Skip to main content
SpringerLink
Log in

The importance of voltage-dependent sodium channels in cerebral ischaemia

  • Review Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Summary

Strategies for the treatment of thromboembolic stroke are based on restoring the blood flow as soon as possible and protecting the neurons from the deleterious consequences of cerebral ischaemia. Interest has focused on blockers of voltage-dependent Na+ channels as potential neuroprotective agents because they prevent neuronal death in various experimental models of cerebral ischaemia and act cytoprotectively in models of white matter damage. Although several Na+ blockers are currently being tested in various phases of clinical development, most of these agents are relatively weak and unspecific. I therefore consider it worthwhile to search for molecules which specifically block voltage-dependent Na+ channels for the treatment of cerebral ischaemia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Albers GW, Atkinson RP, Kelley RE, Rosenbaum DM (1995) Safety, tolerability, and pharmacokinetics of the N-methyl-D-aspartate antagonist dextrorphan in patients with acute stroke. Stroke 26: 254–258

    Google Scholar 

  • Alps BJ, Calder C, Wilson AD, McBean DE, Armstrong JM (1995) Reduction by lifarizine of the neuronal damage induced by cerebral ischaemia in rodents. Br J Pharmacol 115: 1439–1446

    Google Scholar 

  • Anis NA, Berry SC, Burton NR, Lodge D (1983) The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurons by Nmethyl-D-aspartate. Br J Pharmacol 79: 565–575

    Google Scholar 

  • Aronowski J, Ostrow P, Samways E, Strong R, Zivin JA, Grotta JC (1994) Graded bioassay for demonstration of brain rescue from experimental acute ischemia in rats. Stroke 25: 2235–2240

    Google Scholar 

  • Aronowski J, Strong R, Grotta JC (1996) Combined neuroprotection and reperfusion therapy for stroke — effect of lubeluzole and diaspirin cross-linked hemoglobin in experimental focal ischemia. Stroke 27: 1571–1576

    Google Scholar 

  • Attwell D, Barbour B, Szatkowski M (1993) Nonvesicular release of neurotransmitters. Neuron 11: 401–407

    Google Scholar 

  • Bamford J (1992) Clinical examination in diagnosis and subclassification of stroke. Lancet 339: 400–402

    Google Scholar 

  • Barinaga M (1996) Finding new drugs to treat stroke. Science 272: 664–666

    Google Scholar 

  • Benveniste H, Drejer J, Schousboe A, Diemer NH (1984) Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampas during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 43: 1369–1374

    Google Scholar 

  • Bogousslavsky J (1996) Thrombolysis in acute stroke. Br Med J 313: 640–641

    Google Scholar 

  • Bouvier M, Szatkowski M, Amato A, Attwell D (1992) The glial cell glutamate uptake carrier countertransports pH-changing anions. Nature 360: 471–474

    Google Scholar 

  • Butcher STP, Bullock R, Graham DI, McCulloch J (1990) Correlation between amino acid release and neuropathologic outcome in rat brain following middle cerebral artery occlusion. Stroke 21: 1727–1733

    Google Scholar 

  • Carter AJ (1992) Glycine antagonists: regulation of the NMDA receptor-channel complex by the strychnine-insensitive glycine site. Drugs of the Future 17: 595–613

    Google Scholar 

  • Carter AJ (1995) Antagonists of the NMDA receptor-channel complex and motor coordination. Life Sci 57: 917–929

    Google Scholar 

  • Carter AJ, Bechtel WD, Grauert M, Harrison P, Merz H, Stransky W (1995a) BIII 277 CL is a potent and specific ion-channel blocker of the NMDA receptor-channel. J Pharmacol Exp Ther 275: 1382–1389

    Google Scholar 

  • Carter AJ, Mtiller RE, Pschorn U, Stransky W (1995b) Preincubation with creatine enhances levels of creatine phosphate and prevents anoxic damage in rat hippocampal slices. J Neurochem 64: 2691–2699

    Google Scholar 

  • Catterall WA (1980) Neurotoxins that act on voltage-sensitive sodium channels in excitable membranes. Ann Rev Pharmacol Toxicol 20: 15–43

    Google Scholar 

  • Catterall WA (1987) Common modes of drug action on Na+ channels: local anesthetics, antiarrhythmics and anticonvulsants. Trends Pharmacol Sci 8: 57–65

    Google Scholar 

  • Catterall WA (1988) Structure and function of voltage-sensitive ion channels. Science 242: 50–61

    Google Scholar 

  • Catterall WA (1992) Cellular and molecular biology of voltage-gated sodium channels. Physiol Rev 72: 815–848

    Google Scholar 

  • Chopp M, Zhang RL (1995) Animal modeling for developing stroke therapy. In: Fisher M (ed) Stroke therapy. Butterworth-Heinemann, Boston, pp 117–134

    Google Scholar 

  • Danysz W, Parsons CG, Bresink I, Quack G (1995) A revived target for drug development? Glutamate in CNS disorders. Drug News & Perspectives 8: 261–277

    Google Scholar 

  • De Ryck M, Keersmaekers R, Duytschaever H, Claes C, Clincke G, Janssen M, Van Reet G (1996) Lubeluzole protects sensorimotor function and reduces infarct size in a photochemical stroke model in rats. J Pharmacol Exp Ther 279: 748–758

    Google Scholar 

  • del Zoppo GJ (1995) Why do all drugs work in animals but none in stroke patients? I. Drugs promoting cerebral blood flow. J Intern Med 237: 79–88

    Google Scholar 

  • Dessi F, Charriaut-Marlangue C, Ben-Ari Y (1994) Glutamate-induced neuronal death in cerebellar culture is mediated by two distinct components: a sodium-chloride component and a calcium component. Brain Res 650: 49–55

    Google Scholar 

  • Foster AC (1991) Channel blocking drugs for the NMDA receptor. In: Meldrum BS (ed) Excitatory amino acid antagonists. Blackwell, Oxford, pp 164–179

    Google Scholar 

  • Friedman JE, Haddad GG (1994) Removal of extracellular sodium prevents anoxia-induced injury in freshly dissociated rat CAI hippocampal neurons. Brain Res 641: 57–64

    Google Scholar 

  • Gautron S, Santos GD, Pinto-Henrique D, Koulakoff A, Gros F, Berwald-Netter Y (1992) The glial voltage-gated sodium channel: cell- and tissue-specific mRNA expression. Proc Natl Acad Sci USA 89: 7272–7276

    Google Scholar 

  • Ginsberg MD (1997) Injury mechanisms in the ischaemic penumbra — approaches to neuroprotection in acute ischaemic stroke. Cerebrovasc Dis 7: 7–12

    Google Scholar 

  • Ginsberg MD, Busto R (1989) Rodent models of cerebral ischemia. Stroke 20: 1627–1642

    Google Scholar 

  • Globus MY-T, Busto R, Dietrich WD, Martinez E, Valdes I, Ginsberg MD (1988) Effect of ischaemic on thein vivo release of striatal dopamine, glutamate, and t-aminobutyric acid studied in intracerebral microdialysis. J Neurochem 51: 1455–1464

    Google Scholar 

  • Graham SH, Chen J, Sharp FR, Simon RP (1993) Limiting ischemic injury by inhibition of excitatory amino acid release. J Cereb Blood Flow Metab 13: 88–97

    Google Scholar 

  • Graham SH, Chen J, Lan J, Leach MJ, Simon RP (1994) Neuroprotective effects of a usedependent blocker of voltage-dependent sodium channels, BW619C89, in rat middle cerebral artery occlusion. J Pharmacol Exp Ther 269: 854–859

    Google Scholar 

  • Grotta J, Clark W, Coull B, Pettigrew LC, Mackay B, Goldstein LB, Meissner I, Murphy D, LaRue L (1995) Safety and tolerability of the glutamate antagonist CGS 19755 (Selfotel) in patients with acute ischemic stroke: results of a phase IIa randomized trial. Stroke 26: 602–605

    Google Scholar 

  • Hacke W, Kaste M, Fleschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Höxter G, Mahagne M-H, Hennerici M (1995) Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European cooperative acute stroke study (ECASS). JAMA 274: 1017–1025

    Google Scholar 

  • Hartshorne RP, Catterall WA (1984) The sodium channel from rat brain. Purification and subunit composition. J Biol Chem 259: 1667–1675

    Google Scholar 

  • Hasegawa Y, Latour LL, Sotak CH, Dardzinski BJ, Fisher M (1994) Temperature dependent change of apparent diffusion coefficient of water in normal and ischemic brain of rats. J Cereb Blood Flow Metab 14: 383–390

    Google Scholar 

  • Haseldonckx M, Van Reempts J, Van de Ven M, Wouters L, Borgers M (1997) Protection with lubeluzole against delayed ischemic brain damage in rats. Stroke 28: 428–432

    Google Scholar 

  • Kauppinen RA, McMahon HT, Nicholls DG (1988) Ca2+-dependent and Ca2+-independent glutamate release, energy status and cytosolic free Ca2+ concentration in isolated nerve terminals following metabolic inhibition: possible relevance to hypoglycaemia and anoxia. Neurosci 27: 175–182

    Google Scholar 

  • Kayano T, Noda M, Flockerzi V, Takahashi H, Numa S (1988) Primary structure of rat brain sodium channel III deduced from the cDNA sequence. FEBS Lett 228: 187–194

    Google Scholar 

  • Koroshetz WJ, Moskowitz MA (1996) Emerging treatments for stroke in humans. Trends Pharmacol Sci 17: 227–233

    Google Scholar 

  • Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS (1994) Subanesthetic effects of the noncompetitive NMDA antagonist ketamine in humans: psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51: 199–214

    Google Scholar 

  • Kucharczyk J, Mintorovitch J, Moseley ME, Asgari HS, Sevick RJ, Derugin N, Norman D (1991) Ischemic brain damage: reduction by sodium-calcium ion channel modulator RS-87476. Radiology 179: 221–227

    Google Scholar 

  • Lang DG, Wang CM, Cooper BR (1993) Lamotrigine, phenytoin and carbamazepine interactions on the sodium current present in N4TG1 mouse neuroblastoma cells. J Pharmacol Exp Ther 266: 829–835

    Google Scholar 

  • Leach MJ, Swan JH, Eisenthal D, Dopson M, Nobbs M (1993) BW619C89, a glutamate release inhibitor, protects against focal cerebral ischemic damage. Stroke 24: 1063–1067

    Google Scholar 

  • Lekieffre D, Meldrum BS (1993) The pyrimidine-derivative, BW1003C87, protects CAI and striatal neurons following transient severe forebrain ischaemia in rats. A microdialysis and histological study. Neurosci 56: 93–99

    Google Scholar 

  • Lustig HS, von Brauchitsch KL, Chan J, Greenberg DA (1992) A novel inhibitor of glutamate release reduces excitotoxic injuryin vitro. Neurosci Lett 143: 229–232

    Google Scholar 

  • Lynch JJ, III, Yu SP, Canzoniero LMT, Sensi SL, Choi DW (1995) Sodium channel blockers reduce oxygen-glucose deprivation-induced cortical neuronal injury when combined with glutamate receptor antagonists. J Pharmacol Exp Ther 273: 554–560

    Google Scholar 

  • Macrae IM (1992) New models of focal cerebal ischaemia. Br J Clin Pharmacol 34: 302–308

    Google Scholar 

  • Mattson MP, Mark RJ (1996) Excitotoxicity and excitoprotectionin vitro. Adv Neurol 71: 1–35

    Google Scholar 

  • May GR, Rowand WS, McCormack JG, Sheridan RD (1995) Neuroprotective profile of lifarizine (RS-87476) in rat cerebrocortical neurones in culture. Br J Pharmacol 114: 1365–1370

    Google Scholar 

  • McBean DE, Winters V, Wilson AD, Oswald CB, Alps BJ, Armstrong JM (1995) Neuroprotective efficacy of lifarizine (RS-87476) in a simplified rat survival model of 2 vessel occlusion. Br J Pharmacol 116: 3093–3098

    Google Scholar 

  • Minematsu K, Fisher M, Li L, Davis MA, Knapp AG, Cotter RE, McBurney RN, Sotak CH (1993) Effects of a novel NMDA antagonist on experimental stroke rapidly and quantitatively assessed by diffusion-weighted MRI. Neurology 43: 397–403

    Google Scholar 

  • Muir KW, Lees KR (1995) Clinical experience with excitatory amino acid antagonist drugs. Stroke 26: 503–513

    Google Scholar 

  • Muir KW, Grosset DG, Gamzu E, Lees KR (1994) Pharmacological effects of the noncompetitive NMDA antagonist CNS 1102 in normal volunteers. Br J Clin Pharmacol 38: 33–38

    Google Scholar 

  • Nicholls DG, Attwell D (1990) The release and uptake of excitatory amino acids. Trends Pharmacol Sci 11: 462–468

    Google Scholar 

  • Noda M, Ikeda H, Kayano T, Suzuki H, Takeshima H, Kurasaki M, Takahashi H, Numa S (1986) Existence of distinct sodium channel messenger RNAs in rat brain. Nature 320: 188–192

    Google Scholar 

  • Olverman HJ, Watkins JC (1989) NMDA agonists and competitive antagonists. In: Watkins JC, Collingridge GL (eds) The NMDA receptor. IRL Press, Oxford, pp 19–36

    Google Scholar 

  • Ozyurt E, Graham DI, Woodruff GN, McCulloch J (1988) Protective effect of the glutamate antagonist, MK-801 in focal cerebral ischemia. J Cereb Blood Flow Metab 8: 128–143

    Google Scholar 

  • Önal MZ, Fisher M (1996) Thrombolytic and cytoprotective therapies for acute ischemic stroke: a clinical overview. Drugs of Today 32: 573–592

    Google Scholar 

  • Park CK, Nehls DG, Graham DI, Teasdale GM, McCulloch J (1988) The glutamate antagonist MK-801 reduces focal ischemic brain damage in the rat. Ann Neurol 24: 543–551

    Google Scholar 

  • Pschorn U, Carter AJ (1996) The influence of repeated doses, route and time of admistration on the neuroprotective effects of BIII 277 CL in a rat model of focal cerebral ischaemia. J Stroke Cerebrovasc Dis 6: 93–99

    Google Scholar 

  • Ragsdale DS, McPhee JC, Scheuer T, Catterall WA (1994) Molecular determinants of state-dependent block of Na+ channels by local anesthetics. Science 265: 1724–1728

    Google Scholar 

  • Ransom BR, Stys PK, Waxman SG (1990) The pathophysiology of anoxic injury in central nervous system white matter. Stroke 21: III?52-III?57

    Google Scholar 

  • Reddy NL, Hu L-Y, Cotter RE, Fischer JB, Wong WJ, McBurney RN, Weber E, Holmes DL, Wong ST, Prasad R, Keana JFW (1994) Synthesis and structure-activity studies of N,N′-diarylguanidine derivatives. N-(1-naphthyl)-N′-(3-ethylphenyl)-N′-methylgua-nidine: a new, selective noncompetitive NMDA receptor antagonist. J Med Chem 37: 260–267

    Google Scholar 

  • Reynolds IJ, Miller RJ (1988) Multiple sites for the regulation of the N-methyl-Daspartate receptor. Mol Pharmacol 33: 581–584

    Google Scholar 

  • Rothman SM (1983) Synaptic activity mediates death of hypoxic neurons. Science 220: 536–537

    Google Scholar 

  • Rothman SM (1984) Synaptic release of excitatory amino acid neurotransmitter mediates anoxic neuronal death. J Neurosci 4: 1884–1891

    Google Scholar 

  • Schaller KL, Krzemien DM, Yarowsky PJ, Krueger BK, Caldwell JH (1995) A novel, abundant sodium channel expressed in neurons and glia. J Neurosci 15: 3231–3242

    Google Scholar 

  • Schehr RS (1996) New treatments for acute stroke. Nature Biotechnology 14: 1549–1554

    Google Scholar 

  • SCRIP (1995) Ciba suspends Selfotel trials. No 2086, 15th December: 25

  • SCRIP (1997) Cerestat stroke study suspended. No 2245, 1st July: 15

  • Simon RP, Swan JH, Griffiths T, Meldrum BS (1984) Blockade of N-methyl-D-aspartate receptors may protect against ischemic damage in the brain. Science 226: 850–852

    Google Scholar 

  • Smith SE, Al-Zubaidy ZA, Chapman AG, Meldrum BS (1993a) Excitatory amino acid antagonists, lamotrigine and BW 1003C87 as anticonvulsants in the genetically epilepsy-prone rat. Epilepsy Res 15: 101–111

    Google Scholar 

  • Smith SE, Lekieffre D, Sowinski P, Meldrum BS (1993b) Cerebroprotective effect of BW619C89 after focal or global cerebral ischaemia in the rat. NeuroReport 4: 1339–1342

    Google Scholar 

  • Squire IB, Lees KR, Pryse-Phillips W, Kertesz A, Bamford J (1996) The effects of lifarizine in acute cerebral infarction: a pilot safety study. Cerebrovasc Dis 6: 156–160

    Google Scholar 

  • Stys PK (1996) Ions, channels, and transporters involved in anoxic injury of central nervous system white matter. In: Siesjö BK, Wieloch T (eds) Cellular and molecular mechanisms of ischemic brain damage. Advances in neurology, vol 71. LippincottRaven, Philadelphia, pp 153–166

    Google Scholar 

  • Stys PK, Waxman SG, Ransom BR (1992) Ionic mechanisms of anoxic injury in mammalian CNS white matter: role of Na+ channels and Na+-Ca2+ exchanger. J Neurosci 12: 430–439

    Google Scholar 

  • Szatkowski M, Barbour B, Attwell D (1990) Non-vesicular release of glutamate from glial cells by reversed electrogenic glutamate uptake. Nature 348: 443–446

    Google Scholar 

  • Takagi K, Ginsberg MD, Globus MY-T, Dietrich WD, Martinez E, Kraydieh S, Busto R (1993) Changes in amino acid neurotransmitters and cerebral blood flow in the ischemic penumbral region following middle cerebral artery occlusion in the rat: correlation with histopathology. J Cereb Blood Flow Metab 13: 575–585

    Google Scholar 

  • Taylor CP, Meldrum BS (1995) Na+ channels as targets for neuroprotective drugs. Trends Pharmacol Sci 16: 309–316

    Google Scholar 

  • Taylor CP, Geer JJ, Burke SP (1992) Endogenous extracellular glutamate accumulation in rat neocortical cultures by reversal of the transmembrane sodium gradient. Neurosci Lett 145: 197–200

    Google Scholar 

  • The Multicenter Acute Stroke Trial (1996) Thrombolytic therapy with streptokinase in acute ischemic stroke. N Engl J Med 335: 145-150

    Google Scholar 

  • Tymianski M, Tator CH (1996) Normal and abnormal calcium homeostasis in neurons: a basis for the pathophysiology of traumatic and ischemic central nervous system injury. Neurosurgery 38: 1176–1195

    Google Scholar 

  • Urenjak J, Obrenovitch TP (1996) Pharmacological modulation of voltage-gated Na+ channels: a rational and effective strategy against ischemic brain damage. Pharmacol Rev 48: 21–67

    Google Scholar 

  • Vornov JJ, Tasker RC, Coyle JT (1994) Delayed protection by MK-801 and tetrodotoxin in a rat organotypic hippocampal culture model of ischemia. Stroke 25: 457–465

    Google Scholar 

  • Watkins JC, Krogsgaard-Larsen P, Honoré T (1990) Structure-activity relationships in the development of excitatory amino acid receptor agonists and competitive antagonists. Trends Pharmacol Sci 11: 25–33

    Google Scholar 

  • Westenbroek RE, Noebels JL, Catterall WA (1992) Elevated expression of type II Na+ channels in hypomyelinated axons of shiverer mouse brain. J Neurosci 12: 2259–2267

    Google Scholar 

  • Wong EHF, Kemp JA, Priestley T, Knight AR, Woodruff GN, Iversen LL (1986) The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist. Proc Natl Acad Sci USA 83: 7104–7108

    Google Scholar 

  • Yarowski PJ, Krueger BK, Olson CE, Clevinger EC, Koos RD (1991) Brain and heart sodium channel subtype mRNA expression in rat cerebral cortex. Proc Natl Acad Sci USA 88: 9453–9457

    Google Scholar 

  • Zeevalk GD, Nicklas WJ (1991) Mechanisms underlying initiation of excitotoxicity associated with metabolic inhibition. J Pharmacol Exp Ther 257: 870–878

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Central Nervous System Research, Boehringer Ingelheim, D-55216, Ingelheim am Rhein, Germany

    A. J. Carter

Authors
  1. A. J. Carter
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Carter, A.J. The importance of voltage-dependent sodium channels in cerebral ischaemia. Amino Acids 14, 159–169 (1998). https://doi.org/10.1007/BF01345257

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01345257

Keywords

Search

Navigation