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HDAC inhibition prevents hypobaric hypoxia‐induced spatial memory impairment through PΙ3K/GSK3β/CREB pathway
Author(s) -
Kumar Rahul,
Jain Vishal,
Kushwah Neetu,
Dheer Aastha,
Mishra Kamla Prasad,
Prasad Dipti,
Singh Shashi Bala
Publication year - 2021
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.30337
Subject(s) - sodium butyrate , creb , hdac3 , histone deacetylase , hypoxia (environmental) , neurodegeneration , acetylation , histone , histone deacetylase 5 , biology , endocrinology , creb binding protein , neun , medicine , pharmacology , chemistry , biochemistry , transcription factor , organic chemistry , oxygen , gene , immunohistochemistry , disease
Hypobaric hypoxia at higher altitudes usually impairs cognitive function. Previous studies suggested that epigenetic modifications are the culprits for this condition. Here, we set out to determine how hypobaric hypoxia mediates epigenetic modifications and how this condition worsens neurodegeneration and memory loss in rats. In the current study, different duration of hypobaric hypoxia exposure showed a discrete pattern of histone acetyltransferases and histone deacetylases (HDACs) gene expression in the hippocampus when compared with control rat brains. The level of acetylation sites in histone H2A, H3 and H4 was significantly decreased under hypobaric hypoxia exposure compared to the control rat's hippocampus. Additionally, inhibiting the HDAC family with sodium butyrate administration (1.2 g/kg body weight) attenuated neurodegeneration and memory loss in hypobaric hypoxia‐exposed rats. Moreover, histone acetylation increased at the promoter regions of brain‐derived neurotrophic factor (BDNF); thereby its protein expression was enhanced significantly in hypobaric hypoxia exposed rats treated with HDAC inhibitor compared with hypoxic rats. Thus, BDNF expression upregulated cAMP‐response element binding protein (CREB) phosphorylation by stimulation of PI3K/GSK3β/CREB axis, which counteracts hypobaric hypoxia‐induced spatial memory impairment. In conclusion, these results suggested that sodium butyrate is a novel therapeutic agent for the treatment of spatial memory loss associated with hypobaric hypoxia, and also further studies are warranted to explore specific HDAC inhibitors in this condition.