The Ketogenic Diet Inhibits Epileptogenesis in EL Mice: A Genetic Model for Idiopathic Epilepsy

Abstract

Summary: Purpose: The ketogenic diet (KD) is a high-fat, low-carbohydratc and -protein diet that has been used to treat refractory seizures in children for more than 75 years. However, little is known about how the KD inhibits seizures or its el'fects on epilcptogcnesis. Several animal models of epilepsy have responded favorably to KD treatment, but the KD has not been studied in animals with a genetic predisposition to seizures. Here we studied the antiepileptogenic effect of the KD in EL mice, an animal model for human idiopathic epilepsy.M&ods: Young male EL mice (postnatal day 30) were randomly separated into two groups fed ad libitum with either the KD (treated, n = 21) or Agway chow (control, n = 19). The mice werc wcighcd and tested for seizures once per week for a total of 10 weeks. The effects of the KD on plasma levels of ketone bodies and glucose were analyzed at several time points throughout the study. Associative learning was compared between treated and control animals using a water maze.Results: KD treatment delayed seizure onset in young male EL mice by 1 month; however, seizure protection was transient, inasmuch as the treated and control mice experienced a similar number and intensity of seizures after 6 wccks on the diet. Plasma glucose levels and associativc learning were similar in the treated and control groups, but the plasma P-hydroxybutyrate levels were significantly highcr in mice on the KD. The level of ketosis, however, was not predictive of seizure protection in EL mice.Conclusion: The KD delayed seizure onset in EL mice, suggesting a transient protection against epileptogcnesis. The KD did not influence plasma glucose levels or learning. Therefore, the EL mousc may serve as a good model to study the antiepileptogenic mechanisms of the KD.

Role of glucose and ketone bodies in the metabolic control of experimental brain cancer

“…Although the ketone levels in the KD-UR and KD-R groups were not significantly different, the ketone levels in both these groups were significantly greater than that in the SD-UR. These findings are consistent with previous studies in mice that b-OHB levels are increased under caloric restriction or the KD (Todorova et al, 2000;Greene et al, 2001). …”

“…Plasma glucose levels, however, were similar in both UR-fed mouse groups. These findings are consistent with previous studies in mice that the KD, fed ad libitum, does not significantly alter plasma glucose levels (Todorova et al, 2000). In contrast to glucose levels, b-OHB levels were two-fold greater in the SD-R mice than in the SD-UR mice (Table 1).…”

“…The ketogenic diet (KD) is a high-fat, low-protein, low-carbohydrate diet that has been used for decades to treat patients with refractory epilepsies (Freeman et al, 2000;Todorova et al, 2000;Greene et al, 2003). It was not clear, however, whether KD controlled paediatric astrocytoma through effects on plasma glucose or ketone bodies since the diet was administered under restricted conditions where blood glucose levels were also reduced .…”

Neuroprotective and disease-modifying effects of the ketogenic diet

“…In addition, animals fed the diet have reduced hippocampal excitability and decreased supragranular mossy fiber sprouting in comparison with rats fed a normal diet. Further evidence supporting the antiepileptogenic activity of the ketogenic diet is the demonstration that the development of spontaneous seizures in inbred EL/Suz mice, a genetic model of idiopathic epilepsy, is retarded by the diet (Todorova et al, 2000). In other studies, caloric restriction, which often occurs with the ketogenic diet, has also been demonstrated to have antiepileptogenic effects in EL/Suz mice (Greene et al, 2001;Mantis et al, 2004).…”

The Cross-Talk Between Mitochondria and the Nucleus in the Response to Oxidative Stress Associated with Mitochondrial Dysfunction in Mitochondrial Encephalomyopathies

“…These observations suggest that creatine treatment has the potential neuroprotective effect for patients with epilepsy, although it remains to be proven by clinical trials. Additionally, diet modification by caloric restriction or ketogenic diet has been used to inhibit seizure susceptibility in epileptic EL mice through a reduction of glucose metabolism (Todorova et al, 2000). Accumulating evidence support that chronic use of ketogenic diet can alter mitochondrial function, which includes promotion of mitochondrial biogenesis, decrease of ROS production and induction of GSH biosynthesis that ultimately lead to cellular adaption and restoration of mitochondrial redox state (Jrrett et al, 2008).…”