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Long-term expression of metabolism-associated genes in the rat hippocampus following recurrent neonatal seizures and its regulation by melatonin

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Despite the effective use of antiepileptic drugs (AEDs) for epilepsy, therapeutic failure occurs in 30% of patients. Novel approaches are targeting the inhibition of epileptogenesis. Nacetyl5methoxytryptamine (melatonin) is an indoleamine produced mainly by the pineal gland, and has been observed to exhibit antiepileptic and neuroprotective effects in experimental and clinical investigations. In the present study, the underlying protective mechanism of melatonin on neonatal seizureinduced longterm excitotoxicity was examined in the hippocampus of rats, predominantly on the metabolismassociated genes. Sprague Dawley rats (6dayold; P6) were randomly divided into four groups, the control (Cont), melatonintreated control (Mel), recurrent neonatal seizure (RS) and treatment with melatonin and RS combined (Mel+RS). At P35, mossy fiber sprouting and changes in gene expression in hippocampus were assessed using Timm staining, reverse transcriptionquantitative polymerase chain reaction and use of the 2ΔCT methods, respectively. The aberrant mossy fiber sprouting in the supra granular region of the dentate gyrus and CA3 subfield of the hippocampus was suppressed by pretreatment with melatonin. In addition, among the nineteen genes identified, four energy metabolismassociated genes (Kcnj11, leptin receptor, dopamine receptor D2 and melanocortin 4 receptor), four lipid metabolismassociated genes (apolipoprotein AI, opioid receptor κ 1, pyruvate dehydrogenase kinase, isozyme 4 and cytochrome P450, family 46, subfamily a, polypeptide 1) and zinc transporter 1 (ZnT1), sphingomyelinase (nSMase) and CathepsinE, were markedly downregulated by melatonin treatment in the Mel group or in the developmental seizure RS and Mel+RS groups, compared with that in the Cont group. Furthermore, the melatoninpretreated seizure rats (Mel+RS) exhibited a significantly upregulated expression of calcium/calmodulindependent protein kinase II α (CaMKIIα), acetylCoenzyme A acetyltransferase 1 (ACAT1), ZnT1, metallothionein 1 (MT1), nSMase and CathepsinE, compared with the RS rats. Thus, the present study investigated changes in the expression of metabolic genes in the hippocampus following pretreatment with melatonin. Fluorthylinduced decreases in the expression levels of ACAT1/nSMase/CathepsinE, ZnT1/MT1 and CaMKIIα in the hippocampus, and the reversal by melatonin may be associated with a decrease in neonatal seizureinduced aberrant mossy fiber sprouting, which requires further investigation.
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Document Type: Research Article

Affiliations: 1: Neurology Laboratory, Institute of Pediatrics, Children's Hospital of Soochow University, Suzhou, Jiangsu 215003, P.R. China 2: Department of Neurology, Key Laboratory of Cerebral Microcirculation, University of Shandong, Affiliated Hospital of Taishan Medical College, Taian, Shandong 271000, P.R. China

Publication date: August 1, 2015

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  • Molecular Medicine Reports is a monthly, peer-reviewed journal available in print and online, that includes studies devoted to molecular medicine, underscoring aspects including pharmacology, pathology, genetics, neurosciences, infectious diseases, molecular cardiology and molecular surgery. In vitro and in vivo studies of experimental model systems pertaining to the mechanisms of a variety of diseases offer researchers the necessary tools and knowledge with which to aid the diagnosis and treatment of human diseases.
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