Int Neurourol J.
2019 Feb;23(Suppl 1):S11-S21. 10.5213/inj.1938040.020.
Gadd45b Acts as Neuroprotective Effector in Global Ischemia-Induced Neuronal Death
- Affiliations
-
- 1Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, NY, USA. jeeyeonhwang@creighton.edu suzanne.zukin@einstein.yu.edu
- 2Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe - Universidad de Valencia; Departamento de FisiologÃa, Universidad de Vale---ncia, Valencia, Spain.
- 3Department of Beauty-Art, Seo-Jeong University, Seoul, Korea.
- 4Department of Pharmacology, Creighton University School of Medicine, Omaha, NE, USA.
- KMID: 2448803
- DOI: http://doi.org/10.5213/inj.1938040.020
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.
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