title: Neurobehavioral Deficits in a Rat Model of Recurrent Neonatal Seizures Are Prevented by a Ketogenic Diet and Correlate with Hippocampal Zinc/Lipid Transporter Signals.
abstract: The ketogenic diet (KD) has been shown to be effective as an antiepileptic therapy in adults, but it has not been extensively tested for its efficacy in neonatal seizure-induced brain damage. We have previously shown altered expression of zinc/lipid metabolism-related genes in hippocampus following penicillin-induced developmental model of epilepsy. In this study, we further investigated the effect of KD on the neurobehavioral and cognitive deficits, as well as if KD has any influence in the activity of zinc/lipid transporters such as zinc transporter 3 (ZnT-3), MT-3, ApoE, ApoJ (clusterin), and ACAT-1 activities in neonatal rats submitted to flurothyl-induced recurrent seizures. Postnatal day 9 (P9), 48 Sprague-Dawley rats were randomly assigned to two groups: flurothyl-induced recurrent seizure group (EXP) and control group (CONT). On P28, they were further randomly divided into the seizure group without ketogenic diet (EXP1), seizure plus ketogenic diet (EXP2), the control group without ketogenic diet (CONT1), and the control plus ketogenic diet (CONT2). Neurological behavioral parameters of brain damage (plane righting reflex, cliff avoidance reflex, and open field test) were observed from P35 to P49. Morris water maze test was performed during P51-P57. Then hippocampal mossy fiber sprouting and the protein levels of ZnT3, MT3, ApoE, CLU, and ACAT-1 were detected by Timm staining and Western blot analysis, respectively. Flurothyl-induced neurobehavioral toxicology and aberrant mossy fiber sprouting were blocked by KD. In parallel with these behavioral changes, rats treated with KD (EXP2) showed a significant down-regulated expression of ZnT-3, MT-3, ApoE, clusterin, and ACAT-1 in hippocampus when compared with the non-KD-treated EXP1 group. Our findings provide support for zinc/lipid transporter signals being potential targets for the treatment of neonatal seizure-induced brain damage by KD.
authors.affiliation: Neurology Laboratory, Children's Hospital of Soochow University, No.303, Jingde Road, Suzhou, 215003, People's Republic of China.
authors.forename: Tian
authors.initials: T
authors.lastname: Tian
authors.forename: Hong
authors.initials: H
authors.lastname: Ni
authors.forename: Bao-liang
authors.initials: BL
authors.lastname: Sun
mesh_terms: D000328:Adult; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002352:Carrier Proteins / Q000378:metabolism*; D055423:Diet, Ketogenic; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000178:diet therapy / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D015032:Zinc / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D015032:Zinc