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Vitamin C Neuroprotection Against Dose-Dependent Glutamate-Induced Neurodegeneration in the Postnatal Brain

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Abstract

Glutamate-induced excitotoxicity due to over-activation of glutamate receptors and associated energy depletion (phosphorylation and activation of AMPK) results in neuronal cell death in various neurological disorders. Restoration of energy balance during an excitotoxic insult is critical for neuronal survival. Ascorbic acid (vitamin C), an essential nutrient with well-known antioxidant potential, protects the brain from oxidative damage in various models of neurodegeneration. In this study, we reported the therapeutic efficacy of vitamin C in response to glutamate-induced excitation, resulting in energy depletion and apoptosis in the hippocampus of the developing rat brain. A single subcutaneous injection of glutamate at two different concentrations (5 and 10 mg/kg) in postnatal day 7 rat pups increased brain glutamate levels and increased the protein expression of neuronal apoptotic markers. Both doses of glutamate upregulated the ratio of pro-apoptotic Bax to anti-apoptotic Bcl-2, cytochrome-c release, caspase-3 activation and the expression of PARP-1. However, co-treatment of vitamin C (250 mg/kg) with glutamate decreased brain glutamate levels and reversed the changes induced by glutamate in the developing hippocampus. Interestingly, only a high dose of glutamate caused the phosphorylation and activation of AMPK and induced neuronal cell death, whereas a low dose of glutamate failed to mediate these effects. Vitamin C supplementation reduced the glutamate-induced phosphorylation of AMPK and attenuated neuronal cell death, as assessed morphologically by Fluoro Jade B in the hippocampal CA1 region of the developing brain. Taken together, our results indicated that glutamate in both concentrations is toxic to the immature rat brain, whereas vitamin C is pharmacologically effective against glutamate-induced neurodegeneration.

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Acknowledgments

This study was supported by the Pioneer Research Centre Program of the National Research Foundation of Korea, which is funded by the Ministry of Science, ICT & Future Planning (2012-0009521).

Conflict of interest

It is hereby declared that we have no conflicts of interest in this study.

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    Authors and Affiliations

    1. Department of Biology and Applied of Life Science (BK 21), College of Natural Sciences, Gyeongsang National University, Jinju, 660-701, Republic of Korea

      Shahid Ali Shah, Gwang Ho Yoon & Myeong Ok Kim

    2. School of Medicine, Gyeongsang National University, Jinju, 660-701, Republic of Korea

      Hyun-Ok Kim

    3. Department of Biology, Neuroscience Pioneer Research Center, College of Natural Sciences, Gyeongsang National University, Jinju, 660-701, Republic of Korea

      Myeong Ok Kim

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    1. Shahid Ali Shah
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    Correspondence to Myeong Ok Kim.

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    Shahid Ali Shah and Gwang Ho Yoon have contributed equally to this manuscript.

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    Shah, S.A., Yoon, G.H., Kim, HO. et al. Vitamin C Neuroprotection Against Dose-Dependent Glutamate-Induced Neurodegeneration in the Postnatal Brain. Neurochem Res 40, 875–884 (2015). https://doi.org/10.1007/s11064-015-1540-2

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