Abstracts

Glucose uptake into the brain is greater during epileptic seizures than during most other brain activities suggesting a key role for glucose in the initiation and spread of seizure activity. Under conditions of fasting or caloric restriction (CR), however, brain cells can also derive energy from ketone bodies (acetoacetate and beta-hydroxybutyrate, [beta]-OHB). The high fat, low carbohydrate ketogenic diet (KD) was developed as an alternative to fasting for seizure management. We previously showed that CR and a restricted lard-based KD inhibited seizure susceptibility in epileptic EL mice. The EL mouse is a model for age-dependent multifactorial idiopathic generalized epilepsy (IGE) and expresses complex partial seizures with secondary generalization. The efficacy of the KD in managing epileptic seizures is dependent on the restriction of caloric intake that lowers glucose thereby allowing the brain to metabolize ketones for energy. KetoCal[reg] (KC) is a commercially prepared soy-oil-based KD for children with a fat to protein carbohydrate ratio of 4:1 and is more palatable than lard-based or medium chain triglyceride (MCT) formulations. In this study we evaluated the antiepileptic and anticonvulsant efficacy of KC in young adult EL mice., EL mice (about 70 days of age) that experienced at least 2 complex generalized seizures were separated in three groups (n = 8 mice/group) and were fed either a standard high carbohydrate (chow) diet unrestricted (SD-UR), KC unrestricted (KC-UR), or KC restricted (KC-R) to reduce body weight by approximately 20%. Seizure susceptibility, body weights, and food intake were measured once/week over a nine-week treatment period. The handling-induced seizure test was used to evaluate seizure susceptibility in each mouse group. Plasma glucose and [beta]-OHB levels were measured once every three weeks, using enzymatic analyses., Body weights, plasma glucose levels, and seizure susceptibility were significantly lower in the KC-R group over the nine-week testing period than in the SD-UR and KC-UR groups. Plasma [beta]-OHB levels were significantly higher in the KC-R group (4mM) than in the SD-UR group (0.45mM) or the KC-UR group (1.1mM) after week three of the study. Seizure susceptibility was lower (P [lt] 0.05) in the KC-UR group than in the SD-UR group only at the last week of the dietary treatment despite similarities in body weight and glucose levels., KetoCal[reg] is as effective as the lard-based KD in managing IGE in EL mice. No adverse side effects were detected in EL mice receiving KetoCal[reg]. Anticonvulsant efficacy is best when KetoCal[reg] is administered in restricted amounts to lower blood glucose and to elevate blood ketone bodies. We predict that KetoCal[reg] will be effective in the clinic and can be used as a standard ketogenic diet therapy for both human and animal studies., (Supported by the Epilepsy Foundation, and NIH (HD39722), and the Boston College Research Expense Fund.)