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Long-Term Effects of Ketogenic Diet on Subsequent Seizure-Induced Brain Injury During Early Adulthood: Relationship of Seizure Thresholds to Zinc Transporter-Related Gene Expressions

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Abstract

The divalent cation zinc is associated with cortical plasticity. However, the mechanism of zinc in the pathophysiology of cortical injury-associated neurobehavioral damage following neonatal seizures is uncertain. We have previously shown upregulated expression of ZnT-3; MT-3 in hippocampus of neonatal rats submitted to flurothyl-induced recurrent seizures, which was restored by pretreatment with ketogenic diet (KD). In this study, utilizing a novel “twist” seizure model by coupling early-life flurothyl-induced seizures with later exposure to penicillin, we further investigated the long-term effects of KD on cortical expression of zinc homeostasis-related genes in a systemic scale. Ten Sprague-Dawley rats were assigned each averagely into the non-seizure plus normal diet (NS + ND), non-seizure plus KD (NS + KD), recurrent seizures plus normal diet (RS + ND) and recurrent seizures plus KD (RS + KD) group. Recurrent seizures were induced by volatile flurothyl during P9-P21. During P23-P53, rats in NS + KD and RS + KD groups were dieted with KD. Neurological behavioral parameters of brain damage (plane righting reflex, cliff avoidance reflex, and open field test) were observed at P43. At P63, we examined seizure threshold using penicillin, then the cerebral cortex were evaluated for real-time RT-PCR and western blot study. The RS + ND group showed worse performances in neurological reflex tests and reduced latencies to myoclonic seizures induced by penicillin compared with the control, which was concomitant with altered expressions of ZnT-7, MT-1, MT-2, and ZIP7. Specifically, there was long-term elevated expression of ZIP7 in RS + ND group compared with that in NS + ND that was restored by chronic ketogenic diet (KD) treatment in RS + KD group, which was quite in parallel with the above neurobehavioral changes. Taken together, these findings indicate that the long-term altered expression of the metal transporter ZIP7 in adult cerebral cortex might correlate with neurobehavioral damage and reduced seizure threshold following recurrent neonate seizures and further highlights ZIP7 as a candidate for therapeutic target of KD for the treatment of neonatal seizure-induced long-term brain damage.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (81271458, 81471337), Jiangsu Province’s Key Provincial Talents Program (RC2011113).

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Authors and Affiliations

  1. Neurology Laboratory, Institute of Pediatrics, Children’ Hospital of Soochow University, No.303, Jingde Road, 215003, Suzhou, People’s Republic of China

    Tian Tian, Li-Li Li, Shu-Qi Zhang & Hong Ni

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  1. Tian Tian
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  2. Li-Li Li
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  4. Hong Ni
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Correspondence to Hong Ni.

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All experiments procedures were in agreement with the principles approved by the National Institutes of Health Guide for the Humane Treatment of Laboratory animals.

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Tian, T., Li, LL., Zhang, SQ. et al. Long-Term Effects of Ketogenic Diet on Subsequent Seizure-Induced Brain Injury During Early Adulthood: Relationship of Seizure Thresholds to Zinc Transporter-Related Gene Expressions. Biol Trace Elem Res 174, 369–376 (2016). https://doi.org/10.1007/s12011-016-0730-3

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  • DOI: https://doi.org/10.1007/s12011-016-0730-3

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