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Purpose: Although the number of antiepileptic drugs (AEDs) is increasing, none displays neuroprotective or antiepileptogenic properties that could prevent status epilepticus (SE)–induced drug-resistant epilepsy. Ketogenic diet (KD) and calorie restriction (CR) are proposed as alternative treatments in epilepsy. Our goal was to assess the neuroprotective or antiepileptogenic effect of these diets in a well-characterized model of mesial temporal lobe epilepsy following initial SE induced by lithium-pilocarpine in adult rats.
Methods: Seventy-five P50 male Wistar rats were fed a specific diet: normocalorie carbohydrate (NC), hypocalorie carbohydrate (HC), normocalorie ketogenic (NK), or hypocalorie ketogenic (HK). Rats were subjected to lithium-pilocarpine SE, except six NC to constitute a control group for histology (C). Four rats per group were implanted with epidural electrodes to record electroencephalography (EEG) during SE and the next six following days. From the seventh day, the animals were video-recorded 10 h daily to determine latency to epilepsy onset. Neuronal loss in hippocampus and parahippocampal cortices was analyzed 1 month after the first spontaneous seizure.
Results: After lithium-pilocarpine injection, neither KD nor CR modified SE features or latency to epilepsy. In hippocampal layers, KD or CR exhibited a neuroprotective potential without cooperative effect. Parahippocampal cortices were not protected by the diets.
Conclusion: The antiepileptic effect of KD and/or CR is overwhelmed by lithium-pilocarpine injection. The isolated protection of hippocampal layers induced by KD or CR or their association failed to modify the course of epileptogenesis.
More than 10 new antiepileptic drugs (AEDs) have been developed during the last two decades. They especially improved patients’ quality of life but failed to demonstrate a neuroprotective or antiepileptogenic effect. In the peculiar case of chronic drug-resistant epilepsy, a neuroprotective therapy design has to be acceptable for a long period with few adverse effects. The ketogenic diet (KD) could match these features. For almost a century, the KD has been a commonly used alternative therapy to manage drug-resistant epilepsies, especially in childhood (Swink et al., 1997; Vining et al., 1998; Hartman & Vining, 2007; Cross, 2009). The KD is a high-fat, low-protein plus low-carbohydrate diet with a usual ratio by weight of 4:1 fats to carbohydrates plus proteins. The antiepileptic effect of the KD increases for the first 2 weeks after its onset (Freeman et al., 2000). A moderate (5–10%) calorie restriction can be a part of the KD in clinical practice (Bough et al., 2000a,b).
Animal studies support the antiepileptic efficacy of the KD. In rodents, the KD increases epileptic seizure threshold significantly about 1–2 weeks after initiation (Appleton & DeVivo, 1974; Bough & Eagles, 1999; Rho et al., 1999; Bough et al., 2006). In addition, a potential neuroprotective effect of KD is suggested by its ability to reduce cellular loss and mossy fiber sprouting after status epilepticus (SE) (Muller-Schwarze et al., 1999; Su et al., 2000; Noh et al., 2003; Sullivan et al., 2004).
The aim of our study was to assess the antiepileptogenic efficacy of a calorie-restricted KD in the model of limbic epilepsy subsequent to lithium-pilocarpine–induced SE in rats. Because the antiepileptic potential of a calorie-restricted carbohydrate diet is also reported in animal models (Bough et al., 2003; Eagles et al., 2003; Raffo et al., 2008), our additional goal was to determine the respective impact of the KD and calorie restriction (CR) alone or combined.