hav e been used to define the receptor sub-types. PHARMACOLOGY OF RETINAL ISCHAEMIA 195 eral different receptors in eNS. At least three major receptor sub-types are recognised: the N-methyl-D-asparate preferring (NMDA) receptor, the quisqualate/kainate receptor (activated selectively by these agonists) and a 'metabotropic' quisqualate preferring recep­ tor, in which recognition of agonist is coupled to breakdown of membrane phosphoinosi­ tides. The first two receptors control cation Fig. 2. DlZOCILPINE (MK-80l) = (+)-5-methy l- 10, ll-dihydro-5H-dibenzo[a, dJcy clohepten-5, JO-imine. channels, allowing the entry of sodium or sodium and calcium (NMDA) to depolarise lowing ischaemia or hypoglycaemia may target neurones (Fig. 1). result partly as a consequence of increased A range of anatogonists acting at the release of glutamate and/or over stimulation NMDA receptor have been described; these of excitatory amino acid receptors during such include competitive antagonists of the amino conditions.8.9 phosphonate series, and non-competitive antagonists. The most potent of the latter is Excitatory Amino Acid Antagonists as the research compound MK-801 (dizocilpine) . Neuroprotective Agents (Fig. 2), others include the intravenous anaes­ L-glutamate and related excitants act on sev- thetics ketamine and phencyclidine, and the . a b� c Fig. 3. Light micrograph of 15 day old chick embry o retinafollowing 30 min incubation in balnced salt solution containing no excitotoxin (a), or200 [.1MNMDA (b), or200 [.1MNMDA + 0. 1 [.1M MK-801 (c). The typical pattern a/neuronal necrosis induced by NMDA is apparent in (b), including marked thickening of inner neural lay ers due to oedema. Retina in (c) although exposed to the same excitotoxin was completely protected by MK-801. From Olney et al. (ref. 14). 196 L. L. IVERSEN opiate derivatives dextromethorphan.1O-12 tion of the non-selective glutamate antagonist There has been less progress in identifying gamma-glutamylglycine. Levy and Lipton19 antagonists acting on non-NMDA receptors, have described an in vitro model using rat ret­ although recently quinoxaline derivatives inal ganglion cells in culture, and found that have been discovered which act in this way, eg the damage elicited by exposure to elevated CNQX.13 external calcium concentrations (10 mM) was NMDA antagonists, both of the competi­ prevented by addition of NMDA antagonists, tive and non-competitive types have been suggesting mediation by glutamate. They found to offer protection against the neural found that addition of MK-801 could be damage normally evoked by L-glutamate, delayed for 4 h after initial exposure to ele­ NMDA and other excitoxins which act at vated calcium, and still remain neuroprotec­ NMDA receptors. Such experiments have tive. Other studies using a variety of in vivo been performed using neurones in tissue cul­ models of cerebral ischaemia or exitotoxin­ ture or in isolated fragments of CNS tissue in induced damage to hippocampal or cortical vitro, and also in vivo. For example, Olney et neurones have also revealed a delayed effi­ al.14 found that MK-801 was remarkably cacy of MK-801 in offering neuroprotection, effective in preventing the histological dam­ suggesting a possible clinical utility of this or age normally evoked by exposure of 15 day related NMDA antagonists in the acute treat­ old chick retina to 200 �M NMDA in vitro. A ment of stroke, prenatal-ischemia or other concentration of 0.1 �M MK-801 wa able to forms of cerebral ischaemia or hypoglycaemia offer complete protection in this model. (for reviews see 20-21). (Fig. 3). The excitatory amino acid antagonists Other experiments have attempted to sim­ represent a promising new approach to the ulate conditions of ischaemia and/or hypo­ development of neuroprotective agents, although it is too soon to judge whether the glycaemia in vitro. Choi and colleagues have effectiveness of such compounds in labora­ used primary cultures of mouse cortical neu­ tory models will translate into clinical rones for such studies, and exposed them to a practice. brief period of hypoxia (4-6h) or to glucose­ Key words: ischaemic, glutamate, NMDA receptor, free medium. The damage which ensued neuroprotective agents, MK-801, dizocilpine. appeared to be mediated largely by excitoxic References mechanisms, since MK-801 and other NMDA 1 Krieglstein J (ed): 'Pharmacology of Cerebral antagonists provided complete protection in Ischaemia 1988', CRC Press, Boca Raton, Flor­ this in vitro model. The EC50 for MK-801 was ida, 1989 . 0.1 �M.15 Zeevalk and Nicklas used 13 day old 2 Krieglstein J (ed): 'Pharmacology of Cerebral Ischaemia 1990', CRC Press, Boca Raton, Flor­ chick embyro retina in vitro and simulated ida (in press). hypoglycaemia and ischaemia by adding 3 Fieschi C and Lenzi GL (eds.): Proceedings of Brain iodoacetate or potassium cyanide respect­ 89. ] Cerebral Blood FlowMetab 1989, 9: Suppl!. ively.16 Again MK-801 afforded complete pro­ 4 Lucas DR and Newhouse JP: The toxic effects of L-glutamate on the inner layers of the retina. tection, whereas the non-NMDA antagonist Arch Ophthalmol1957,58: 193-201. CNQX was ineffective. Olney et al. 17 however 5 Olney JW: Brain lesions obesity and other disturb­ reported that in chick embryo retina a combi­ ances in mice treated with monosodium gluta­ nation of MK-801 with CNQX was more mate. Science1969, 164: 719-21. 6 Olney JW: The toxic effects of glutamate and effective than either compound alone in pro­ related compounds in the retina and the brain. tecting against ischaemic damage, suggesting Retina1982, 2: 341-59 . a possible involvement of both NMDA and 7 Watkins JC and Evans RH: Excitatory amino acid transmitters. Ann Rev Pharmacal Toxicol 1981, non-NMDA receptors. The involvement of 21: 165-204. excitotoxic mechanisms in mediating retinal 8 Schwarcz R and Meldrum B: Excitatory amino acid damage after ischaemia was strongly sug­ antagonists provide a therapeutic approach to gested by the findings of David et al.18 who neurological disorders. Lancet 1985,ii, 140--3. found that damage elicited by exposure of 9 Rothman S: Synaptic release of excitatory amino acid neurotransmitter mediates anoxic neuronal chick embryo retina to a 40 minute period of death. ] Neuroscience 1984,4: 1884-91. hypoxia could be largely prevented by addi- 10 Cotman CW and Iversen LL: Excitatory amino acids PHARMACOLOGY OF RETINAL ISCHAEMIA 197 in the brain-focus on NMDA receptors. Trends 17 Price MT, Honore T, Mueller MEM, Labruyere J, in Neurosciences 1987, 10: 263-301.
Load more

Recommended publications
  • A Guide to Glutamate Receptors
    A guide to glutamate receptors 1 Contents Glutamate receptors . 4 Ionotropic glutamate receptors . 4 - Structure ........................................................................................................... 4 - Function ............................................................................................................ 5 - AMPA receptors ................................................................................................. 6 - NMDA receptors ................................................................................................. 6 - Kainate receptors ............................................................................................... 6 Metabotropic glutamate receptors . 8 - Structure ........................................................................................................... 8 - Function ............................................................................................................ 9 - Group I: mGlu1 and mGlu5. .9 - Group II: mGlu2 and mGlu3 ................................................................................. 10 - Group III: mGlu4, mGlu6, mGlu7 and mGlu8 ............................................................ 10 Protocols and webinars . 11 - Protocols ......................................................................................................... 11 - Webinars ......................................................................................................... 12 References and further reading . 13 Excitatory synapse pathway
    [Show full text]
  • Glycine Activated Ion Channel Subunits Encoded by Ctenophore
    Glycine activated ion channel subunits encoded by PNAS PLUS ctenophore glutamate receptor genes Robert Albersteina, Richard Greya, Austin Zimmeta, David K. Simmonsb, and Mark L. Mayera,1 aLaboratory of Cellular and Molecular Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; and bThe Whitney Laboratory for Marine Bioscience, University of Florida, St. Augustine, FL 32080 Edited by Christopher Miller, Howard Hughes Medical Institute, Brandeis University, Waltham, MA, and approved September 2, 2015 (received for review July 13, 2015) Recent genome projects for ctenophores have revealed the subunits and glutamate to GluN2 subunits for activation of ion presence of numerous ionotropic glutamate receptors (iGluRs) in channel gating (12, 14–17), as well as depolarization to relieve + Mnemiopsis leidyi and Pleurobrachia bachei, among our earliest ion channel block by extracellular Mg2 (18, 19). The initial metazoan ancestors. Sequence alignments and phylogenetic analy- annotation of the M. leidyi genome identified 16 candidate iGluR sis show that these form a distinct clade from the well-characterized genes (4), whereas in the draft genome of P. bachei, 14 iGluRs AMPA, kainate, and NMDA iGluR subtypes found in vertebrates. were annotated as kainate-like receptors (5). In view of growing Although annotated as glutamate and kainate receptors, crystal interest in the molecular evolution of ion channels and receptors, structures of the ML032222a and PbiGluR3 ligand-binding domains and the pivotal role that ctenophores play in our current un- (LBDs) reveal endogenous glycine in the binding pocket, whereas derstanding of nervous system development (20), we initiated a ligand-binding assays show that glycine binds with nanomolar af- structural and functional characterization of glutamate receptors finity; biochemical assays and structural analysis establish that glu- expressed in both species.
    [Show full text]
  • Physiological and Pharmacological Characteristics of Quisqualic Acid-Induced K؉-Current Response in the Ganglion Cells of Aplysia
    Japanese Journal of Physiology, 51, 511–521, 2001 Physiological and Pharmacological Characteristics of Quisqualic Acid-Induced K1-Current Response in the Ganglion Cells of Aplysia Shingo KIMURA, Satoshi KAWASAKI, Koichiro TAKASHIMA, and Kazuhiko SASAKI Department of Physiology and Advanced Medical Science Research Center, School of Medicine, Iwate Medical University, Morioka, 020–8505 Japan Abstract: The extracellular application of ei- the application of either kainate or AMPA, ago- ther quisqualic acid (QA) or Phe-Met-Arg-Phe- nists for non-NMDA receptors, produced no type NH2 (FMRFamide) induces an outward current in of response in the same neurons. The QA-in- identified neurons of Aplysia ganglion under volt- duced K1-current response was not depressed age clamp. The time course of the QA-induced at all by an intracellular injection of either gua- response is significantly slower than that induced nosine 59-O-(2-thiodiphosphate) (GDP-bS) or by FMRFamide. The reversal potential for both guanosine 59-O-(3-thiotriphosphate) (GTP-gS), responses was 292 mV and was shifted 17 mV but the FMRFamide-induced response was in a positive direction for a twofold increase in markedly blocked by both GDP-bS and GTP-gS the extracellular K1 concentration. The QA-in- in the same cell. Furthermore, the QA- and FMR- duced response was markedly depressed in the Famide-induced K1-current responses were both presence of Ba21, a blocker of inward rectifier decreased markedly when the temperature was K1-channel, whereas TEA, a Ca21-activated K1- lowered to 15°C, from 23°C. These results sug- 1 1 channel (BKCa) blocker, or 4-AP, a transient K gested that the QA-induced K -current response (A)-channel blocker, had no effect on the re- is produced by an activation of a novel type of sponse.
    [Show full text]
  • Download Product Insert (PDF)
    Product Information CNQX Item No. 14618 CAS Registry No.: 115066-14-3 Formal Name: 1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6- quinoxalinecarbonitrile H Synonyms: 6-cyano-7-Nitroquinoxaline-2,3-dione, NC N O FG 9065 MF: C9H4N4O4 FW: 232.2 O O N N Purity: ≥98% 2 Stability: ≥2 years at -20°C H Supplied as: A crystalline solid λ UV/Vis.: max: 217, 275, 315 nm Laboratory Procedures For long term storage, we suggest that CNQX be stored as supplied at -20°C. It should be stable for at least two years. CNQX is supplied as a crystalline solid. A stock solution may be made by dissolving the CNQX in the solvent of choice. CNQX is soluble in organic solvents such as DMSO and dimethyl formamide (DMF), which should be purged with an inert gas. The solubility of CNQX in these solvents is approximately 5 and 12 mg/ml, respectively. CNQX is sparingly soluble in aqueous buffers. For maximum solubility in aqueous buffers, CNQX should first be dissolved in DMF and then diluted with the aqueous buffer of choice. CNQX has a solubility of approximately 0.5 mg/ml in a 1:1 solution of DMF:PBS (pH 7.2) using this method. We do not recommend storing the aqueous solution for more than one day. CNQX is a competitive, non-NMDA glutamate receptor antagonist (IC50s = 0.3 and 1.5 μM for AMPA and kainate 1,2 receptors, respectively, versus IC50 = 25 μM for NMDA receptors). This compound has been used to specifically target AMPA and kainate receptor responses and thus differentiate from that of NMDA receptors.
    [Show full text]
  • Switch to Tonic Discharge by Thyrotropin-Releasing Hormone
    Neuron Article Synchronized Network Oscillations in Rat Tuberoinfundibular Dopamine Neurons: Switch to Tonic Discharge by Thyrotropin-Releasing Hormone David J. Lyons,1,* Emilia Horjales-Araujo,1 and Christian Broberger1,* 1Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden *Correspondence: [email protected] (D.J.L.), [email protected] (C.B.) DOI 10.1016/j.neuron.2009.12.024 SUMMARY most common form of pituitary tumor (Burrow et al., 1981), and by the hyperprolactinaemia and sometimes galactorrhea that The pituitary hormone, prolactin, triggers lactation in is a side effect of antipsychotic drugs with DA antagonist prop- nursing mothers. Under nonlactating conditions, erties (Clemens et al., 1974; Meltzer and Fang, 1976). Yet, to prolactin secretion is suppressed by powerful inhibi- date, the cellular and network electrophysiological properties tion from hypothalamic tuberoinfundibular dopamine of the TIDA cell population have not been described. These (TIDA) neurons. Although firing pattern has been sug- factors are potentially fundamental features of prolactin regula- gested as integral to neuroendocrine control, the tion since discharge pattern may determine the functional output of neuroendocrine control of the anterior pituitary, as is observed electrical behavior of TIDA cells remains unknown. in the magnocellular system (Wakerley and Lincoln, 1973; Hatton We demonstrate that rat TIDA neurons discharge et al., 1983). Thus, the periodic bursting pattern in hypothalamic rhythmically in a robust 0.05 Hz oscillation. The oscil- gonadotropin-releasing hormone neurons is required for stimu- lation is phase locked between neurons, and while it lation of target gonadotrophs in the pituitary (Knobil, 1980). persists during chemical synaptic transmission When bursting is artificially replaced by continuous agonist stim- blockade, it is abolished by gap junction antagonists.
    [Show full text]
  • Interplay Between Gating and Block of Ligand-Gated Ion Channels
    brain sciences Review Interplay between Gating and Block of Ligand-Gated Ion Channels Matthew B. Phillips 1,2, Aparna Nigam 1 and Jon W. Johnson 1,2,* 1 Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA; [email protected] (M.B.P.); [email protected] (A.N.) 2 Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA * Correspondence: [email protected]; Tel.: +1-(412)-624-4295 Received: 27 October 2020; Accepted: 26 November 2020; Published: 1 December 2020 Abstract: Drugs that inhibit ion channel function by binding in the channel and preventing current flow, known as channel blockers, can be used as powerful tools for analysis of channel properties. Channel blockers are used to probe both the sophisticated structure and basic biophysical properties of ion channels. Gating, the mechanism that controls the opening and closing of ion channels, can be profoundly influenced by channel blocking drugs. Channel block and gating are reciprocally connected; gating controls access of channel blockers to their binding sites, and channel-blocking drugs can have profound and diverse effects on the rates of gating transitions and on the stability of channel open and closed states. This review synthesizes knowledge of the inherent intertwining of block and gating of excitatory ligand-gated ion channels, with a focus on the utility of channel blockers as analytic probes of ionotropic glutamate receptor channel function. Keywords: ligand-gated ion channel; channel block; channel gating; nicotinic acetylcholine receptor; ionotropic glutamate receptor; AMPA receptor; kainate receptor; NMDA receptor 1. Introduction Neuronal information processing depends on the distribution and properties of the ion channels found in neuronal membranes.
    [Show full text]
  • Cellular Trafficking of Nicotinic Acetylcholine Receptors
    npg Acta Pharmacol Sin 2009 Jun; 30 (6): 656–662 Review Cellular trafficking of nicotinic acetylcholine receptors Paul A ST JOHN* Department of Cell Biology and Anatomy, University of Arizona College of Medicine, Tucson, AZ 85724, USA Nicotinic acetylcholine receptors (nAChRs) play critical roles throughout the body. Precise regulation of the cellular loca- tion and availability of nAChRs on neurons and target cells is critical to their proper function. Dynamic, post-translational regulation of nAChRs, particularly control of their movements among the different compartments of cells, is an important aspect of that regulation. A combination of new information and new techniques has the study of nAChR trafficking poised for new breakthroughs. Keywords: membrane traffic; protein traffic; biosynthesis; endocytosis; endoplasmic reticulum-associated degradation Acta Pharmacologica Sinica (2009) 30: 656–662; doi: 10.1038/aps.2009.76 Introduction ways, but two particular perturbations have been especially well studied and exert their effects at least in part by altering Nicotinic acetylcholine receptors (nAChRs) mediate the trafficking of nAChRs: 1) denervation changes the total synaptic transmission in the CNS, in autonomic ganglia, and number, the distribution, and the turnover rate of nAChRs in at neuromuscular junctions and other peripheral synapses. skeletal muscle; 2) prolonged exposure to nicotine increases The functional properties of these synapses differ, but in each the total number of nAChRs in neurons. Several of the stud- case, properly functional signaling requires cellular control ies reviewed here addressed the mechanisms by which these of the number, type, and location of nAChRs. Trafficking treatments alter nAChR trafficking. Other authors in this of nAChRs – the movement of nAChRs between compart- special issue will address other aspects of the effects of nico- ments of a cell, including the cell's biosynthetic and degrada- tine on nAChRs.
    [Show full text]
  • Kainate Receptors Depress Excitatory Synaptic Transmission at CA33CA1 Synapses in the Hippocampus Via a Direct Presynaptic Action
    The Journal of Neuroscience, May 1, 2001, 21(9):2958–2966 Kainate Receptors Depress Excitatory Synaptic Transmission at CA33CA1 Synapses in the Hippocampus via a Direct Presynaptic Action Matthew Frerking,1 Dietmar Schmitz,1 Qiang Zhou,1 Joshua Johansen,2 and Roger A. Nicoll1,2 Departments of 1Cellular and Molecular Pharmacology and 2Physiology, University of California, San Francisco, California 94143-0450 Kainate receptor activation depresses synaptic release of neu- excitation and subsequent release of a neuromodulator. Pre- rotransmitter at a number of synapses in the CNS. The mech- synaptic depolarization, achieved via increasing extracellular anism underlying this depression is controversial, and both K ϩ, caused a depression of the presynaptic fiber volley and an ionotropic and metabotropic mechanisms have been sug- increase in the frequency of miniature EPSCs. Neither effect gested. We report here that the AMPA/kainate receptor ago- was observed with DA, suggesting that DA does not depress nists domoate (DA) and kainate (KA) cause a presynaptic de- transmission via a presynaptic depolarization. However, the pression of glutamatergic transmission at CA33CA1 synapses effects of DA were abolished by the G-protein inhibitors in the hippocampus, which is not blocked by the AMPA recep- N-ethylmaleimide and pertussis toxin. These results suggest tor antagonist GYKI 53655 but is blocked by the AMPA/KA that KA receptor activation depresses synaptic transmission at receptor antagonist CNQX. Neither a blockade of interneuronal this synapse via a direct, presynaptic, metabotropic action. discharge nor antagonists of several neuromodulators affect Key words: domoate; kainate; metabotropic; presynaptic; the depression, suggesting that it is not the result of indirect hippocampus; CA1 Neurotransmitter receptors in the CNS can be separated into two use-dependent depression.
    [Show full text]
  • Functional Kainate-Selective Glutamate Receptors in Cultured Hippocampal Neurons (Excitatory Amino Acid Receptors/Hippocampus) JUAN LERMA*, ANA V
    Proc. Natl. Acad. Sci. USA Vol. 90, pp. 11688-11692, December 1993 Neurobiology Functional kainate-selective glutamate receptors in cultured hippocampal neurons (excitatory amino acid receptors/hippocampus) JUAN LERMA*, ANA V. PATERNAIN, JosE R. NARANJO, AND BRITT MELLSTR6M Departamento de Plasticidad Neural, Instituto Cajal, Consejo Superior de Investigaciones Cientfficas, Avenida Doctor Arce 37, 28002-Madrid, Spain Communicated by Michael V. L. Bennett, September 15, 1993 ABSTRACT Glutamate mediates fast synaptic transmis- experiments, the regional distribution of high-affinity sion at the majority of excitatory synapses throughout the [3H]kainate binding sites does not match the AMPA receptor central nervous system by interacting with different types of distribution but corresponds well to the brain areas with high receptor channels. Cloning of glutamate receptors has pro- susceptibility to the neurotoxic actions of kainate (e.g., vided evidence for the existence of several structurally related hippocampal CA3 field) (13). However, patch-clamp record- subunit families, each composed of several members. It has ings from adult hippocampal neurons have revealed that been proposed that KA1 and KA2 and GluR-5, GluR-6, and native glutamate receptors are similar to the AMPA-type GluR-7 families represent subunit classes of high-affinity kain- recombinant glutamate receptors expressed from cDNA ate receptors and that in vivo different kainate receptor sub- clones but have failed so far to detect receptor channels ofthe types might be constructed from these subunits in heteromeric kainate type (14, 15). The only apparently high-affinity kain- assembly. However, despite some indications from autoradio- ate receptor channels have been found in the peripheral graphic studies and binding data in brain membranes, no nervous system (16, 17), although they are also activated by functional pure kainate receptors have so far been detected in AMPA.
    [Show full text]
  • Kainate Receptor-Mediated Depression of Glutamate Release
    Article Kainate Receptor‐Mediated Depression of Glutamate Release Involves Protein Kinase A in the Cerebellum Rafael Falcón‐Moya, Pilar Losada‐Ruiz and Antonio Rodríguez‐Moreno * Laboratorio de Neurociencia Celular y Plasticidad, Departamento de Fisiología, Anatomía y Biología Celular, Universidad Pablo de Olavide, ES‐41013 Sevilla, Spain * Correspondence: [email protected]; Tel: +34‐95497‐7393 Received: 20 July 2019; Accepted: 23 August 2019; Published: 23 August 2019 Abstract: Kainate (KA) receptors (KAR) have important modulatory roles of synaptic transmission. In the cerebellum, the action mechanisms of KAR‐mediated glutamatergic depression are unknown. We studied these mechanisms by recording evoked excitatory postsynaptic currents (eEPSCs) from cerebellar slices using the whole‐cell configuration of the patch‐clamp technique. We observed that 3 μM KA decreased the amplitude of eEPSCs and increased the number of failures at the synapses established between parallel fibers (PF) and Purkinje neurons, and the effect was antagonized by NBQX under the condition where AMPA receptors were previously blocked. The inhibition of protein kinase A (PKA) suppressed the effect of KAR activation on eEPSC, and effect was not prevented by protein kinase C inhibitors. Furthermore, in the presence of Pertussis toxin, the depression of glutamate release mediated by KAR activation was prevented, invoking the participation of a Gi/o protein in this modulation. Finally, the KAR‐mediated depression of glutamate release was not prevented by blocking calcium‐permeable KARs or by treatments that affect calcium release from intracellular stores. We conclude that KARs present at these synapses mediate an inhibition of glutamate release through a mechanism that involves the activation of G‐protein and protein kinase A.
    [Show full text]
  • Isoflurane Inhibits Dopaminergic Synaptic Vesicle Exocytosis Coupled to Cav2.1 and Cav2.2 in Rat Midbrain Neurons
    This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Article: New Research | Neuronal Excitability Isoflurane inhibits dopaminergic synaptic vesicle exocytosis coupled to CaV2.1 and CaV2.2 in rat midbrain neurons Christina L. Torturo1,2, Zhen-Yu Zhou1, Timothy A. Ryan1,3 and Hugh C. Hemmings1,2 1Departments of Anesthesiology, Weill Cornell Medicine, New York, NY 10065 2Pharmacology, Weill Cornell Medicine, New York, NY 10065 3Biochemistry, Weill Cornell Medicine, New York, NY 10065 https://doi.org/10.1523/ENEURO.0278-18.2018 Received: 16 July 2018 Revised: 18 December 2018 Accepted: 21 December 2018 Published: 10 January 2019 Author Contributions: CLT, ZZ, TAR and HCH designed the research; CLT performed the research, TAR contributed unpublished reagents/analytic tools; CLT and ZZ analyzed the data; CLT, ZZ, TAR, and HCH wrote the paper. Funding: http://doi.org/10.13039/100000002HHS | National Institutes of Health (NIH) GM58055 Conflict of Interest: HCH: Editor-in-Chief of the British Journal of Anaesthesia; consultant for Elsevier. Funding Sources: NIH GM58055 Corresponding author: Hugh C. Hemmings, E-mail: [email protected] Cite as: eNeuro 2019; 10.1523/ENEURO.0278-18.2018 Alerts: Sign up at www.eneuro.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process. Copyright © 2019 Torturo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
    [Show full text]
  • Excitatory Amino Acid Β-N-Methylamino-L-Alanine Is a Putative
    J. Serb. Chem. Soc. 76 (4) 479–490 (2011) UDC 547.466.23+547.416:616.8+ JSCS–4134 620.266.1:628.513 Review REVIEW Excitatory amino acid β-N-methylamino-L-alanine is a putative environmental neurotoxin SRDJAN LOPIČIĆ1*, MARIJA BRATIĆ-STANOJEVIĆ1, PATHAK DHRUBA1, DRAGAN PAVLOVIĆ2, MILICA PROSTRAN3 and VLADIMIR NEDELJKOV1 1Institute for Pathological Physiology, School of Medicine, University of Belgrade, 11000 Belgrade, Serbia, 2Ernst Moritz Arndt University, Greifswald, Germany and 3Institute of Pharmacology, Clinical Pharmacology and Toxicology, School of Medicine, University of Belgrade, 11000 Belgrade, Serbia (Received 29 July, revised 4 October 2010) Abstract: The amino acid β-N-methylamino-L-alanine (L-BMAA) has been associated with the amyotrophic lateral sclerosis/parkinsonism-dementia complex in three distinct western Pacific populations. The putative neurotoxin is produced by cyanobacteria, which live symbiotically in the roots of cycad trees. L-BMAA was thought to be a threat only to those few populations whose diet and medicines rely heavily on cycad seeds. However, the recent discovery that cyanobacteria from diverse terrestrial, freshwater, and saltwater ecosys- tems around the world produce the toxin requires a reassessment of whether it poses a larger health threat. Therefore, it is proposed that monitoring L-BMAA levels in cyanobacteria-contaminated water supplies might be prudent. Keywords: β-N-methylamino-L-alanine; neurodegenerative diseases; neuro- toxicity; environmental toxin. CONTENTS 1. INTRODUCTION 2. THE BMAA NEUROTOXICITY 3. MECHANISMS OF BMAA NEUROTOXICITY 4. BMAA AND THE ENVIRONMENT 5. CONCLUSIONS 1. INTRODUCTION It has been well established that cyanobacterial and other environmental toxins cause and/or promote the development of a vast variety of diseases and * Corresponding author.
    [Show full text]