Gadd45b Acts as Neuroprotective Effector in Global Ischemia-Induced Neuronal Death
- Author:
Chang Hoon CHO
1
;
Hyae Ran BYUN
;
Teresa JOVER-MENGUAL
;
Fabrizio PONTARELLI
;
Christopher DEJESUS
;
Ah Rhang CHO
;
R Suzanne ZUKIN
;
Jee Yeon HWANG
Author Information
- Publication Type:Original Article
- From:International Neurourology Journal 2019;23(Suppl 1):S11-S21
- CountryRepublic of Korea
- Language:English
-
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 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.
