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Salubrinal, ER stress inhibitor, attenuates kainic acid-induced hippocampal cell death

Journal of Neural Transmission volume 121, pages 1233–1243 (2014)Cite this article

Abstract

Kainic acid (KA)-induced neuronal death is closely linked to endoplasmic reticulum (ER) and mitochondrial dysfunction. Parkin is an ubiquitin E3 ligase that mediates the ubiquitination of the Bcl-2 family of proteins and its mutations are associated with neuronal apoptosis in neurodegenerative diseases. We investigated the effect of salubrinal, an ER stress inhibitor, on the regulation of ER stress and mitochondrial apoptosis induced by KA, in particular, by controlling parkin expression. We showed that salubrinal significantly reduced seizure activity and increased survival rates of mice with KA-induced seizures. We found that salubrinal protected neurons against apoptotic death by reducing expression of mitochondrial apoptotic factors and elF2α–ATF4–CHOP signaling proteins. Interestingly, we showed that salubrinal decreased the KA-induced parkin expression and inhibited parkin translocation to mitochondria, which suggests that parkin may regulate a cross-talk between ER and mitochondria. Collectively, inhibition of ER stress attenuates mitochondrial apoptotic and ER stress pathways and controls parkin-mediated neuronal death following KA-induced seizures.

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Acknowledgments

We would like to thank Lauren Shields at the Gladstone Institutes affiliated with the University of California, San Francisco (UCSF) for editing our manuscript. This research was supported by the Basic Science Research Program through the National Research Foundation (NRF) of Korea, funded by the Ministry of Science, ICT, and Future Planning (No. 2005-0049415).

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Affiliations

  1. Department of Neurosurgery, Haeundae Paik Hospital, College of Medicine, Inje University, Busan, Republic of Korea

    Jung Soo Kim

  2. Department of Anatomy and Neurobiology, Medical Research Center for Neural Dysfunction, Institute of Health Sciences, Gyeongsang National University School of Medicine, 15 Jinju-daero, 816 Beongil, Jinju, Gyeongnam, 660-751, Republic of Korea

    Rok Won Heo, Hwajin Kim, Chin-ok Yi, Hyun Joo Shin & Gu Seob Roh

  3. Department of Neurosurgery, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea

    Jong Woo Han

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  1. Jung Soo Kim
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  2. Rok Won Heo
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Correspondence to Gu Seob Roh.

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J. S. Kim and R. W. Heo contributed equally to this study.

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Kim, J.S., Heo, R.W., Kim, H. et al. Salubrinal, ER stress inhibitor, attenuates kainic acid-induced hippocampal cell death. J Neural Transm 121, 1233–1243 (2014). https://doi.org/10.1007/s00702-014-1208-0

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  • DOI: https://doi.org/10.1007/s00702-014-1208-0

Keywords

  • Salubrinal
  • ER stress
  • Mitochondrial apoptosis
  • Parkin
  • Seizures