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Modulation by Topiramate of AMPA and Kainate Mediated Calcium Influx in Cultured Cerebral Cortical, Hippocampal and Cerebellar Neurons

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Abstract

The effect of the antiepileptic drug topiramate on Ca2+ uptake through (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionate (AMPA) and kainate (KA) receptors was investigated in different cell culture systems consisting of neurons from the cerebral cortex, hippocampus, and cerebellum. Ca2+ influx was assayed using a fluorescent Ca2+ chelator to monitor changes in the intracellular Ca2+ concentration or cobalt staining to assess the effect of topiramate on Ca2+-permeable AMPA/KA receptors. In all types of neuronal cultures studied, AMPA and KA were found to elicit an influx of Ca2+ in a subset of the neuronal population. Topiramate, at concentrations of 30 and 100 μM, inhibited Ca2+ influx by up to 60%. Modulation of AMPA and KA-evoked Ca2+ influx may contribute to both the antiepileptic and neuroprotective properties of topiramate.

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REFERENCES

  1. Löscher, W. 1998. New visions in the pharmacology of anticonvulsion. Eur. J. Pharmacol. 342:1–13.

    Google Scholar 

  2. Zona, C., Giotti, M. T., and Avoli, M. 1997. Topiramate attenuates voltage-gated sodium currents in rat cerebellar granule cells. Neurosci. Lett. 231:123–126.

    Google Scholar 

  3. White, H. S., Brown, S. D., Woodhead, J. H., Skeen, G. A., and Wolf, H. H. 1997. Topiramate enhances GABA-mediated chloride flux and GABA-evoked chloride currents in murine brain neurons and increases seizure threshold. Epilepsy Res. 28:167–179.

    Google Scholar 

  4. Gibbs, J. W. III, Sombati, S., DeLorenzo, R. J., and Coulter, D. A. 2000. Cellular actions of topiramate: Blockade of kainate-evoked inward currents in cultured hippocampal neurons. Epilepsia 41: S10–S16.

    Google Scholar 

  5. McLean, M. J., Bukhari, A. A., and Wamil, A. W. 2000. Effects of topiramate on sodium-dependent action-potential firing by mouse spinal cord neurons in cell culture. Epilepsia 41: S21–S24.

    Google Scholar 

  6. Zhang, X.-L., Velumian, A. A., Jones, O. T., and Carlen, P. L. 2000. Modulation of high-voltage-activated calcium channels in dentate granule cells by topiramate. Epilepsia 41:S52–S60.

    Google Scholar 

  7. Skradski, S. and White, H. S. 2000. Topiramate blocks kainate-evoked cobalt influx into cultured neurons. Epilepsia 41:S45–S47.

    Google Scholar 

  8. White, H. S. 2002. Topiramate: Mechanisms of action. Pages 719–726, in Levy, R. H., Mattson, R. H., Meldrum, B. S., and Perucca, E. (eds.), Antiepileptic drugs, 5th ed., Philadelphia, PA: Lippincott Williams & Wilkins.

    Google Scholar 

  9. Sarup, A. and Schousboe, A. 2002. Alterations in glutamate transporter protein expression and activity in cultures of astrocytes after topiramate treatment. Epilepsia 43:S136–S137.

    Google Scholar 

  10. Schousboe, A. 1990. Neurochemical alterations associate with epilepsy or seizure activity. Pages 1–16, in Dam, M. and Gram, L. (eds.), Comprehensive epileptology, New York: Raven Press.

    Google Scholar 

  11. Shank, R. P., Gardocki, J. F., Streeter, A. J., and Maryanoff, B. E. 2000. An overview of the preclinical aspects of topiramate: Pharmacology, pharmacokinetics, and mechanism of action. Epilepsia 41:S3–S9.

    Google Scholar 

  12. Sommer, B. 1997. Ionotropic glutamate receptors. Pages 81–98, in Monaghan, D. T. and Wenthold, R. J. (eds.), The ionotropic glutamate receptors, NJ: Humana Press.

    Google Scholar 

  13. Frandsen, A. and Schousboe, A. 1993. Excitatory amino acid mediated cytotoxicity and calcium homeostasis in cultured neurons. J. Neurochem. 60:1202–1211.

    Google Scholar 

  14. Frandsen, A. and Schousboe, A. 2003. AMPA receptor mediated neurotoxicity: Role of Ca2+ and desensitisation. Neurochem. Res. 28:1493–1497.

    Google Scholar 

  15. Partin, K. M., Patneau, D. K., and Mayer, M. L. 1994. Cyclothiazide differentially modulates desensitization of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor splice variants. Mol. Pharmacol. 46:129–138.

    Google Scholar 

  16. Lodge, D. 1997. Subtypes of glutamate receptors. Pages 1–38, in Monaghan, D. T. and Wenthold, R. J. (eds.), The ionotropic glutamate receptors, NJ: Humana Press.

    Google Scholar 

  17. Pruss, R. M., Akeson, R. L., Racke, M. M., and Wilburn, J. L. 1991. Agonist-activated cobalt uptake identifies divalent cation-permeable kainate receptors on neurons and glial cells. Neuron 7:509–518.

    Google Scholar 

  18. Drejer, J., Honoré, T., and Schousboe, A. 1987. Excitatory amino acid induced release of 3H-GABA from cultured mouse cerebral cortex interneurons. J. Neurosci. 7:2910–2916.

    Google Scholar 

  19. Drejer, J. and Schousboe, A. 1989. Selection of a pure cerebellar granule cell culture by kainate treatment. Neurochem. Res. 14:751–754.

    Google Scholar 

  20. Hertz, E., Yu, A. C. H., Hertz, L., Juurlink, B. H. J., and Schousboe, A. 1989. Preparation of primary cultures of mouse cortical neurons. Pages 183–186, in Shahar, A., De Vellis, J., Vernadakis, A., and Haber, B. (eds.), A dissection and tissue culture manual for the nervous system, New York: Alan R. Liss.

    Google Scholar 

  21. Schousboe, A., Meier, E., Drejer, and Hertz, L. 1989. Preparation of primary cultures of mouse (rat) cerebellar granule cells. Pages 203–206, in Shahar, A., De Vellis, J., Vernadakis, A., and Haber, B. (eds.), A dissection and tissue culture manual of the nervous system, New York: Alan R. Liss.

    Google Scholar 

  22. Hertz, L., Juurlink, B. H. J., Fosmark, H., and Schousboe, A. 1982. Astrocytes in primary cultures. Pages 175–186, in Pfeiffer, S. E. (ed.), Neuroscience approached through cell culture, Boca Raton, FL: CRC Press.

    Google Scholar 

  23. Mattson, M. P. 1994. Secreted forms of beta-amyloid precursor protein modulate dendrite outgrowth and calcium responses to glutamate in cultured embryonic hippocampal neurons. J. Neurobiol. 25:439–450.

    Google Scholar 

  24. Niebauer, M. and Gruenthal, M. 1999. Topiramate reduces neuronal injury after experimental status epilepticus. Brain Res. 837: 263–269.

    Google Scholar 

  25. Yang, Y., Shuaib, A., Li, Q., and Siddiqui, M. M. 1998. Neuroprotection by delayed administration of topiramate in a rat model of middle cerebral artery embolization. Brain Res. 804: 169–176.

    Google Scholar 

  26. Lee, S. R., Kim, S. P., and Kim, J. E. 2000. Protective effect of topiramate against hippocampal neuronal damage after global ischemia in the gerbils. Neurosci. Lett. 281:183–186.

    Google Scholar 

  27. Koh, S. and Jensen, F. E. 2001. Topiramate blocks perinatal hypoxia-induced seizures in rat pups. Ann. Neurol. 50:366–372.

    Google Scholar 

  28. Yoneda, S., Tanaka, E., Goto, W., Ota, T., and Hara, H. 2003. Topiramate reduces excitotoxic and ischemic injury in the rat retina. Brain Res. 967:257–266.

    Google Scholar 

  29. Maragakis, N. J., Jackson, M., Ganel, R., and Rothstein, J. D. 2003. Topiramate protects against motor neuron degeneration in organotypic spinal cord cultures but not in G93A SOD1 transgenic mice. Neurosci. Lett. 338:107–110.

    Google Scholar 

  30. Smith-Swintosky, V. L., Zhao, B., Shank, R. P., and Plata-Salaman, C. R. 2001. Topiramate promotes neurite outgrowth and recovery of function after nerve injury. Neuroreport 12:1031–1034.

    Google Scholar 

  31. Murphy, S. N. and Miller, R. J. 1988. A glutamate receptor regulates Ca2+ mobilization in hippocampal neurons. Proc. Natl. Acad. Sci. USA 85:8737–8741.

    Google Scholar 

  32. Murphy, S. N. and Miller, R. J. 1989. Two distinct quisqualate receptors regulate Ca2+ homeostasis in hippocampal neurons in vitro. Mol. Pharmacol. 35:671–680.

    Google Scholar 

  33. Frandsen, A. and Schousboe, A. 1992. Mobilization of dantrolene-sensitive intracellular calcium pools is involved in the cytotoxicity induced by quisqualate and N-methyl-<small-caps>D</small-caps>-aspartate but not by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionate and kainate in cultured cerebral cortical neurons. Proc. Natl. Acad. Sci. USA 89:2590–2594.

    Google Scholar 

  34. Ogura, A., Nakazawa, M., and Kudo, Y. 1992. Further evidence for calcium permeability of non-NMDA receptor channels in hippocampal neurons. Neurosci. Res. 12:606–616.

    Google Scholar 

  35. Witt, M.-R., Dekermendjian, K., Frandsen, A., Schousboe, A., and Nielsen, M. 1994. Complex correlation between excitatory amino acid induced increase in the intracellular Ca2+ concentration and subsequent loss of neuronal function in individual neocortical neurons in culture. Proc. Natl. Acad. Sci. USA 91: 12303–12307.

    Google Scholar 

  36. Jensen, J. B., Schousboe, A., and Pickering, D. 1999. Role of desensitization and subunit expression for kainate receptor-mediated neurotoxicity in murine neocortical cultures. J. Neurosci. Res. 55:208–217.

    Google Scholar 

  37. Zhou, N., Taylor, D. A., and Parks, T. N. 1995. Cobalt-permeable non-NMDA receptors in developing chick brainstem auditory nuclei. Neuroreport 6:2273–2276.

    Google Scholar 

  38. Savidge, J. R., Bleakman, D., and Bristow, D. R. 1997. Identification of kainate receptor-mediated intracellular calcium increases in cultured rat cerebellar granule cells. J. Neurochem. 69: 1763–1766.

    Google Scholar 

  39. Jensen, J. B., Lund, T. M., Timmermann, D. B., Schousboe, A., and Pickering, D. S. 2001. Role of GluR2 expression in AMPA-induced toxicity in cultured murine cerebral cortical neurons. J. Neurosci. Res. 65:267–277.

    Google Scholar 

  40. Jensen, J. B., Schousboe, A., and Pickering, D. 1998. Development of calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in cultured neocortical neurons visualized by cobalt staining. J. Neurosci. Res. 54:273–281.

    Google Scholar 

  41. Turetsky, D. M., Canzoniero, L. M., Sensi, S. L., Weiss, J. H., Goldberg, M. P., and Choi, D. W. 1994. Cortical neurones exhibiting kainate-activated Co2+ uptake are selectively vulnerable to AMPA/kainate receptor-mediated toxicity. Neurobiol. Dis. 1: 101–110.

    Google Scholar 

  42. Smith, L., Price-Jones, M., Hughes, K., Egebjerg, J., Poulsen, F., Wiberg, F. C., and Shank, R. P. 2000. Effects of topiramate on kainate-and domoate-activated [14C]guanidinium ion flux through GluR6 channels in transfected BHK cells using cytostar-T scintillating microplates. Epilepsia 41:S48–S51.

    Google Scholar 

  43. Gryder, D. S. and Rogawski, M. A. 2002. Topiramate selectively blocks GluR5 kainate receptor-mediated excitatory synaptic transmission in amygdala: Evidence for indirect action via modulation of protein kinase A-dependent phosphorylation. Epilepsia 43: S129.

    Google Scholar 

  44. Garnett, W. R. 2000. Clinical pharmacology of topiramate: A review. Epilepsia 41:S61–S65.

    Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology, The Danish University of Pharmaceutical Sciences, Copenhagen, Danmark

    Claus F. Poulsen, Thomas E. Maar & Arne Schousboe

  2. Program in Neuroscience, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah

    Timothy A. Simeone, Virginia Smith-Swintosky & H. Steven White

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  1. Claus F. Poulsen
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  2. Timothy A. Simeone
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Correspondence to Arne Schousboe.

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Poulsen, C.F., Simeone, T.A., Maar, T.E. et al. Modulation by Topiramate of AMPA and Kainate Mediated Calcium Influx in Cultured Cerebral Cortical, Hippocampal and Cerebellar Neurons. Neurochem Res 29, 275–282 (2004). https://doi.org/10.1023/B:NERE.0000010456.92887.3b

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  • DOI: https://doi.org/10.1023/B:NERE.0000010456.92887.3b

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