Glutamate Receptor Antagonists and Benzodiazepine Inhibit the Progression of Granule Cell Dispersion in a Mouse Model of Mesial Temporal Lobe Epilepsy

Feb 1, 2005Epilepsia

Blocking glutamate receptors and using benzodiazepines may slow spread of brain cell changes in a mouse model of temporal lobe epilepsy

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Abstract

Unilateral intrahippocampal injection of kainic acid in adult mice leads to significant granule cell dispersion, with a nearly complete inhibition of this effect observed when NMDA receptor antagonism is applied post-injection.

Granule cell dispersion in the hippocampus is a key pathological change associated with mesial temporal lobe epilepsy.
Injection of kainic acid triggers this dispersion, which may be influenced by glutamatergic and GABAergic neurotransmission.
Post-injection administration of the NMDA receptor antagonist MK-801 significantly reduces granule cell dispersion for up to 14 days.
Mild to moderate granule cell dispersion persists even with MK-801 treatment after 28 days.
The non-NMDA receptor antagonist GYKI52466 is effective only when administered before kainic acid injection.
Continuous administration of the GABA(A) receptor agonist midazolam also leads to a significant reduction in granule cell dispersion.

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PURPOSE: Unilateral intrahippocampal injection of kainic acid (KA) in adult mice induces the progressive dispersion of dentate granule cells, one of the characteristic pathologic changes of mesial temporal lobe epilepsy. However, little is known about the mechanisms that trigger this dispersion. In this study, the possible involvement of glutamatergic and gamma-aminobutyric acid (GABA)ergic neurotransmissions in the development of granule cell dispersion (GCD) was examined in this model.

METHODS: Antagonists of N-methyl-d-aspartate (NMDA) receptor (MK-801) and non-NMDA receptor (GYKI52466), and an agonist of benzodiazepine-GABA(A) receptor (midazolam) were injected before and after KA in various ways, and the morphologic changes of the hippocampus, especially GCD, were examined.

RESULTS: MK-801 (5 mg/kg, i.p.) did not reduce GCD when injected 2 h before KA injection but inhibited GCD almost completely for <or=14 days, when injected 4 h after KA. However, mild to moderate dispersion was observed at 28 days, indicating that MK-801 may delay the progression of GCD. Similarly, daily treatment with MK-801 (2 x 1 mg/kg i.p./day) for the first 26 days after KA significantly reduced GCD. In contrast, GYKI52466 (30 mg/kg, s.c.) was effective only when it was injected before KA. A significant reduction of GCD was also observed after continuous administration of midazolam (10 mg/kg/h) after KA.

CONCLUSIONS: These data show that GCD in this mouse model is triggered by either the stimulation of the NMDA receptor or reduction of GABA(A)-mediated inhibition after intrahippocampal injection of KA. It is suggested that the increased excitation or the reduced inhibition or both could be one of the factors triggering or maintaining or both the process of GCD.

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Glutamate Receptor Antagonists and Benzodiazepine Inhibit the Progression of Granule Cell Dispersion in a Mouse Model of Mesial Temporal Lobe Epilepsy

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