Ketogenic Diet in Epileptic Encephalopathies

Department of Pediatrics, Lady Hardinge Medical College and Associated Kalawati Saran Children's Hospital, New Delhi 110001, India.
Epilepsy research and treatment 07/2013; 2013:652052. DOI: 10.1155/2013/652052
Source: PubMed


The ketogenic diet is a medically supervised high-fat, low-carbohydrate diet that has been found useful in patients with refractory epilepsy. It has been shown to be effective in treating multiple seizure types and epilepsy syndromes. In this paper, we review the use of the ketogenic diet in epileptic encephalopathies such as Ohtahara syndrome, West syndrome, Dravet syndrome, epilepsy with myoclonic atonic seizures, and Lennox-Gastaut syndrome.

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Available from: Manjari Tripathi, Jan 26, 2014
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    ABSTRACT: Oxidative stress triggers the peroxidation of omega-6 polyunsaturated fatty acids (n-6 PUFAs) to reactive lipid fragments including 4-hydroxy-2(E)-nonenal (HNE). We previously reported two parallel catabolic pathways of HNE. In this study we report a novel metabolite that accumulates in rat liver perfused with HNE or 4-hydroxynonanoic acid (HNA), identified as 3-(5-oxotetrahydro-2-furanyl)propanoyl-CoA, OTHFPA-CoA. In experiments using a combination of isotopic analysis and metabolomics studies, three catabolic pathways of HNE were delineated following HNE conversion to HNA: (i) omega-hydroxylation to 4,9-dihydroxynonanoic acid (4,9-DHNA), which is subsequently oxidized to 4-hydroxynonanedioic acid. This is followed by the degradation of 4-hydroxynoanedioic acid via beta oxidation originating from C-9 of HNA breaking down to: 4-hydroxynonanedioyl-CoA, 4-hydroxyheptanedioyl-CoA or its lactone, 2-hydroxyglutaryl-CoA, and 2-ketoglutarate entering citric acid cycle; (ii) omega-1 hydroxylation of HNA led to 4,8-dihydroxynonanoic acid (4,8-DHNA), which is subsequently catabolized via two parallel pathways we previously reported. In catabolic pathway A, 4,8-DHNA is catabolized to 4-phospho-8-hydroxynonanoyl-CoA, 3,8-dihydroxynonanoyl-CoA, 6-hydroxyheptanoyl-CoA, 4-hydroxypentanoyl-CoA, propionyl-CoA and acetyl-CoA; (iii) the catabolic pathway B of 4,8-DHNA leads to 2,6-dihydroxyheptanoyl-CoA, 5-hydroxyhexanoyl-CoA, 3-hydroxybutyryl-CoA and acetyl-CoA. Both in vivo and in vitro experiments showed that HNE can be catabolically disposed via omega- and omega-1 oxidation in rat liver and kidney, with little activity in brain and heart. Dietary experiments showed that omega- and omega-1 hydroxylation of HNA in rat liver was dramatically up regulated by a ketogenic diet, which lowered HNE basal level. HET0016 inhibition and mRNA expression level suggested that the cytochrome P450 4A are main enzymes responsible for the NADPH-dependent omega- and omega-1 hydroxylation of HNA/HNE.