Elsevier

Neuroscience

Volume 99, Issue 3, 16 August 2000, Pages 469-481
Neuroscience

The lesional and epileptogenic consequences of lithium–pilocarpine-induced status epilepticus are affected by previous exposure to isolated seizures: effects of amygdala kindling and maximal electroshocks

https://doi.org/10.1016/S0306-4522(00)00209-8Get rights and content

Abstract

In temporal lobe epilepsy, the occurrence of seizures seems to correlate with the presence of lesions underlying the establishment of a hyperexcitable circuit. However, in the lithium–pilocarpine model of epilepsy, neuronal damage occurs both in the structures belonging to the circuit of initiation and maintenance of the seizures (forebrain limbic system) as in the propagation areas (cortex and thalamus) and in the circuit of remote control of seizures (substantia nigra pars reticulata). To determine whether or not we could protect the brain from lesions and epileptogenesis induced by status epilepticus and identify cerebral structures involved in the genesis of epilepsy, we studied the effects of the chronic exposure to non-deleterious seizures, either focalized with secondary generalization (amygdala kindling, kindled-pilocarpine rats), or primary generalized (ear-clip electroshocks, electroshock-pilocarpine rats) on neuronal damage and epileptogenesis induced by lithium–pilocarpine status epilepticus. These animals were compared to rats subjected to status epilepticus but not pretreated with seizures (sham-kindled-pilocarpine or sham-electroshock-pilocarpine rats). Compared to sham-pilocarpine rats, neuronal damage was prevented in the limbic system of the kindled-pilocarpine rats, except in the hilus of the dentate gyrus and the entorhinal cortex, while it was enhanced in rats pretreated with electroshocks, mainly in the entorhinal and perirhinal cortices. Most sham-kindled- and sham-electroshock-pilocarpine rats (92–100%) developed recurrent seizures after a silent period of 40–54 days. Likewise, all kindled-pilocarpine rats developed spontaneous seizures after the same latency as their sham controls, while only two of 10 electroshock-pilocarpine rats became epileptic after a delay of 106–151 days.

The present data show that the apparent antiepileptic properties of electroshocks correlate with extensive damage in midbrain cortical regions, which may prevent the propagation of seizures from the hippocampus and inhibit their motor expression. Conversely, the extensive neuroprotection of the limbic system but not the hilus and entorhinal cortex provided by amygdala kindling does not prevent epileptogenesis. Thus, the hilus, the entorhinal and/or perirhinal cortex may be key structure(s) for the establishment of epilepsy.

Section snippets

Animals

Male Wistar rats weighing 225–250 g, provided by Janvier Breeding Center (Le Genest-St-Isle, France), were housed under controlled standard conditions (light–dark cycle, lights on 7.00 a.m. to 7.00 p.m.), with food and water available ad libitum. All animal experimentation was performed in accordance with the rules of the European Committee Council Direction of 24 November 1986 (86/69/EEC) and the French Department of Agriculture (License No. 00733). For electrode implantation, all rats were

Rats subjected only to lithium–pilocarpine status epilepticus

In the sham-pilocarpine rats of both groups, the EEG and behavioral events leading to SE were similar to those described previously after the injection of a high dose of pilocarpine or lithium and pilocarpine.19., 23., 94.

Rats subjected to kindling and lithium–pilocarpine status epilepticus

The first electrographic spikes occurred after a mean duration of 27 min in both the sham-K-pilocarpine and the K-pilocarpine groups (Table 1). Rats developed stage 5 seizures at 7.8–7.9 min after the occurrence of the first electrographic seizures in both groups. All 18

Discussion

The exposure to amygdala kindling or repeated ECSs have different consequences on lesions and epilepsy induced by lithium–pilocarpine. Amygdala kindling decreases the sensitivity of rats to the convulsant, triggers large neuroprotective effects, mainly in the piriform and entorhinal cortices and in the hippocampus, but does not prevent epileptogenesis. Conversely, ECSs delay the onset of seizures, trigger more extended damage in the entorhinal and perirhinal cortices, and delay or prevent SRSs.

Conclusion

The present data show that repeated ECSs do not protect neurons from damage induced by lithium–pilocarpine SE, but prevent or delay the occurrence of SRSs. This apparent antiepileptic effect of ECS may relate to the extensive damage recorded in the entorhinal and perirhinal cortices that may inhibit the expression of motor seizures by preventing their propagation from the hippocampus. Conversely, amygdala kindling that triggers extensive neuroprotection in the limbic system but not the hilus

Acknowledgements

This work was supported by a grant from INSERM U398, and by a joint grant from the French League against Epilepsy and Cassenne-Marion Laboratories attributed to Véronique André.

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