Caloric Restriction Inhibits Seizure Susceptibility in Epileptic EL Mice by Reducing Blood Glucose

Abstract

Summary:Purpose: Caloric restriction (CR) involves underfeeding and has long been recognized as a dietary therapy that improves health and increases longevity. In contrast to severe fasting or starvation, CR reduces total food intake without causing nutritional deficiencies. Although fasting has been recognized as an effective antiseizure therapy since the time of the ancient Greeks, the mechanism by which fasting inhibits seizures remains obscure. The influence of CR on seizure susceptibility was investigated at both juvenile (30 days) and adult (70 days) ages in the EL mouse, a genetic model of multifactorial idiopathic epilepsy.Methods: The juvenile EL mice were separated into two groups and fed standard lab chow either ad libitum (control, n ‫ס‬ 18) or with a 15% CR diet (treated, n ‫ס‬ 17). The adult EL mice were separated into three groups; control (n ‫ס‬ 15), 15% CR (n ‫ס‬ 6), and 30% CR (n ‫ס‬ 3). Body weights, seizure susceptibility, and the levels of blood glucose and ketones (␤-hydroxybutyrate) were measured over a 10-week treatment period. Simple linear regression and multiple logistic regression were used to analyze the relations among seizures, glucose, and ketones.Results: CR delayed the onset and reduced the incidence of seizures at both juvenile and adult ages and was devoid of adverse side effects. Furthermore, mild CR (15%) had a greater antiepileptogenic effect than the well-established high-fat ketogenic diet in the juvenile mice. The CR-induced changes in blood glucose levels were predictive of both blood ketone levels and seizure susceptibility.Conclusions: We propose that CR may reduce seizure susceptibility in EL mice by reducing brain glycolytic energy. Our preclinical findings suggest that CR may be an effective antiseizure dietary therapy for human seizure disorders.

Dietary restriction reduces angiogenesis and growth in an orthotopic mouse brain tumour model

“…It is documented that human and experimental gliomas are dependent on glycolysis for energy (Mies et al, 1990;Ikezaki et al, 1992;Oudard et al, 1997), and that DR-induced caloric restriction reduces glycolytic energy and down-regulates glycolytic gene expression (Lee et al, 2000;Cao et al, 2001;Greene et al, 2001). Additionally, the DR-induced down regulation of glycolysis should also reduce the level of pyruvic acid, a glycolytic end product with angiogenic activity .…”

“…Glucose is used exclusively for adult brain energy metabolism under normal physiological conditions, but the brain will metabolise ketone bodies for energy when blood glucose levels decrease as during fasting or DR (Clarke and Sokoloff, 1999;Greene et al, 2001). Since ketone bodies are metabolised directly to acetyl-CoA in the mitochondria, they bypass cytoplasmic glycolysis and provide energy directly through the Krebs cycle (Nehlig and Pereira de Vasconcelos, 1993;Clarke and Sokoloff, 1999).…”

“…Since ketone bodies are metabolised directly to acetyl-CoA in the mitochondria, they bypass cytoplasmic glycolysis and provide energy directly through the Krebs cycle (Nehlig and Pereira de Vasconcelos, 1993;Clarke and Sokoloff, 1999). We recently showed that DR produces ketosis in epileptic mice and that the degree of ketosis is inversely proportional to blood glucose levels (Greene et al, 2001). Further studies will be needed to determine if reduced glycolytic energy and elevated ketosis underlie the antiangiogenic and growth inhibitory effects of DR.…”

“…Moreover, the reliance of brain tumours on glycolysis for energy should make them especially vulnerable to DR, as DR shifts energy metabolism from glucose to ketone utilisation (Oudard et al, 1997;Greene et al, 2001). With the exception of an anecdotal report on the potential efficacy of a ketogenic diet toward paediatric astrocytoma (Nebeling et al, 1995), no studies have been performed to our knowledge on the effects of DR as a therapeutic intervention for brain tumours.…”

Neuroprotective and disease-modifying effects of the ketogenic 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). (Although the ketogenic diet is designed to provide calories adequate for growth, patients and animals may eat less because the diet may be unpalatable to some.…”