Elsevier

Neuroscience

Volume 118, Issue 3, 25 May 2003, Pages 727-740
Neuroscience

Research paper
N-methyl-d-aspartate receptor blockade after status epilepticus protects against limbic brain damage but not against epilepsy in the kainate model of temporal lobe epilepsy

https://doi.org/10.1016/S0306-4522(03)00027-7Get rights and content

Abstract

Most patients with temporal lobe epilepsy (TLE), the most common type of epilepsy, show pronounced loss of neurons in limbic brain regions, including the hippocampus. The massive neurodegeneration in the hippocampus is known as hippocampal sclerosis, and is considered one of the hallmarks of this type of difficult-to-treat epilepsy. There is a long and ongoing debate on whether this sclerosis is the result of an initial pathological event, such as a status epilepticus (S.E.), stroke or head trauma, which often precedes the development of TLE, or is caused by the spontaneous recurrent seizures (SRS) once epilepsy has developed. At present, pharmacological prevention of limbic sclerosis is not available. In a clinical situation, such prevention would only be possible if delayed cell death developing after an initial pathological event is involved. Assuming that sclerotic brain lesions provoke epileptogenesis and that delayed cell death is involved in these lesions, it should be possible to prevent both the lesions and the epilepsy by a prophylactic treatment after an initial insult such as an S.E. In order to test this hypothesis, we used a rat model of TLE in which limbic brain lesions and epilepsy with SRS develop after a kainate-induced S.E. A single low dose of the N-methyl-d-aspartate (NMDA) receptor blocker dizocilpine (MK-801) significantly reduced the damage in limbic regions, including the hippocampus and piriform cortex, and completely protected several rats from such damage when given after an S.E. of 90 min induced by kainate, strongly suggesting that delayed cell death is involved in the damage. This was substantiated by the use of molecular and immunohistochemical markers of delayed active (“programmed”) cell death. However, the neuroprotection by dizocilpine did not prevent the development of SRS after the S.E., suggesting that structures not protected by dizocilpine may play a role in the genesis of SRS or that epileptogenesis is not the consequence of structural lesions in the limbic system. The only brain regions that exhibited neuronal damage in all rats with SRS were the hilus of the dentate gyrus and the mediodorsal thalamus, although treatment with dizocilpine reduced the severity of damage in the latter region. The data indicate that NMDA receptor blockade immediately after a prolonged S.E. is an effective means to reduce the damage produced by a sustained S.E. in several brain regions, including the hippocampus, but show that this partial neuroprotection of the limbic system does not prevent the development of epilepsy.

Section snippets

Animals

Adult female Wistar rats (Harlan-Winkelmann, Borchen, Germany; about 12 weeks old) were used. During the experiments the rats were kept under controlled environmental conditions (24–25 °C, 50–60% humidity, 12-h light/dark cycle, light on at 6 a.m.) with free access to standard laboratory chow (Altromin 1324 standard diet) and to tap water. Animal care and all experimental procedures were conducted in compliance with the German Animal Welfare Act and were approved by the local committee on

Kainate-induced S.E

For all experiments described in the following, rats developing a convulsive S.E. with continuous generalized seizure activity for 90 min were used. The S.E. was terminated after 90 min by i.p. injection of 4–6 mg/kg diazepam, which completely stopped clinical (clonic) seizure activity. In order to be sure that diazepam blocked both clinical seizures and persistent electrographic seizure discharges, in some rats continuous video and EEG recording was used to monitor the rats for up to 20 h

Discussion

The present experiments indicate that blockade of the NMDA receptor after a generalized S.E. of sufficient length to produce neuronal damage is an efficacious means to protect several brain regions from such damage. Whereas all rats developed massive neuronal damage in several brain regions after a kainate-induced S.E., administration of a single, low dose of dizocilpine immediately after the S.E. protected several rats almost completely against this damage. The only regions that were not

Acknowledgements

This work was supported by a grant from the German Bundesministerium für Bildung und Forschung (BMBF). We would like to thank U. Heinemann, S. L. Moshé, and R. Schwarcz for critical comments on the manuscript, and M. Weissing, B. Klein and C. Bartling for technical assistance.

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