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Decreased cysteine uptake by EAAC1 gene deletion exacerbates neuronal oxidative stress and neuronal death after traumatic brain injury

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Abstract

Excitatory amino acid carrier type 1 (EAAC1), a high-affinity glutamate transporter, can expend energy to move glutamate into neurons. However, under normal physiological conditions, EAAC1 does not have a great effect on glutamate clearance but rather participates in the neuronal uptake of cysteine. This process is critical to maintaining neuronal antioxidant function by providing cysteine for glutathione synthesis. Previous study showed that mice lacking EAAC1 show increased neuronal oxidative stress following transient cerebral ischemia. In the present study, we sought to characterize the role of EAAC1 in neuronal resistance after traumatic brain injury (TBI). Young adult C57BL/6 wild-type or EAAC1 −/− mice were subjected to a controlled cortical impact model for TBI. Neuronal death after TBI showed more than double the number of degenerating neurons in the hippocampus in EAAC1 −/− mice compared with wild-type mice. Superoxide production, zinc translocation and microglia activation similarly showed a marked increase in the EAAC1 −/− mice. Pretreatment with N-acetyl cysteine (NAC) reduced TBI-induced neuronal death, superoxide production and zinc translocation. These findings indicate that cysteine uptake by EAAC1 is important for neuronal antioxidant function and survival following TBI. This study also suggests that administration of NAC has therapeutic potential in preventing TBI-induced neuronal death.

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Acknowledgments

This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2012R1A2A2A01046132) and by Hallym University Specialization Fund (HRF-S-52).

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Authors and Affiliations

  1. Department of Physiology, Hallym University, College of Medicine, 1-Okcheon Dong, 39 Hallymdaehak-gil, Chuncheon, 200-702, Korea

    Bo Young Choi, In Yeol Kim, Jin Hee Kim, Bo Eun Lee, Song Hee Lee, A. Ra Kho, Hee Jae Jung & Sang Won Suh

  2. Department of Neurology, Hallym University, College of Medicine, Chuncheon, Korea

    Hong Ki Song

  3. Department of Nursing, Inha University, Incheon, Korea

    Min Sohn

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  1. Bo Young Choi
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  2. In Yeol Kim
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Correspondence to Sang Won Suh.

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Choi, B.Y., Kim, I.Y., Kim, J.H. et al. Decreased cysteine uptake by EAAC1 gene deletion exacerbates neuronal oxidative stress and neuronal death after traumatic brain injury. Amino Acids 48, 1619–1629 (2016). https://doi.org/10.1007/s00726-016-2221-4

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