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KMID : 1240020190230000011
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International Neurourology Journal
2019 Volume.23 No. 0 p.11 ~ p.21
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Gadd45b Acts as Neuroprotective Effector in Global Ischemia-Induced Neuronal Death
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Cho Chang-Hoon
Byun Hyae-Ran
Jover-Mengual Teresa
Pontarelli Fabrizio
Dejesus Christopher
Cho Ah-Rhang
Zukin R. Suzanne
Hwang Jee-Yeon
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Abstract
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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 wellknown 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.
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KEYWORD
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Global ischemia, Gadd45b, Mitochondrial dysfunction, Brain-derived neurotrophic factor, Neuroprotection
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