Neuronal Cell Death in a Rat Model for Mesial Temporal Lobe Epilepsy Is Induced by the Initial Status Epilepticus and Not by Later Repeated Spontaneous Seizures *† 1 Jan A. Gorter, * 1 Pedro M. Gonc ¸alves Pereira, *Erwin A. van Vliet, †‡Eleonora Aronica, *†Fernando H. Lopes da Silva, and *Paul J. Lucassen *Swammerdam Institute for Life Sciences, Section Neurobiology, University of Amsterdam, Amsterdam; †Stichting Epilepsie Instellingen Nederland, Heemstede; and ‡Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Summary: Purpose: To determine whether repeated seizures contribute to hippocampal sclerosis, we investigated whether cell loss in the (para) hippocampal region was related to the severity of chronic seizure activity in a rat model for temporal lobe epilepsy (TLE). Methods: Chronic epilepsy developed after status epilepticus (SE) that was electrically induced 3–5 months before. The pres- ence of neuronal damage was assessed by using Fluoro-Jade and dUTP nick end-labeling (TUNEL) of brain sections coun- terstained with Nissl. Results: We found a negative correlation between the num- bers of surviving hilar cells and the duration of the SE (r  –0.66; p < 0.01). In the chronic phase, we could discriminate between rats with occasional seizures (0.15 ± 0.05 seizures per day) without progression and rats with progressive seizure ac- tivity (8.9 ± 2.8 seizures/day). In both groups, the number of TUNEL-positive cells in parahippocampal regions was similar and higher than in controls. In the hippocampal formation, this was not significantly different from controls. Fluoro-Jade stain- ing showed essentially the same pattern at 1 week and no positive neurons in chronic epileptic rats. Conclusions: Cell death in this rat model is related to the initial SE rather than to the frequency of spontaneous seizures. These results emphasize that it is of crucial importance to stop the SE as soon as possible to prevent extended cell loss and further progression of the disease. They also suggest that neu- roprotectants can be useful during the first week after SE, but will not be very useful in the chronic epileptic phase. Key Words: Necrosis—Apoptosis—Parahippocampal region— TUNEL—Fluoro-Jade—Sclerosis—Epileptogenesis— Progression. Since the discovery that a specific neuropathologic syndrome of temporal lobe epilepsy (TLE) is associated with hippocampal mesial sclerosis, there has been a con- troversy whether the sclerosis is the cause or conse- quence of repeated complex partial seizures [reviewed in (1,2)]. Various reports on experimental TLE models, in particular the kindling model, suggest that repeated sei- zures cause progressive hippocampal damage (3,4). However, the kindling model is a model for repeated seizures in which seizures are triggered by electrical stimulation, whereas spontaneous seizures are rarely re- corded. Moreover, kindling-induced damage is relatively mild, and the claim of cell loss due to repeated seizures is not always confirmed when cell densities are taken into account (5,6). Previous research in animal models in which chronic seizures developed after a pharmacologi- cally or electrically induced status epilepticus (SE) have shown that extensive cell death occurs almost immedi- ately after the SE in various brain regions (7–9). How- ever, studies that investigated the effects of chronic seizures on cell death have relied mainly on morpho- logic/stereologic measurements (10,11), so that subtle seizure-induced cell loss might have remained undetec- ted. In this study we used the post-SE model in which an SE was induced by electrical stimulation of the angular bundle (12). By using continuous hippocampal EEG monitoring, we reported previously that the SE can pro- duce two types of epileptic evolutions in the rats: (a) epileptic rats that display an increasing number of sei- zures after a latent period, called “progressive post-SE rats” (p-SE); and (b) epileptic rats that display only oc- casional spontaneous seizures without an increase in sei- zure frequency for 5 months after the SE, called Accepted December 14, 2002. Address correspondence and reprint requests to Dr. J. A. Gorter at Kruislaan 320, 1098 SM, Amsterdam, The Netherlands. E-mail: gorter@science.uva.nl 1 Co-first authors for citation purposes. Epilepsia, 44(5):647–658, 2003 Blackwell Publishing, Inc. © 2003 International League Against Epilepsy 647