Skip to main content
SpringerLink
Log in

Neuroprotection — rationale for pharmacological modulation of Na+-channels

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

Summary

The primary factor detrimental to neurons in neurological disorders associated with deficient oxygen supply or mitochondrial dysfunction is insufficient ATP production relative to their requirement. As a large part of the energy consumed by brain cells is used for maintenance of the Na+ gradient across the cellular membrane, reduction of energy demand by down-modulation of voltage-gated Na+-channels is a rational strategy for neuroprotection. In addition, preservation of the inward Na+ gradient may be beneficial because it is an essential driving force for vital ion exchanges and transport mechanisms such as Ca2+ homeostasis and neurotransmitter uptake.

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

  • Ames III A (1997) Energy requirements of brain function: when is energy limiting? In: Beal MF, Howell N, Bodis-Wollner I (eds) Mitochondria and free radicals in neurodegenerative diseases. Wiley-Liss, Baltimore, pp 17–27

    Google Scholar 

  • Ames III A, Li Y-Y, Heher EC, Kimble CR (1992) Energy metabolism of rabbit retina as related to function: high cost of Na+ transport. J Neurosci 12: 840–853

    Google Scholar 

  • Artru F, Terrier A, Tixier S, Jourdan Ch, Deleuze R (1991) The use of intravenous lidocaine in neuro-anesthesia and neuro-intensive care. Agressol 32: 439–443

    Google Scholar 

  • Astrup J (1982) Energy-requiring cell functions in the ischemic brain. Their critical supply and possible inhibition in protective therapy. J Neurosurg 56: 482–487

    Google Scholar 

  • Boening JA, Kass IS, Cottrell JE, Chambers G (1989) The effect of blocking sodium influx on anoxic damage in the rat hippocampal slice. Neuroscience 33: 263–268

    Google Scholar 

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

    Google Scholar 

  • Cherubini E, Ben-Ari Y, Krnjevic K (1989) Anoxia produces smaller changes in synaptic transmission, membrane potential, and input resistance in immature rat hippocampas. J Neurophysiol 62: 882–895

    Google Scholar 

  • Cheung H, Kamp D, Harris E (1992) Anin vitro investigation of the action of lamotrigine on neuronal voltage-activated sodium channels. Epilepsy Res 13: 107–112

    Google Scholar 

  • Cummins TR, Xia Y, Haddad GG (1994) Functional properties of rat and human neocortical voltage-sensitive sodium currents. J Neurophysiol 71: 1052–1064

    Google Scholar 

  • Dargent B, Couraud F (1990) Down-regulation of voltage-dependent sodium channels initiated by sodium influx in developing neurons. Proc Natl Acad Sci USA 87: 5907–5911

    Google Scholar 

  • Douglas SM, Panizzon KL, Wallis RA (1996) Sodium channel blockers protect against traumatic neuronal injury in the adult rat spinal cord. Soc Neurosci Abstr 22: 230

    Google Scholar 

  • Edwards RA, Lutz PL, Baden DG (1989) Relationship between energy expenditure and ion channel density in the turtle and rat brain. Am J Physiol 257 (6 Pt 2): R1354-R1358

    Google Scholar 

  • Erecinska M, Silver IA (1989) ATP and brain function. J Cereb Blood Flow Metab 9: 2–19

    Google Scholar 

  • Evans DE, Kobrine AI, Legrys DC, Bradley ME (1984) Protective effect of lidocaine in acute cerebral ischemia induced by air embolism. J Neurosurg 60: 257–263

    Google Scholar 

  • Fern R, Ransom BR, Stys PK, Waxman SG (1993) Pharmacological protection of CNS white matter during anoxia: actions of phenytoin, carbamazepine and diazepam. J Pharmacol Exp Ther 266: 1549–1555

    Google Scholar 

  • Friedman JE, Haddad GG (1994) Removal of extracellular sodium prevents anoxiainduced injury in freshly dissociated rat CA1 hippocampal neurons. Brain Res 641: 57–64

    Google Scholar 

  • Gilland E, Malgorzata P-S, Andiné P, Bona E, Hagberg H (1994) Hypoxic-ischemic injury in the neonatal rat brain: effects of pre- and post-treatment with the glutamate release inhibitor BW1003C87. Brain Res Dev Brain Res 83: 79–84

    Google Scholar 

  • Ginsberg MD, Sternau LL, Globus MY-T, Dietrich WD, Busto R (1992) Therapeutic modulation of brain temperature: relevance to ischemic brain injury. Cerebrovasc Brain Metab Rev 4: 189–225

    Google Scholar 

  • Graham SH, Chen J, Sharp FR, Simon RP (1993) Limiting 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 

  • Hakim AM, Shoubridge EA (1989) Cerebral acidosis in focal ischemia. J Cereb Blood Flow Metab 1: 115–119

    Google Scholar 

  • Hansen AJ (1985) Effect of anoxia on ion distribution in the brain. Physiol Rev 65: 101–148

    Google Scholar 

  • Hoehn K, Watson TWJ, MacVitar BA (1993) A novel tetrodotoxin-insensitive, slow sodium current in striatal and hippocampal neurons. Neuron 10: 543–552

    Google Scholar 

  • Kempski O, Staub F, v Rosen F, Zimmer M, Neu A, Bacthmann A (1988) Molecular mechanisms of glial cell swellingin vitro. Neurochem Path 9: 109–125

    Google Scholar 

  • Kozlowski DA, James DC, Schallert T (1996) Use-dependent exaggeration of neuronal injury after unilateral sensorimotor cortex lesions. J Neurosci 16: 4776–4786

    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, Marden CM, Miller AA (1986) Pharmacological studies on Lamotrigine, a novel antiepileptic drug: II. Neurochemical studies on the mechanism of action. Epilepsia 27: 490–497

    Google Scholar 

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

    Google Scholar 

  • Lees G, Leach MJ (1993) Studies on the mechanism of action of the novel anticonvulsant lamotrigine (Lamictal) using primary neuroglial cultures from rat cortex. Brain Res 612: 190–199

    Google Scholar 

  • Lekieffre D, Meldrum BS (1993) The pyrimidine-derivative, BW1003C87, protects CA1 and striatal neurons following transient severe forebrain ischaemia in rats. A microdialysis and histological study. Neuroscience 56: 93–99

    Google Scholar 

  • Lucas LF, West CA, Rigor BM, Schurr A (1989) Protection against cerebral hypoxia by local anesthetics: a study using brain slices. J Neurosci Meth 28: 47–50

    Google Scholar 

  • Lysko PG, Yue TL, Gu JL, Webb CL, Feuerstein G (1993) Neuroprotective effects of tetrodotoxin in cultured cerebellar neurons and in gerbil global brain ischemia. Soc Neurosci Abstr 19: 286

    Google Scholar 

  • Meldrum BS, Swan JH, Leach MJ, Millan MH, Gwinn R, Kadota K, Graham SH, Chen J, Simon RP (1992) Reduction of glutamate release and protection against ischaemic brain damage by BW1003C87. Brain Res 593: 1–6

    Google Scholar 

  • Messenheimer JA (1995) Lamotrigine. Epilepsia 36 [Suppl 2] S87-S94

    Google Scholar 

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

    Google Scholar 

  • Obrenovitch TP (1997) Sodium and potassium channel modulators: their role in neuroprotection. In: Cross AJ, Green AR (eds) Neuroprotective agents and cerebral ischaemia. Academic Press, London, pp 109–135

    Google Scholar 

  • Obrenovitch TP, Urenjak J (1997) Actions of riluzole in animal models of CNS ischaemia and trauma. Rev Contemp Pharmacother 8: 227–235

    Google Scholar 

  • Obrenovitch TP, Sarna GS, Symon L (1990a) Ionic homeostasis and neurotransmitter changes in ischaemia. In: Krieglstein J, Oberpichler H (eds) Pharmacology of cerebral ischemia 1990. Wissenschaftliche Verlagsgesellschaft, Stuttgart, pp 97–112

    Google Scholar 

  • Obrenovitch TP, Scheller D, Matsumoto T, Tegtmeier F, Höller M, Symon L (1990b) Rapid redistribution of hydrogen ions is associated with depolarization and repolarization subsequent to cerebral ischaemia-reperfusion. J Neurophysiol 64: 1125–1133

    Google Scholar 

  • Okiyama K, Smith DH, Gennarelli TA, Simon RP, Leach M, McIntosh TK (1995) The sodium channel blocker and glutamate release inhibitor BW1003C87 and magnesium attenuate regional cerebral edema following experimental brain injury in the rat. J Neurochem 64: 802–809

    Google Scholar 

  • Pérez-Pinzón MA, Rosenthal M, Sick TJ, Lutz PL, Pablo J, Mash D (1992) Downregulation of sodium channels during anoxia: a putative survival strategy of turtle brain. Am J Physiol 262: R712-R715

    Google Scholar 

  • Prenen GHM, Go GK, Postema F, Zuiderveen F, Korf J (1988) Cerebral cation shifts in hypoxic-ischemic brain damage are prevented by the sodium channel blocker tetrodotoxin. Exp Neurol 99: 118–132

    Google Scholar 

  • Rasool N, Faroqui M, Rubinstein, EH (1990) Lidocaine accelerates neuroelectrical recovery after incomplete global ischemia in rabbits. Stroke 21: 929–935

    Google Scholar 

  • Rataud J, Debarnot F, Mary V, Pratt J, Stutzmann J-M (1994) Comparative study of voltage-sensitive sodium channel blockers in focal ischaemia and electric convulsions in rodents. Neurosci Lett 172: 19–23

    Google Scholar 

  • Rothman SM (1985) The neurotoxicity of excitatory amino acids is produced by passive chloride influx. J Neurosci 5: 1483–1489

    Google Scholar 

  • Schulz JB, Matthews RT, Henshaw DR, Beal MF (1996) Neuroprotective strategies for treatment of lesions produced by mitochondrial toxins: implications for neurodegenerative diseases. Neuroscience 71: 1043–1048

    Google Scholar 

  • Siesjö BK, Bengtsson F (1989) Calcium fluxes, calcium antagonists and calcium-related pathology in brain ischemia, hypoglycemia and spreading depression: a unifying hypothesis. J Cereb Blood Flow Metab 9: 127–140

    Google Scholar 

  • Silver IA, Deas J, Erecinska M (1997) Ion homeostasis in brain cells: differences in intracellular ion responses to energy limitation between cultured neurons and glial cells. Neuroscience 78: 589–601

    Google Scholar 

  • Skilling SR, Smullin DH, Beitz AJ, Larson AA (1988) Extracellular amino acid concentrations in the dorsal spinal cord of freely moving rats following veratridine and nociceptive stimulation. J Neurochem 51: 127–132

    Google Scholar 

  • Smith SE, Meldrum BS (1995) Cerebroprotective effect of lamotrigine after focal ischemia in rats. Stroke 26: 117–122

    Google Scholar 

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

    Google Scholar 

  • Spetzler RE, Hadley MN (1989) Protection against cerebral ischemia: the role of barbiturates. Cerebrovasc Brain Metabol Rev 1: 212–229

    Google Scholar 

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

    Google Scholar 

  • Sun F-Y, Faden AI (1995) Neuroprotective effect of 619C89, a use-dependent sodium channel blocker, in rat traumatic brain injury. Brain Res 673: 133–140

    Google Scholar 

  • Taylor CP (1993) Na+ currents that fail to inactivate. Trends Neurosci 16: 455–460

    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 

  • Urenjak J, Tegtmeier F, Beile A, Khan S, Peters T (1991) Synaptosomal respiration: a potent indicator of veratridine-induced Na+ influx. Pharmacology 43: 26–35

    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 

  • Waxman SG, Black JA, Ransom BR, Stys PK (1994) Anoxic injury of rat optic nerve: ultrastructural evidence for coupling between Na+ influx and Ca2+-mediated injury in myelinated CNS axons. Brain Res 644: 197–204

    Google Scholar 

  • Wiard RP, Dickerson MC, Beek O, Norton R, Cooper BR (1995) Neuroprotective properties of the novel antiepileptic lamotrigine in a gerbil model of global cerebral ischemia. Stroke 26: 466–472

    Google Scholar 

  • Xia Y, Haddad GG (1993) Neuroanatomical distribution and binding properties of saxitonin sites in the rat and turtle CNS. J Comp Neurol 330: 363–380

    Google Scholar 

  • Xia Y, Haddad GG (1994) Postnatal development of voltage-sensitive Na+ channels in rat brain. J Comp Neurol 345: 279–287

    Google Scholar 

  • Xie XM, Garthwaite J (1996) State-dependent inhibition of Na+ currents by the neuroprotective agent 619C89 in rat hippocampal neurons and in a mammalian cell line expressing rat brain type Ila Na+ channels. Neuroscience 73: 951–962

    Google Scholar 

  • Xie XM, Lancaster B, Peakman T, Garthwaite J (1995) Interaction of the antiepileptic drug lamotrigine with recombinant rat brain type Ila Na+ channels and with native Na+ channels in rat hippocampal neurons. Eur J Physiol 430: 437–446

    Google Scholar 

  • Xie Y, Dengler K, Zacharias E, Wilffert B, Tegtmeier F (1994) Effects of the sodium channel blocker tetrodotoxin (TTX) on cellular ion homeostasis in rat brain subjected to complete ischemia. Brain Res 652: 216–224

    Google Scholar 

  • Yamasaki Y, Kogure K, Hara H, Ban H, Akaike N (1991) The possible involvement of tetrodotoxin-sensitive ion channels in ischemic neuronal damage in the rat hippocampus. Neurosci Lett 121: 251–254

    Google Scholar 

  • Young AM, Foley PM, Bradford HE (1990) Preloadingin vivo: a rapid and reliable method for measuring gamma-aminobutyric acid and glutamate fluxes by microdialysis. J Neurochem 55: 1060–1063

    Google Scholar 

Download references

Author information

Author notes

  1. J. Urenjak & T. P. Obrenovitch

    Present address: Postgraduate Pharmacology, School of Pharmacy, University of Bradford, Bradford, UK

Authors and Affiliations

  1. Discovery Biology, Pfizer Central Research, Sandwich

    J. Urenjak

  2. Department of Neurochemistry, Institute of Neurology, London, UK

    T. P. Obrenovitch

Authors
  1. J. Urenjak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T. P. Obrenovitch
    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

Urenjak, J., Obrenovitch, T.P. Neuroprotection — rationale for pharmacological modulation of Na+-channels. Amino Acids 14, 151–158 (1998). https://doi.org/10.1007/BF01345256

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01345256

Keywords

Search

Navigation