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Neuroprotective effects of NS-7, voltage-gated Na+/Ca2+ channel blocker in a rodent model of transient focal ischemia

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Abstract

The aim of the present study was to characterize neuroprotective activity of NS-7, a mixed voltage-gated sodium and calcium channel blocker in a model of transient focal ischemia in rats. Ischemia was induced by a 75-min reversible occlusion of middle cerebral artery (MCAo) using a nylon filament. NS-7 (0.5 mg/kg i.v.) or 0.9% NaCl (1 ml/kg i.v.) were infused over 3 min starting 30 min after the MCAo. Infarct analysis was performed 72 h after ischemia. Application of NS-7 produced significant protection seen in neurological tests and diminished brain damage by 37% in total infarct (17.7±3.0% vs. 27.9±3.2% control; p<0.01; t-test), by 47.8% in cortical infarct size (8.5±2.4% vs. 16.2±2.4% control; p<0.01) and by 21.5% in striatal infarction (9.2±0.8% vs. 11.7±0.9% control; p<0.05). The results indicate that NS-7 has potential for neuroprotection against transient ischemic insult.

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References

  • Aoki, Y., Shibahara, R., Itoh, Y., Yoshikuni, Y. and Kimura, K. (1997) “Cerebroprotective effects of NS-7, a novel pyrimidine derivative, in rats after permanent middle cerebral artery occlusion”, Jpn. J. Pharmacol. (Suppl.), 90.

  • Aronowski, J., Strong, R. and Grotta, J.C. (1996) “Combined neuroprotection and reperfusion therapy for stroke: Effect of lubeluzole and diaspirin cross-linked hemoglobin in experimental focal ischemia”, Stroke 27, 1571–1577.

    PubMed  CAS  Google Scholar 

  • Back, T., Ginsberg, M.D., Dietrich, W.D. and Watson, B.D. (1996) “Induction of spreading depression in the ischemic hemisphere following experimental middle cerebral artery occulusion: effect on infarct morphology”, J. Cereb. Blood Flow Metab. 16, 202–213.

    Article  PubMed  CAS  Google Scholar 

  • Bederson, J.B., Pitts, L.H., Tsuji, M., Nishimura, M.C., Davis, R.L., and Bartkowski, H. (1986) “Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination”, Stroke 17, 472–476.

    PubMed  CAS  Google Scholar 

  • Benham, C.D., Brown, T.H., Cooper, D.G., Evans, M.L., Harries, M.H., Herdon, H.J., Meakin, J.E., Murkitt, K.L., Patel, S.R., Roberts, J.C., Rothaul, A.L., Smith, S.J., Wood, N. and Hunter, A.J. (1993) “SB-201823-a, a neuronal Ca2+ antagonist is neuroprotective in two models of cerebral ischaemia”, Neuropharmacology 32, 1249–1257.

    Article  PubMed  CAS  Google Scholar 

  • Buchan, A.M., Gertler, S.Z., Li, H., Xue, D., Huang, Z.G., Chaundy, K.E., Barnes, K. and Lesiuk, H.J. (1994) “A selective n-type Ca2+-channel blocker prevents CA1 injury 24 h following severe forebrain ischemia and reduces infarction following focal ischemia”, J. Cereb. Blood Flow Metab. 14, 903–910.

    PubMed  CAS  Google Scholar 

  • Clark, R.K., Lee, E.V., Fish, C.J., White, R.F., Price, W.J., Jonak, Z.L.. Feuerstein, G.Z. and Barone, F.C. (1993) “Development of tissue damage, inflammation and resolution following stroke: an immunohistochemical and quantitative planimetric study”, Brain Res. Bull. 31, 565–572.

    Article  PubMed  CAS  Google Scholar 

  • De Ryck, M. (1997) “Protection of neurological function in stroke models and neuroprotective properties of lubeluzole”, Cerebrovasc. Dis. 7, 18–30.

    Article  Google Scholar 

  • Doble, A. (1996) “The pharmacology and mechanism of action of riluzole”, Neurology 47, S233-S241.

    PubMed  CAS  Google Scholar 

  • Du, C., Hu, R., Csernansky, C.A., Hsu, C.Y. and Choi, D.W. (1996) “Very delayed infarction after mild focal cerebral ischemia: a role for apoptosis?”, J. Cereb. Blood Flow Metab. 16, 195–201.

    Article  PubMed  CAS  Google Scholar 

  • Geter-Douglass, B. and Witkin, J.M. (1999) “Behavioral effects and anticonvulsant efficacies of low-affinity, uncompetitive NMDA antagonists in mice”, Psychopharmacology 146, 280–289.

    Article  PubMed  CAS  Google Scholar 

  • Ginsberg, M.D., Belayev, L. and Zhao, W.Z. (1997) “Recruitment of the ischemic penumbra into the necrotic core”, Cerebrovasc. Dis. 7, 14–18.

    Article  Google Scholar 

  • Goldin, S.M., Subbarao, K., Sharma, R., Knapp, A.G., Fischer, J.B., Daly, D., Durant, G.J., Reddy, N.L., Hu, L.Y. and Magar, S. (1995) “Neuroprotective use-dependent blockers of Na+ and Ca2+ channels controlling presynaptic release of glutamate”, Ann. N.Y. Acad. Sci. 765, 210–229.

    Article  PubMed  CAS  Google Scholar 

  • Hossmann, K.A. (1994) “Glutamate-mediated injury in focal cerebral ischemia: the excitotoxin hypothesis revised”, Brain Pathol. 4, 23–36.

    PubMed  CAS  Google Scholar 

  • Itoh, Y., Aoki, Y., Nonaka, K., Ukai, Y., Yoshikuni, Y. and Kimura, K. (1997) “Permeability of a neuroprotective compound NS-7 into brain: comparison between normal and middle cerebral artery-occluded rats”, Life Sci. 61, 957–966.

    Article  PubMed  CAS  Google Scholar 

  • Kimelberg, H.K., Goderie, S.K., Higman, S., Pang, S. and Waniewski, R.A. (1990) “Swelling-induced release of glutamate, aspartate, and taurine from astrocyte cultures”, J. Neurosci. 10, 1583–1591.

    PubMed  CAS  Google Scholar 

  • Lekieffre, D., Benavides, J., Scatton, B. and Nowicki, J.P. (1997) “Neuroprotection afforded by a combination of eliprodil and a thrombolytic agent, rt-PA, in a rat thromboembolic stroke model”, Brain Res. 776, 88–95.

    Article  PubMed  CAS  Google Scholar 

  • Liu, Y., Belayev, L., Zhao, W., Busto, R. and Ginsberg, M.D. (2000) “MRZ 2/579, a novel uncompetitive N-methyl-d-aspartate antagonist, reduces infarct volume and brain swelling and improves neurological deficit after focal ischemia in rats”, Brain Res. 862, 111–119.

    Article  PubMed  CAS  Google Scholar 

  • Longa, E.Z., Weinstein, P.R., Carlson, S. and Cummins, R. (1989) “Reversible middle cerebral artery occlusion without craniectomy in rats”, Stroke 20, 84–91.

    PubMed  CAS  Google Scholar 

  • Lynch, J.J., Yu, S.P., Canzoniero, L.M.T., Sensi, S.L. and Choi, D.W. (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.

    PubMed  CAS  Google Scholar 

  • Mcculloch, J. (1992) “Excitatory amino acid antagonists and their potential for the treatment of ischaemic brain damage in man”, Br. J. Clin. Pharmacol. 34, 106–114.

    PubMed  CAS  Google Scholar 

  • O’Neill, M.J., Bath, C.P., Dell, C.P., Hicks, C.A., Gilmore, J., Ambler, S.J., Ward, M.A. and Bleakman, D. (1997) “Effects of Ca(2+) and Na(+) channel inhibitors in vitro and in global cerebral ischaemia in vivo”, Eur. J. Pharmacol. 332, 121–131.

    Article  PubMed  CAS  Google Scholar 

  • Obrenovitch, T.P. and Urenjak, J. (1998) “Glutamate release inhibitors: a critical assessment of their action mechanism”, Amino Acids 14, 143–150.

    Article  PubMed  CAS  Google Scholar 

  • Oka, M., Itoh, Y., Ukai, Y. and Kimura, K. (1999) “Blockade by NS-7, a neuroprotective compound, of both L-type and P/Q-type Ca2+ channels involving depolarization-stimulated nitric oxide synthase activity in primary neuronal culture”, J. Neurochem. 72, 1315–1322.

    Article  PubMed  CAS  Google Scholar 

  • Paschen, W. (1996) “Glutamate excitotoxicity in transient global cerebral ischemia”, Acta Neurobiol. Exp. 56, 313–322.

    CAS  Google Scholar 

  • Pratt, J., Rataud, J., Bardot, F., Roux, M., Blanchard, J.C., Laduron, P.M. and Stutzmann, J.M. (1992) “Neuroportective actions of Riluzole in rodent models of global and focal cerebral ischaemia”, Neurosci. Lett. 140, 225–230.

    Article  PubMed  CAS  Google Scholar 

  • Rami, A. and Krieglstein, J. (1994) “Neuronal protective effects of calcium antagonists in cerebral ischemia”, Life Sci. 55, 2105–2113.

    Article  PubMed  CAS  Google Scholar 

  • Read, S.J., Hirano, T., Davis, S.M. and Donnan, G.A. (1999) “Limiting neurological damage after stroke—a review of pharmacological treatment options”, Drug Aging 14, 11–39.

    Article  CAS  Google Scholar 

  • Rogawski, M. (2000) “Low affinity channel blocking (uncompetitive) NMDA receptor antagonists as therapeutic agents— toward an understanding of their favourable tolerability”, Amino Acids 19, 133–149.

    Article  PubMed  CAS  Google Scholar 

  • Shimidzu, T., Itoh, Y., Tatsumi, S., Hayashi, S., Ukai, Y., Yoshikuni, Y. and Kimura, K. (1997) “Blockade of voltage-sensitive sodium channels by NS-7, a novel neuroprotective compound, in the rat brain”, Naunyn-Schmied. Arch. Pharmacol. 355, 601–608.

    Article  CAS  Google Scholar 

  • Smith, S.E., Hodges, H., Sowinski, P., Man, C.M., Leach, M.J., Sinden, J.D., Gray, J.A. and Meldrium, B.S. (1997) “Long-term beneficial effects of BW619C89 on neurological deficit, cognitive deficit and brain damage after middle cerebral artery occlusion in the rat”, Neuroscience 77, 1123–1135.

    Article  PubMed  CAS  Google Scholar 

  • Steiner, T. and Hacke, W. (1998) “Combination therapy with neuroprotectants and thrombolytics in acute ischaemic stroke”, Eur. Neurol. 40, 1–8.

    Article  PubMed  CAS  Google Scholar 

  • Suma, C., Hayashi, S., Ukai, Y., Yoshikuni, Y. and Kimura, K. (1997). “Na+ and high-voltage-activated Ca2+ channel blocking actions of NS-7, a novel neuroprotective agent, in NG108-15 cells”, Eur. J. Pharmacol. 336, 283–290.

    Article  PubMed  CAS  Google Scholar 

  • Swanson, R.A., Morton, M.T., Tsao-Wu, G., Savalos, R.A., Davidson, C. and Sharp, F.R. (1990) “A semiautomated method for measuring brain infarct volume”, J. Cereb. Blood Flow Metab. 10, 290–293.

    PubMed  CAS  Google Scholar 

  • Takagaki, Y., Itoh, Y., Aoki, Y., Ukai, Y., Yoshikuni, Y. and Kimura, K. (1997) “Inhibition of ischemia-induced fodrin breakdown by a novel phenylpyrimidine derivative NS-7: an implication for its neuroprotective action in rats with middle cerebral artery occlusion”, J. Neurochem. 68, 2507–2513.

    PubMed  CAS  Google Scholar 

  • Tatsumi, S., Itoh, Y., Ma, F.H., Higashira, H., Ukai, Y., Yoshikuni, Y. and Kimura, K. (1998a) “Inhibition of depolarization-induced nitric oxide synthase activation by NS-7, a phenylpyrimidine derivative, in primary neuronal culture”, J. Neurochem. 70 59–65.

    Article  PubMed  CAS  Google Scholar 

  • Tatsumi, S., Itoh, Y., Ukai, Y. and Kimura, K. (1998b) “A novel Na+/Ca2+ channel blocker, NS-7, suppresses hypoxic injury in rat cerebrocortical slices”, Naunyn-Schmied. Arch. Pharmacol. 358, 191–196.

    Article  CAS  Google Scholar 

  • Turski, L. (1990) “N-methyl-d-aspartate receptor complex. Different sites for regulation and clinical consequences”, Arzneimittelforschung 40, 511–514.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Merz Pharmaceuticals GmbH, Preclinical Research and Development, Eckenheimer Landstrasse 100, 60318, Frankfurt/Main, Germany

    Monika Sopala, Wojciech Danysz & Guenter Quack

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  1. Monika Sopala
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  2. Wojciech Danysz
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  3. Guenter Quack
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Correspondence to Wojciech Danysz.

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Sopala, M., Danysz, W. & Quack, G. Neuroprotective effects of NS-7, voltage-gated Na+/Ca2+ channel blocker in a rodent model of transient focal ischemia. neurotox res 4, 655–661 (2002). https://doi.org/10.1080/1029842021000045462

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  • DOI: https://doi.org/10.1080/1029842021000045462

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