Potassium Channel Blockers Tetraethylammonium and 4-Aminopyridine Fail to Prevent Microglial Activation Induced by Elevated Potassium Concentration


The effect of potassium channel blockers tetraethylammonium and 4-aminopyridine was examined on the elevated K+ concentration-induced microglial activation on rat hippocampal slice preparations. Microglial cells were detected by immunohistochemistry with a monoclonal antibody (OX 42) raised against a type 3 complement receptor. During activation the morphology of the microglial cells changes and the staining intensity increases. The degree of microglial activation was determined by measuring the integrated optical density of the cells. Tetraethylammonium and 4-aminopyridine failed to reduce the elevated K+ concentration-induced microglial activation. Both potassium channel blockers, when applied on the hippocampal slices without K+, caused significantly increased microglial activation as compared to the control slices. In order to check whether the functional alteration of the neuronal population induced by 4-aminopyridine caused the activation of the microglial cells, Schaffer collaterals were cut to block spreading of epileptiform hyperactivity of the CA3 pyramidal cells to the CA1 region. No significant differences were found in microglial activation between the CA3 and CA1 regions, indicating that the effect of 4-aminopyridine on microglial cells is independent of the epileptiform activity caused by the drug.


  1. 1.

    Ábrahám, H., Losonczy, A., Czéh, G., Lázár, Gy. (2001) Rapid activation of microglial cells by hypoxia, kainic acid, and potassium ions in slice preparations of the rat hippocampus. Brain Res. 906, 115–126.

    Article  Google Scholar 

  2. 2.

    Bordey, A., Sontheimer, H. (2000) Ion channel expression by astrocytes in situ: comparison of different CNS region. Glia 30, 27–38.

    CAS  Article  Google Scholar 

  3. 3.

    Boucsein, C., Kettenmann, H., Nolte, C. (2000) Electrophysiological properties of microglial cells in normal and pathological rat brain slices. Eur. J. Neurosci. 12, 2049–2058.

    CAS  Article  Google Scholar 

  4. 4.

    Eder, C. (1998) Ion channels in microglia (brain macrophages). Am. J. Physiol. 275 (Cell Physiol. 44), C327-C342.

    Google Scholar 

  5. 5.

    Finsen, B. R., Jorgensen, M. B., Diemer, N. H., Zimmer, J. (1993) Microglial MHC antigen expression after ischemic and kainic acid lesions of the adult rat hippocampus. Glia 7, 41–49.

    CAS  Article  Google Scholar 

  6. 6.

    Gehrmann, J., Bonnekoh, P., Miyazawa, T., Hossmann, K. A., Kreutzberg, G. W. (1992) Immuno-cytochemical study of an early microglial activation in ischemia. J. Cereb. Blood Flow Metab. 12, 257–269.

    CAS  Article  Google Scholar 

  7. 7.

    Gehrmann, J., Kreutzberg, G. W. (1995) Microglia in experimental neuropathology. In: Kettenmann, H., Ransom, B. R. (eds) Neuroglia. Oxford University Press, Oxford, pp. 883–904.

    Google Scholar 

  8. 8.

    Hansen, A. J., Zeuthen, T. (1981) Extracellular ion concentrations during spreading depression and ischemia in the rat brain cortex. Acta Physiol. (Scand.) 113, 437–445.

    CAS  Article  Google Scholar 

  9. 9.

    Hu, P. S., Benishin, C., Fredholm, B. B. (1991) Comparison of the effects of four dendrotoxin pep-tides, 4-aminopyridine and tetraethylammonium on the electrically evoked [3H]-noradrenaline from rat hippocampus. Eur. J. Pharmacol. 20, 87–93.

    Article  Google Scholar 

  10. 10.

    Hu, P. S., Fredholm, B. B. (1991) 4-aminopyridine-induced increase in basal and stimulation evoked [3H]-NA release in slices from rat hippocampus: Ca2+ sensitivity and presynaptic control. Br. J. Pharmacol. 102, 764–768.

    CAS  Article  Google Scholar 

  11. 11.

    Jou, I., Pyo, H., Chung, S., Jung, S. Y., Gwag, B. J., Joe, E. H. (1998) Expression of Kv1.5 K+ channels in activated microglia in vivo. Glia 24, 408–414.

    CAS  Article  Google Scholar 

  12. 12.

    Kloss, C. U., Kreutzberg, G. W., Raivich, G. (1997) Proliferation of ramified microglia on an astro-cyte monolayer: characterization of stimulatory and inhibitory cytokines. J. Neurosci. Res. 49, 248–254.

    CAS  Article  Google Scholar 

  13. 13.

    Kotecha, S. A., Schlichter, L. G. (1999) A Kv1.5 to Kv1.3 switch in endogenous hippocampal microglia and a role in proliferation. J. Neurosci. 19, 10680–10693.

    CAS  Article  Google Scholar 

  14. 14.

    Morioka, T., Kalehua, A. H., Streit, W. J. (1991) The microglial reaction in the rat dorsal hippocampus following transient forebrain ischemia. J. Cereb. Blood Flow Metab. 11, 966–973.

    CAS  Article  Google Scholar 

  15. 15.

    Poopalasundaram, S., Knott, C., Shamotienko, O. G., Foran, P. G., Dolly, J. O., Ghiani, C. A., Gallo, V., Wilkin, G. P. (2000) Glial heterogeneity in expression of the inwardly rectifying K(+) channel Kir4.1, in adult rat CNS. Glia 30, 362–372.

    CAS  Article  Google Scholar 

  16. 16.

    Schechter, L. E. (1997) The potassium channel blockers 4-aminopyridine and tetraethylammonium increase the spontaneous basal release of [3H]5-hydroxytryptamine in rat hippocampal slices. J. Pharmacol. Exp. Ther. 282, 262–270.

    CAS  PubMed  Google Scholar 

  17. 17.

    Shaw, J. A., Perry, V. H., Mellanby, J. (1990) Tetanus toxin-induced seizures cause microglial activation in rat hippocampus. Neurosci. Lett. 120, 66–69.

    CAS  Article  Google Scholar 

  18. 18.

    Siesjö, B. K. (1981) Cell damage in the brain. A speculative synthesis. J. Cereb. Blood Flow Metab. 1, 155–185.

    Article  Google Scholar 

  19. 19.

    Streit, W. J., Graeber, M. B., Kreutzberg, G. W. (1988) Functional plasticity of microglia. A review. Glia 1, 301–307.

    CAS  Article  Google Scholar 

  20. 20.

    Streit, W. J. (1995) Microglial cells. In: Kettenmann, H., Ransom, B. R. (eds) Neuroglia. Oxford University Press, Oxford, pp. 85–96.

    Google Scholar 

  21. 21.

    Tapia, R., Sitges, M. (1982) Effect of 4-aminopyridine on transmitter release in synaptosomes. Brain Res. 250, 291–299.

    CAS  Article  Google Scholar 

  22. 22.

    Tapia, R., Sitges, M., Morales, E. (1985) Mechanism of the calcium dependent stimulation of transmitter release by 4-aminopyridine in synaptosomes. Brain Res. 361, 373–382.

    CAS  Article  Google Scholar 

  23. 23.

    Voskuyl, R. A., Albus, H. (1985) Spontaneous epileptiform discharges in hippocampal slices induced by 4-aminopyridine. Brain Res. 342, 54–66.

    CAS  Article  Google Scholar 

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This work was supported by the grants of the Hungarian Science Research Fund (OTKA) T 025759 and A 234.

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Correspondence to Gy. Lázár.

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Ábrahám, H., Losonczy, A., Czéh, G. et al. Potassium Channel Blockers Tetraethylammonium and 4-Aminopyridine Fail to Prevent Microglial Activation Induced by Elevated Potassium Concentration. BIOLOGIA FUTURA 54, 63–78 (2003). https://doi.org/10.1556/ABiol.54.2003.1.7

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  • Glial cells
  • epileptiform activity
  • electrophysiology
  • OX-42