Abstract
The ketogenic diet (KD) demonstrates antiepileptogenic and neuroprotective efficacy, but the precise mechanisms are unclear. Here we explored the mechanism through systematic proteomics analysis of the lithium chloride-pilocarpine rat model. Sprague-Dawley rats (postnatal day 21, P21) were randomly divided into control (Ctr), seizure (SE), and KD treatment after seizure (SE + KD) groups. Tandem mass tag (TMT) labeling and liquid chromatography-tandem mass spectroscopy (LC-MS/MS) were utilized to assess changes in protein abundance in the hippocampus. A total of 5,564 proteins were identified, of which 110 showed a significant change in abundance between the SE and Ctr groups (18 upregulated and 92 downregulated), 278 between SE + KD and SE groups (218 upregulated and 60 downregulated), and 180 between Ctr and SE + KD groups (121 upregulated and 59 downregulated) (all p < 0.05). Seventy-nine proteins showing a significant change in abundance between SE and Ctr groups were reciprocally regulated in the SD + KD group compared to the SE group (i.e., the seizure-induced change was reversed by KD). Of these, five (dystrobrevin, centromere protein V, oxysterol-binding protein, tetraspanin-2, and progesterone receptor membrane component 2) were verified by parallel reaction monitoring. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that proteins of the synaptic vesicle cycle pathway were enriched both among proteins differing in abundance between SE and Ctr groups as well as between SE + KD and SE groups. This comprehensive proteomics analyze of KD-treated epilepsy by quantitative proteomics revealed novel molecular mechanisms of KD antiepileptogenic efficacy and potential treatment targets.
Highlights
Epilepsy is a chronic disease characterized clinically by recurrent and unpredictable seizures (Fisher et al, 2005) due to uncontrolled neuronal hyperactivity
79 proteins met this condition (Supplementary Table S2), of which 72 were downregulated in the SE group compared to the Ctr group but upregulated in the SE + ketogenic diet (KD) group compared to the SE group
The other seven proteins showing reciprocal regulation were upregulated in the SE group compared to the Ctr group but downregulated in the SE + KD group compared to the SE group
Summary
Epilepsy is a chronic disease characterized clinically by recurrent and unpredictable seizures (Fisher et al, 2005) due to uncontrolled neuronal hyperactivity. The KD was found to influence mood Most of these studies reported positive effects (Halyburton et al, 2007; McClernon et al, 2007; Dm et al, 2016), some reported no effects or even negative effects on mood (Lambrechts et al, 2013; Iacovides et al, 2019). These inconsistences may be related to the type of disease before KD treatment, the number of subjects, and the duration of KD compliance, necessitating larger-scale, multiple-center studies to assess the influence of the KD on mood in specific diseases. A better understanding of the therapeutic mechanisms may improve clinical application and reveal new targets for clinical anti-epileptic treatment
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