Abstracts

RATIONALE: Clinically, the ketogenic diet (KD) has been felt to be more efficacious at younger ages, presumably because of the enhanced ability of the immature brain to extract and utilize ketone bodies. We previously reported that the KD decreased pentylenetetrazol (PTZ)-induced seizure severity in immature rats (3 weeks postnatal). In the present study, older rats were used to investigate age-dependent effects of the KD on ketosis and PTZ-induced seizure severity.
METHODS: A KD ([fat]:[protein + carbohydrate] ratio of 4.3:1) was administered to male Sprague-Dawley rats for 3 weeks, while control animals were fed a standard rodent chow. Dietary treatment was initiated at either postnatal 9 or 12 weeks. Seizures were chemically induced by intraperitoneal injection of PTZ (60 mg/kg) and blood beta-hydroxybutyrate (BHB) levels were assayed on treatment day 21. Seizure severity was evaluated by using a scoring system of seizure behaviors: 0, no seizure; 0.5, abnormal behavior; 1, myoclonic jerk; 2, myoclonic jerk with jumping; 3, forelimb clonus with preserving righting reflex; 4, generalized clonic seizure with brief loss of righting reflex; 5, generalized tonic clonic seizure; 6, expire. A greater seizure score represents a more severe seizure.
RESULTS: In 9 weeks old rats, the mean ([plusminus] SEM) seizure behavior scores were 3.5 [plusminus] 1.2 [n=19] and 4.4 [plusminus] 0.9 [n=17] for the KD-treated and control groups, respectively (p[lt]0.05), whereas in 12 weeks old animals, no significant differences in seizure behavior scores between the two groups (3.9 [plusminus] 0.3 [n=17] vs. 4.1 [plusminus] 0.3 [n=16], respectively). Blood BHB levels in the KD-treated group were significantly higher than those of the control group in 9 (1.21 [plusminus] 0.14 [n=19] vs. 0.14 [plusminus] 0.12 [n=17] mM, respectively; p[lt]0.001) and 12 (0.64 [plusminus] 0.08 [n=17] vs. 0.18 [plusminus] 0.02 [n=16] mM, respectively; p[lt]0.001) weeks old animals.
CONCLUSIONS: The KD was previously reported to decrease PTZ-induced seizure severity in 3 weeks old rats. In this study, the KD decreases PTZ-induced seizure severity in 9 weeks old rats, but is ineffective in 12 weeks old rats. Furthermore, the levels of the KD-induced ketosis were prominently lower in 12 than in 9 weeks old animals. These results parallel clinical experience, where the beneficial effects of the KD are felt to be age-dependent.
Support: This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea. (HMP-99-N-02-0003)