GADD45B acts as neuroprotective effector in global ischemia-induced neuronal death

Chang Hoon Cho, Hyae Ran Byun, Teresa Jover-Mengual, Fabrizio Pontarelli, Christopher Dejesus, Ah Rhang Cho, R. Suzanne Zukin, Jee Yeon Hwang

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Abstract

Purpose: Transient global ischemia arising in human due to cardiac arrest causes selective, delayed neuronal death in hippocampal CA1 and cognitive impairment. Growth arrest and DNA-damage-inducible protein 45 beta (Gadd45b) is a well-known molecule in both DNA damage-related pathogenesis and therapies. Emerging evidence suggests that Gadd45b is an anti-apoptotic factor in nonneuronal cells and is an intrinsic neuroprotective molecule in neurons. However, the mechanism of Gadd45b pathway is not fully examined in neurodegeneration associated with global ischemia. Methods: Rats were subjected to transient global ischemia by the 4-vessel occlusion or sham operation. The animals were sacrificed at 24 hours, 48 hours, and 7 days after ischemia. The hippocampal CA1 was microdissected and processed to examine mRNA and protein level. To assess neuronal death, tissue sections were cut and processed for Fluoro-Jade and Nissl staining. Results: Here we show that ischemic insults increase abundance of Gadd45b and brain-derived neurotrophic factor, a known target of Gadd45 mediated demethylation, in selectively-vulnerable hippocampal CA1 neurons. We further show that knockdown of Gadd45b increases abundance of a pro-apoptotic Bcl-2 family member Bax while decreasing the antiapoptotic protein Bcl-2, which together promote neuronal death. Conclusions: These findings document a protective role of Gadd45b against neuronal insults associated with global ischemia and identify Gadd45b as a potential therapeutic target for the amelioration of hippocampal neurodegeneration.

Original languageEnglish (US)
Pages (from-to)S11-S21
JournalInternational Neurourology Journal
Volume23
DOIs
Publication statusPublished - Jan 1 2019

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Keywords

  • Brain-derived neurotrophic factor
  • Gadd45b
  • Global ischemia
  • Mitochondrial dysfunction
  • Neuroprotection

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Urology

Cite this

Cho, C. H., Byun, H. R., Jover-Mengual, T., Pontarelli, F., Dejesus, C., Cho, A. R., ... Hwang, J. Y. (2019). GADD45B acts as neuroprotective effector in global ischemia-induced neuronal death. International Neurourology Journal, 23, S11-S21. https://doi.org/10.5213/inj.1938040.020