Elsevier

Brain Research

Volume 705, Issues 1–2, 24 December 1995, Pages 97-104
Brain Research

Excitoprotective effect of felbamate in cultured cortical neurons

https://doi.org/10.1016/0006-8993(95)01147-1Get rights and content

Abstract

The effect of felbamate on excitatory amino acid-induced biochemical changes was investigated in cultured cortical neurons. Felbamate inhibited NMDA- and glutamate-induced neuronal injury in a dose-dependent manner, but it did not rescue cells from kainate-induced neurotoxicity. The neuroprotective effect was accompanied by a decrease in NMDA- and glutamate-induced neuronal calcium (Ca2+) influx. Exogenous addition of glycine failed to modulate the effect of felbamate on NMDA-induced neurotoxicity or Ca2+ influx, although corresponding changes induced by the strychnine-insensitive glycine antagonist, 5,7-dichlorokynurenic acid could be modulated with glycine. Taken together, these results suggest that felbamate acts through a site on the NMDA receptor that is distinct from the strychnine-insensitive site, and that the effect of the drug on neuronal Ca2+ may be pivotal to its neuroprotective mechanism.

References (48)

  • WasterlainC.G. et al.

    Felbamate reduces hypoxic-ischemic brain damage in vivo

    Eur. J. Pharmacol.

    (1992)
  • BealM.F.

    Mechanisms of excitotoxicity in neurologic diseases

    FASEB J.

    (1992)
  • CarterA.J.

    Many agents that antagonize the NMDA receptor-channel complex in vivo also causes disturbances of motor coordination

    J. Pharmacol. Exp. Ther.

    (1994)
  • ChiamuleraC. et al.

    Effects of NMDA and strychnine-insensitive glycine site antagonists on NMDA-mediated convulsions and learning

    Psychopharmacology

    (1990)
  • ChoiD.W.

    Ionic dependence of glutamate neurotoxicity in cortical cell culture

    J. Neurosci.

    (1987)
  • ChoiD.W. et al.

    Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists

    J. Neurosci.

    (1989)
  • ChoiD.W. et al.

    The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death

    Annu. Rev. Neurosci.

    (1990)
  • FadenA.I. et al.

    The role of excitatory amino acids and NMDA receptors in traumatic brain injury

    Science

    (1989)
  • HartleyD.M. et al.

    7-Chlorokynurenate blocks NMDA receptor-mediated neurotoxicity in murine cortical culture

    Eur. J. Neurosci.

    (1990)
  • HartleyD.M. et al.

    Glutamate receptor-induced 45Ca2+ accumulation in cortical cell culture correlates with subsequent neuronal degeneration

    J. Neurosci.

    (1993)
  • JohnsonJ.W. et al.

    Glycine potentiates the NMDA responses in cultured mouse brain neurons

    Nature

    (1987)
  • KempJ.A. et al.

    7-Chlorokynureic acid is a selective antagonist at the glycine site of N-methyl-d-asparate receptor complex

  • KlecknerN.W. et al.

    Requirement for glycine in activation of NMDA receptor expressed in Xenopus oocytes

    Science

    (1988)
  • KoekW. et al.

    Selective blockade of N-methyl-d-aspartate (NMDA)-induced convulsions by NMDA antagonists and putative glycine antagonists: relationship with phencyclidine-like behavioral effects

    J. Pharmacol. Exp. Ther.

    (1990)
  • Cited by (18)

    • Characterization of the gating conformational changes in the felbamate binding site in NMDA channels

      2007, Biophysical Journal
      Citation Excerpt :

      However, Subramanian et al. (6) showed that FBM competitively inhibited [3H]MK-801 binding but not [3H]5,7-DCKA binding. Also, exogenous addition of glycine failed to modulate the excitoprotective effect of FBM on cultured cortical neurons exposed to glutamate or NMDA (14), and there were no competitive interactions between FBM and glycine in studies of NMDA currents (5). Furthermore, it has been reported that FBM produced an increase rather than a decrease in [3H]glycine binding to the NMDA channel (15).

    • Positive and negative modulation of the GABA(A) receptor and outcome after traumatic brain injury in rats

      2000, Brain Research
      Citation Excerpt :

      Although the precise mechanisms of diazepam's beneficial effects is speculative, it is well documented that TBI produces neuronal depolarization that triggers a cascade of events that can lead to cell death by enabling intracellular levels of Ca2+ to rise [5, 53]. Increasing neuronal hyperpolarization with diazepam may be effective in preventing the increase in intracellular Ca2+, as anticonvulsants have been shown to reduce Ca2+ influx [21, 23, 29, 30]. In addition to reducing Ca2+ influx, the anticonvulsant felbanate also protects CA1 neurons from TBI [49].

    • New antiepileptic drugs

      2000, Journal of Clinical Neuroscience
    View all citing articles on Scopus
    View full text