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Na+Channels and Ca2+ Channels of the Cell Membrane as Targets of Neuroprotective Substances

  • Christian Alzheimer
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 513)

Abstract

Loss of ion homeostasis is the cardinal event in the early neuronal response to acute ischemic and traumatic brain injury.1–3 At short notice, excessive influx of Na+ and Ca2+ overwhelming the compensatory mechanisms of the neuron will cause osmotic volume expansion (swelling), which might be reversible if the impact of the acute injury is limited and small, and appropriate therapeutic actions are taken. However, pathologically elevated Na+ and Ca2+ levels in the cytosol are likely to trigger a cascade of molecular events that eventually lead to neuronal death (e.g., formation of reactive oxygen species, lipid peroxidation, mitochondrial dysfunction, activation of caspases etc.). Owing to its double nature as charge carrier and ubiquitous second messenger, Ca2+ has received much more attention than Na+. Deviating from this usual bias, this Chapter will first take a closer look at the pathways of pathological Na+ influx, at the multiple sequelae of excessive intracellular Na+ accumulation, and at attempts to prevent Na+ overload as a means to fight neuronal loss in acute injury.

Keywords

Traumatic Brain Injury Hippocampal Slice Channel Inhibitor Sodium Channel Blocker Persistent Sodium Current 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Friedman JE, Haddad GG. Removal of extracellular sodium prevents anoxia-induced injury in freshly dissociated rat CAI hippocampal neurons. Brain Res 1994; 641:57–64.PubMedCrossRefGoogle Scholar
  2. 2.
    Martin RL, Lloyd HG, Cowan Al. The early events of oxygen and glucose deprivation: Setting the scene for neuronal death? Trends Neurosci 1994; 17:251–257.PubMedCrossRefGoogle Scholar
  3. 3.
    Taylor CP, Weber ML, Gaughan CL, Lehning EJ, LoPachin RM. Oxygen/glucose deprivation in hippocampal slices: Altered intraneuronal elemental composition predicts structural and functional damage. J Neurosci 1999; 19:619–629.PubMedGoogle Scholar
  4. 4.
    Zhang Y, Lipton P. Cytosolic Ca2+ changes during in vitro ischemia in rat hippocampal slices: major roles for glutamate and Na+-dependent Ca2+ release from mitochondria. J Neurosci 1999; 19:3307–3315.PubMedGoogle Scholar
  5. 5.
    Rossi DJ, Oshima T, Attwell D. Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature 2000; 403:316–321.PubMedCrossRefGoogle Scholar
  6. 6.
    Leao. Further observations on the spreading depression of activity in the cerebral cortex. J Neurophysiol 1947; 10:409–414.PubMedGoogle Scholar
  7. 7.
    Somjen GG. Mechanisms of spreading depression and hypoxie spreading depression-like depolarization. Physiol Rev 2001; 81:1065–1096.PubMedGoogle Scholar
  8. 8.
    Mller M, Somjen GG. Na + dependence and the role of glutamate receptors and Na* channels in ion fluxes during hypoxia of rat hippocampal slices. J Neurophysiol 2000; 84:1869–1880.Google Scholar
  9. 9.
    Yamamoto S, Tanaka E, Higashi H. Mediation by intracellular calcium-dependent signals of hypoxie hyperpolarization in rat hippocampal CAl neurons in vitro. J Neurophysiol 1997; 77:386–392.PubMedGoogle Scholar
  10. 10.
    Patel AJ, Honore E. Properties and modulation of mammalian 2P domain KE channels. Trends Neurosci 2001; 24:339–346.PubMedCrossRefGoogle Scholar
  11. 11.
    LoPachin RM. Intraneuronal ion distribution during experimental oxygen/glucose deprivation. Routes of ion flux as targets of neuroprotective strategies. Ann NY Acad Sci 1999; 890:191–203.PubMedCrossRefGoogle Scholar
  12. 12.
    Crill WE. Persistent sodium current in mammalian central neurons. Annu Rev Physiol 1996; 58:349–362.PubMedCrossRefGoogle Scholar
  13. 13.
    Stafstrom CE, Schwindt PC, Crill WE. Negative slope conductance due to a persistent subthreshold sodium current in cat neocortical neurons in vitro. Brain Res 1982; 236:221–226.PubMedCrossRefGoogle Scholar
  14. 14.
    Stafstrom CE, Schwindt PC, Chubb MC, Crill WE. Properties of persistent sodium conductance and calcium conductance of layer V neurons from cat sensorimotor cortex in vitro. J Neurophysiol 1985; 53:153–170.PubMedGoogle Scholar
  15. 15.
    Connors BW, Gutnick MJ, Prince DA. Electrophysiological properties of neocortical neurons in vitro. J Neurophysiol 1982; 48:1302–1320.PubMedGoogle Scholar
  16. 16.
    Alzheimer C, Schwindt PC, Crill WE. Postnatal development of a persistent Na+ current in pyramidal neurons from rat sensorimotor cortex. J Neurophysiol 1993; 69:290–292.PubMedGoogle Scholar
  17. 17.
    Fleidervish IA, Gutnick MJ. Kinetics of slow inactivation of persistent sodium current in layer V neurons of mouse neocortical slices. J Neurophysiol 1996; 76:2125–2130.PubMedGoogle Scholar
  18. 18.
    French CR, Sah P, Buckett KJ, Gage PW. A voltage-dependent persistent sodium current in mammalian hippocampal neurons. J Gen Physiol 1990; 95:1139–1157.PubMedCrossRefGoogle Scholar
  19. 19.
    Alonso A, Llinas RR. Subthreshold Na*-dependent theta-like rhythmicity in stellate cells of entorhinal cortex layer II. Nature 1989; 342:175–177.PubMedCrossRefGoogle Scholar
  20. 20.
    Magistretti J, Alonso A. Biophysical properties and slow voltage-dependent inactivation of a sustained sodium current in entorhinal cortex layer-II principal neurons: A whole-cell and single-channel study. J Gen Physiol 1999; 114:491–509.PubMedCrossRefGoogle Scholar
  21. 21.
    Agrawal N, Hamam BN, Magistretti J, Alonso A, Ragsdale DS. Persistent sodium channel activity mediates subthreshold membrane potential oscillations and low-threshold spikes in rat entorhinal cortex layer V neurons. Neuroscience 2001; 102:53–64.PubMedCrossRefGoogle Scholar
  22. 22.
    Jahnsen H, Llinas R. Ionic basis for the electro-responsiveness and oscillatory properties of guinea-pig thalamic neurones in vitro. J Physiol (Lond) 1984; 349:227–247.Google Scholar
  23. 23.
    Parri HR, Crunelli V. Sodium current in rat and cat thalamocortical neurons: Role of a non-inactivating component in tonic and burst firing. J Neurosci 1998; 18:854–867.PubMedGoogle Scholar
  24. 24.
    Chao TI, Alzheimer C. Do neurons from rat neostriatum express both a TTX-sensitive and a TTX- insensitive slow Na+ current? J Neurophysiol 1995; 74:934–941.PubMedGoogle Scholar
  25. 25.
    Cepeda C, Chandler SH, Shumate LW, Levine MS. Persistent Na+ conductance in medium-sized neostriatal neurons: Characterization using infrared videomicroscopy and whole cell patch-clamp recordings. J Neurophysiol 1995; 74:1343–1348.PubMedGoogle Scholar
  26. 26.
    Llinas R, Sugimori M. Electrophysiological properties of in vitro Purkinje cell somata in mammalian cerebellar slices. J Physiol (Lond) 1980; 305:171–195.Google Scholar
  27. 27.
    Kay AR, Sugimori M, Llin s R. Kinetic and stochastic properties of a persistent sodium current in mature guinea pig cerebellar Purkinje cells. J Neurophysiol 1998; 80:1167–1179.PubMedGoogle Scholar
  28. 28.
    Taylor CP. Na’ currents that fail to inactivate. Trends Neurosci 1993; 16:455–460.PubMedCrossRefGoogle Scholar
  29. 29.
    Brown AM, Schwindt PC, Crill WE. Voltage dependence and activation kinetics of pharmacologically defined components of the high-threshold calcium current in rat neocortical neurons. J Neurophysiol 1993; 70:1530–1543.PubMedGoogle Scholar
  30. 30.
    Alzheimer C, Schwindt PC, Crill WE. Modal gating of Na+ channels as a mechanism of persistent Na+current in pyramidal neurons from rat and cat sensorimotor cortex. J Neurosci 1993; 13:660–673.PubMedGoogle Scholar
  31. 31.
    Magistretti J, Ragsdale DS, Alonso A. High conductance sustained single-channel activity responsible for the low-threshold persistent Na+current in entorhinal cortex neurons. J Neurosci 1999; 19:7334–7341.PubMedGoogle Scholar
  32. 32.
    Catterall WA. From ionic currents to molecular mechanisms: The structure and function of voltage-gated sodium channels. Neuron 2000; 26:13–25.Google Scholar
  33. 33.
    Hammarstrom AK, Gage PW. Inhibition of oxidative metabolism increases persistent sodium current in rat CAI hippocampal neurons. J Physiol (Lond) 1998; 510 (Pt 3):735–741.CrossRefGoogle Scholar
  34. 34.
    Hammarstrom AK, Gage PW. Nitric oxide increases persistent sodium current in rat hippocampal neurons. J Physiol (Lond) 1999; 520 Pt 2:451–461.CrossRefGoogle Scholar
  35. 35.
    Hammarstrom AK, Gage PW. Oxygen-sensing persistent sodium channels in rat hippocampus. J Physiol (Lond) 2000; 529 (Pt 1):107–118.CrossRefGoogle Scholar
  36. 36.
    Hem EM, Waldrop TG. Hypoxie augmentation of fast-inactivating and persistent sodium currents in rat caudal hypothalamic neurons. J Neurophysiol 2000; 84:2572–2581.Google Scholar
  37. 37.
    Somjen GG, Muller M. Potassium-induced enhancement of persistent inward current in hippocampal neurons in isolation and in tissue slices. Brain Res 2000; 885:102–110.PubMedCrossRefGoogle Scholar
  38. 38.
    Fleidervish IA, Gebhardt C, Astman N, Gutnick MJ, Heinemann U. Enhanced spontaneous transmitter release is the earliest consequence of neocortical hypoxia that can explain the disruption of normal circuit function. J Neurosci 2001; 21:4600–4608.PubMedGoogle Scholar
  39. 39.
    Reilly JP, Cummins TR, Haddad GG. Oxygen deprivation inhibits Na’ current in rat hippocampal neurones via protein kinase C. J Physiol (Lond) 1997; 503 (Pt 3):479–488.CrossRefGoogle Scholar
  40. 40.
    Alroy G, Su H, Yaari Y. Protein kinase C mediates muscarinic block of intrinsic bursting in rat hippocampal neurons. J Physiol (Lund) 1999; 518 (Pt 1):71–79.CrossRefGoogle Scholar
  41. 41.
    Kuo CC, Bean BP. Slow binding of phenytoin to inactivated sodium channels in rat hippocampal neurons. Mol Pharmacol 1994; 46:716–725.PubMedGoogle Scholar
  42. 42.
    Quandt FN. Modification of slow inactivation of single sodium channels by phenytoin in neuroblastoma cells. Mol Pharmacol 1988; 34:557–565.PubMedGoogle Scholar
  43. 43.
    Ragsdale DS, Scheuer T, Catterall WA. Frequency and voltage-dependent inhibition of type IIA Na+ channels, expressed in a mammalian cell line, by local anesthetic, antiarrhythmic, and anticonvulsant drugs. Mol Pharmacol 1991; 40:756–765.PubMedGoogle Scholar
  44. 44.
    Chao TI, Alzheimer C. Effects of phenytoin on the persistent Na+ current of mammalian CNS neurones. NeuroReport 1995; 6:1778–1780.PubMedCrossRefGoogle Scholar
  45. 45.
    Segal MM, Douglas AF. Late sodium channel openings underlying epileptiform activity are preferentially diminished by the anticonvulsant phenytoin. J Neurophysiol 1997; 77:3021–3034.PubMedGoogle Scholar
  46. 46.
    Malgouris C, Bardot F, Daniel M, Pellis F, Rataud J, Uzan A et al. Riluzole, a novel antiglutamate, prevents memory loss and hippocampal neuronal damage in ischemic gerbils. J Neurosci 1989; 9:3720–3727.PubMedGoogle Scholar
  47. 47.
    Hebert T, Drapeau P, Pradier L, Dunn RJ. Block of the rat brain IIA sodium channel alpha subunit by the neuroprotective drug riluzole. Mol Pharmacol 1994; 45:1055–1060.PubMedGoogle Scholar
  48. 48.
    Benoit E, Escande D. Riluzole specifically blocks inactivated Na channels in myelinated nerve fibre. Pfl gers Arch 1991; 419:603–609.CrossRefGoogle Scholar
  49. 49.
    Urbani A, Belluzzi O. Riluzole inhibits the persistent sodium current in mammalian CNS neurons. Eur J Neurosci 2000; 12:3567–3574.PubMedCrossRefGoogle Scholar
  50. 50.
    Martin D, Thompson MA, Nadler JV. The neuroprotective agent riluzole inhibits release of glutamate and aspartate from slices of hippocampal area CAI. Eur J Pharmacol 1993; 250:473–476.PubMedCrossRefGoogle Scholar
  51. 51.
    Prakriya M, Mennerick S. Selective depression of low-release probability excitatory synapses by sodium channel blockers. Neuron 2000; 26:671–682.PubMedCrossRefGoogle Scholar
  52. 52.
    Weber ML, Taylor CP. Damage from oxygen and glucose deprivation in hippocampal slices is prevented by tetrodotoxin, lidocaine and phenytoin without blockade of action potentials. Brain Res 1994; 664:167–177.PubMedCrossRefGoogle Scholar
  53. 53.
    Taylor CP, Meldrum BS. Na+ channels as targets for neuroprotective drugs. Trends Pharmacol Sci 1995; 16:309–316.PubMedCrossRefGoogle Scholar
  54. 54.
    McGivern JG, Patmore L, Sheridan RD. Actions of the novel neuroprotective agent, lifarizine (RS-87476), on voltage-dependent sodium currents in the neuroblastoma cell line, NIE-115. Br J Pharmacol 1995; 114:1738–1744.PubMedCrossRefGoogle Scholar
  55. 55.
    Xie X, Lancaster B, Peakman T, Garthwaite J. Interaction of the antiepileptic drug lamotrigine with recombinant rat brain type IIA Na+ channels and with native Na’ channels in rat hippocampal neurones. Pfl gers Arch 1995; 430:437–446.CrossRefGoogle Scholar
  56. 56.
    Xie XM, Garthwaite J. 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 IIA Na+ channels. Neuroscience 1996; 73:951–962.PubMedCrossRefGoogle Scholar
  57. 57.
    Obrenovitch TP. Sodium and potassium channel modulators: their role in neuroprotection. Int Rev Neurobiol 1997; 40:109–135.PubMedCrossRefGoogle Scholar
  58. 58.
    Obrenovitch TP. Neuroprotective strategies: Voltage-gated Na+-channel down-modulation versus presynaptic glutamate release inhibition. Rev Neurosci 1998; 9:203–211.PubMedGoogle Scholar
  59. 59.
    Urenjak J, Obrenovitch TP. Pharmacological modulation of voltage-gated Na+. channels: A rational and effective strategy against ischemic drain damage. Pharmacol Rev 1996; 48:21–67.PubMedGoogle Scholar
  60. 60.
    Lynch JJ, Ill, Yu SP, Canzoniero LM, Sensi SL, Choi DW. Sodium channel blockers reduce oxygen-glucose deprivation-induced cortical neuronal injury when combined with glutamate receptor antagonists. J Pharmacol Exp Ther 1995; 273:554–560.PubMedGoogle Scholar
  61. 61.
    Breder J, Sabelhaus CF, Opitz T, Reymann KG, Schroder UH. Inhibition of different pathways influencing Na+ homeostasis protects organotypic hippocampal slice cultures from hypoxic/ hypoglycemic injury. Neuropharmacology 2000; 39:1779–1787.PubMedCrossRefGoogle Scholar
  62. 62.
    Tasker RC, Coyle JT, Vornov H. The regional vulnerability to hypoglycemia-induced neurotoxicity in organotypic hippocampal culture: Protection by early tetrodotoxin or delayed MK-801. J Neurosci 1992; 12:4298–4308.PubMedGoogle Scholar
  63. 63.
    Watson GB, Lanthorn TH. Phenytoin delays ischemic depolarization, but cannot block its long-term consequences, in the rat hippocampal slice. Neuropharmacology 1995; 34:553–558.PubMedCrossRefGoogle Scholar
  64. 64.
    Amagasa M, Mizoi K, Ogawa A, Yoshimoto T. Actions of brain-protecting substances against both oxygen and glucose deprivation in the guinea pig hippocampal neurons studied in vitro. Brain Res 1989; 504:87–93.PubMedCrossRefGoogle Scholar
  65. 65.
    Stanton PK, Moskal JR. Diphenylhydantoin protects against hypoxia-induced impairment of hippocampal synaptic transmission. Brain Res 1991; 546:351–354.PubMedCrossRefGoogle Scholar
  66. 66.
    Taft WC, Clifton GL, Blair RE, DeLorenzo RJ. Phenytoin protects against ischemia-produced neuronal cell death. Brain Res 1989; 483:143–148.PubMedCrossRefGoogle Scholar
  67. 67.
    Rataud J, Debamot F, Mary V, Pratt J, Stutzmann JM. Comparative study of voltage-sensitive sodium channel blockers in focal ischaemia and electric convulsions in rodents. Neurosci Lett 1994; 172:19–23.PubMedCrossRefGoogle Scholar
  68. 68.
    Boxer PA, Cordon JJ, Mann ME, Rodolosi LC, Vartanian MG, Rock DM et al. Comparison of phenytoin with noncompetitive N-methyl-D-aspartate antagonists in a model of focal brain ischemia in rat. Stroke 1990; 21: III47- III51.PubMedGoogle Scholar
  69. 69.
    Pratt J, Rataud J, Bardot F, Roux M, Blanchard JC, Laduron PM et al. Neuroprotective actions of riluzole in rodent models of global and focal cerebral ischaemia. Neurosci Lett 1992; 140:225–230.PubMedCrossRefGoogle Scholar
  70. 70.
    Leach MJ, Swan JH, Eisenthal D, Dopson M, Nobbs M. BW619C89, a glutamate release inhibitor, protects against focal cerebral ischemic damage. Stroke 1993; 24:1063–1067.PubMedCrossRefGoogle Scholar
  71. 71.
    Sun FY, Faden AI. Neuroprotective effects of 619C89, a use-dependent sodium channel blocker, in rat traumatic brain injury. Brain Res 1995; 673:133–140.PubMedCrossRefGoogle Scholar
  72. 72.
    Okiyama K, Smith DH, Gennarelli TA, Simon RP, Leach M, McIntosh TIC. The sodium channel blocker and glutamate release inhibitor BW1003C87 and magnesium attenuate regional cerebral edema following experimental brain injury in the rat. J Neurochem 1995; 64:802–809.PubMedCrossRefGoogle Scholar
  73. 73.
    Smith SE, Meldrum BS. Cerebroprotective effect of lamotrigine after focal ischemia in rats. Stroke 1995; 26:117–121.PubMedCrossRefGoogle Scholar
  74. 74.
    Stys PK, Sontheimer H, Ransom BR, Waxman SG. Noninactivating, tetrodotoxin-sensitive Na+conductance in rat optic nerve axons. Proc Natl Acad Sci USA 1993; 90:6976–6980.PubMedCrossRefGoogle Scholar
  75. 75.
    Squire IB, Lees KR, Pryse-Phillips W, Kertesz A, Bamford J. Efficacy and tolerability of lifarizine in acute ischemic stroke. A pilot study. Lifarizine Study Group. Ann NY Acad Sci 1995; 765:317–318.PubMedCrossRefGoogle Scholar
  76. 76.
    Muir KW, Holzapfel L, Lees KR. Phase II clinical trial of sipatrigine (619C89) by continuous infusion in acute stroke. Cerebrovasc Dis 2000; 10:431–436.PubMedCrossRefGoogle Scholar
  77. 77.
    Choi DW. Calcium-mediated neurotoxicity: Relationship to specific channel types and role in ischemic damage. Trends Neurosci 1988; 11:465–469.PubMedCrossRefGoogle Scholar
  78. 78.
    Mattson MP. Calcium and free radicals: Mediators of neurotrophic factor and excitatory transmitter-regulated developmental plasticity and cell death. Perspect Dev Neurobiol 1996; 3:79–91.PubMedGoogle Scholar
  79. 79.
    Xiong Y, Gu Q, Peterson PL, Muizelaar JP, Lee CP. Mitochondrial dysfunction and calcium perturbation induced by traumatic brain injury. J Neurotrauma 1997; 14:23–34.PubMedCrossRefGoogle Scholar
  80. 80.
    Hunter AJ. Calcium antagonists: Their role in neuroprotection. Int Rev Neurobiol 1997; 40:95–108.PubMedCrossRefGoogle Scholar
  81. 81.
    Scriabine A. Calcium channel antagonists as neuroprotective agents. In: B r PR, Flint Beal M, eds. Neuroprotection in CNS Diseases. New York: Marcel Dekker Inc., 1997:27–51.Google Scholar
  82. 82.
    Kobayashi T, Mori Y. Ca2+ channel antagonists and neuroprotection from cerebral ischemia. Eur J Pharmacol 1998; 363:1–15.PubMedCrossRefGoogle Scholar
  83. 83.
    Horn J, Limburg M. Calcium antagonists for ischemic stroke: A systematic review. Stroke 2001; 32:570–576.PubMedCrossRefGoogle Scholar
  84. 84.
    Catterall WA. Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol 2000; 16:521–555.PubMedCrossRefGoogle Scholar
  85. 85.
    Ertel EA, Campbell KP, Harpold MM, Hofmann F, Mori Y, Perez-Reyes E et al. Nomenclature of voltage-gated calcium channels. Neuron 2000; 25:533–535.PubMedCrossRefGoogle Scholar
  86. 86.
    Ertel SI, Ertel EA, Clozel JP. T-type Ca2+ channels and pharmacological blockade: Potential pathophysiological relevance. Cardiovasc Drugs Ther 1997; 11:723–739.PubMedCrossRefGoogle Scholar
  87. 87.
    Sayer RJ, Brown AM, Schwindt PC, Crill WE. Calcium currents in acutely isolated human neocortical neurons. J Neurophysiol 1993; 69:1596–1606.PubMedGoogle Scholar
  88. 88.
    Westenbroek RE, Ahlijanian MK, Catterall WA. Clustering of L-type Ca2+ channels at the base of major dendrites in hippocampal pyramidal neurons. Nature 1990; 347:281–284.PubMedCrossRefGoogle Scholar
  89. 89.
    Westenbroek RE, Hell JW, Warner C, Dubel SJ, Snutch TP, Catterall WA. Biochemical properties and subcellular distribution of an N-type calcium channel alpha 1 subunit. Neuron 1992; 9:1099–1115.PubMedCrossRefGoogle Scholar
  90. 90.
    Mills LR, Niesen CE, So AP, Carlen PL, Spigelman I, Jones OT. N-type Ca2+ channels are located on somata, dendrites, and a subpopulation of dendritic spines on live hippocampal pyramidal neurons. J Neurosci 1994; 14:6815–6824.PubMedGoogle Scholar
  91. 91.
    Pringle AK, Benham CD, Sim L, Kennedy J, Iannotti F, Sundstrom LE. Selective N-type calcium channel antagonist omega conotoxin MVIIA is neuroprotective against hypoxic neurodegeneration in organotypic hippocampal-slice cultures. Stroke 1996; 27:2124–2130.PubMedCrossRefGoogle Scholar
  92. 92.
    Valentino K, Newcomb R, Gadbois T, Singh T, Bowersox S, Bitner S et al. A selective N-type calcium channel antagonist protects against neuronal loss after global cerebral ischemia. Proc Natl Acad Sci USA 1993; 90:7894–7897.PubMedCrossRefGoogle Scholar
  93. 93.
    Buchan AM, Gertler SZ, Li H, Xue D, Huang ZG, Chaundy KE et al. A selective N-type Ca2tchannel blocker prevents CAI injury 24 h following severe forebrain ischemia and reduces infarction following focal ischemia. J Cereb Blood Flow Metab 1994; 14:903–910.PubMedCrossRefGoogle Scholar
  94. 94.
    Takizawa S, Matsushima K, Fujita H, Nanri K, Ogawa S, Shinohara Y. A selective N-type calcium channel antagonist reduces extracellular glutamate release and infarct volume in focal cerebral ischemia. J Cereb Blood Flow Metab 1995; 15:611–618.PubMedCrossRefGoogle Scholar
  95. 95.
    Verweij BH, Muizelaar JP, Vinas FC, Peterson PL, Xiong Y, Lee CP. Mitochondrial dysfunction after experimental and human brain injury and its possible reversal with a selective N-type calcium channel antagonist (SNX-111). Neurol Res 1997; 19:334–339.PubMedGoogle Scholar
  96. 96.
    Verweij BH, Muizelaar JP, Vinas FC, Peterson PL, Xiong Y, Lee CP. Improvement in mitochondrial dysfunction as a new surrogate efficiency measure for preclinical trials: Dose-response and time-window profiles for administration of the calcium channel blocker Ziconotide in experimental brain injury. J Neurosurg 2000; 93:829–834.PubMedCrossRefGoogle Scholar
  97. 97.
    Miljanich GP, Ramachandran J. Antagonists of neuronal calcium channels: Structure, function, and therapeutic implications. Annu Rev Pharmacol Toxicol 1995; 35:707–734.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Christian Alzheimer
    • 1
    • 2
  1. 1.Department of PhysiologyUniversity ofMunich, Pettenkoferstr.MunichGermany
  2. 2.Institute of PhysiologyUniversity of KielKielGermany

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