Abstract
While a ketogenic diet (KD) is a well-established therapy for medically intractable epilepsy, clinical evidence of relevant adverse events of a KD has also been reported. We asked whether this kind of diet would have deleterious effects on wild-type brain function by evaluating KD-induced biochemical changes in the hippocampus as well as neurobehavioral changes occurring in wild-type rats. Fifty-four Sprague-Dawley rats were randomly assigned to three groups on postnatal day 28 (P28): wild-type rats fed with a KD qd (daily for 4 weeks, KD) or qod (every other day for 4 weeks, KOD), and wild-type rats fed with standard normal laboratory diet (ND). Neurobehavioral changes were observed on P35, P42, and P49. The hippocampal mossy fiber sprouting, the expression levels of zinc transporters (ZnTs) and lipid metabolism related genes were detected by Timm staining, RT-qPCR and western blot analysis, respectively, on P58. The KD-treated KOD and KD groups showed a significant delay of negative geotaxis reflex on P35, but not on P42 or P49. In the open field test, daily KD treatment only led to a reduction in exploratory activity and increased grooming times but induced no significant changes in the scores of vertical activity or delay time. KD qod treated rats (KOD) displayed a slight delay in the place navigation test on P35 compared with the KD group. There were no significant differences in Timm staining among the three groups. In parallel with these changes, KD treatment (both KD and KOD) induced significantly downregulated mRNA levels of Apoa1, Pdk4, and upregulated expression of ApoE, ANXN7, and cPLA2 in the hippocampus when compared with the ND group (except in the case of ApoE in the KOD group). Notably, both the mRNA and protein levels of cPLA2 in the KOD rats were significantly downregulated compared with the KD group but still markedly higher than in the ND group. No significant difference was found in ZnTs among the three groups. Our data suggest that early-life KD can provoke minor neurobehavioral effects in particular a delay in negative geotaxis reflex and an increase in grooming activity. The hippocampal lipid metabolism signaling pathway, especially cPLA2, may be the target of the protective effect of KD on long-term brain injury after developmental seizures.
Highlights
Ketogenic diet (KD) is a valuable therapy for medically intractable epilepsy that has been applied for nearly 100 years
At weaning day P21, the animals were randomly divided into three groups (n = 18/group): wildtype rats fed with a ketogenic diet (KD) qd or qod, and wild-type rats fed with standard normal laboratory diet (ND)
Because one of our goals is to study the effect of KD on zinc transporter expressions in the wild-type hippocampus and the expression of zinc transporters involved in the pathogenesis of hippocampal mossy fiber sprouting, we examined the effect of KD on the mossy fiber sprouting of hippocampus in wildtype rats in this study
Summary
Ketogenic diet (KD) is a valuable therapy for medically intractable epilepsy that has been applied for nearly 100 years. It has been reported that a KD can result in a variety of complications, including protein-losing enteropathy, arterial stiffness, nephrolithiasis, cholelithiasis, declined linear growth status, trace mineral deficiencies, and an increased tendency for mood problems [4,5,6,7,8,9], which limits its usefulness. Shiohama et al reported that a ketogenic diet at 4 months of age induced white matter lesions during KD therapy [14]. The adverse effects of KD on the cognitive, behavioral, psychosocial regulation and quality of life of schoolage children and adolescents were investigated by Lambrechts et al The results showed an increase in emotional problems [9]
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