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Published on: April 6, 2014
PKM2 Nuclear Translocation Promotes Glial Cell Activation and Aggravates the Brain Injury of Intracerebral Hemorrhage
Xiao-Yi Xiong1,2,3, Yan-Jing Liang1, Xin-Xiao Zhang1
1Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine; 611137 Chengdu, Sichuan, China.
Background:
The purpose of this study was to investigate the potential involvement of pyruvate kinase M2 (PKM2), an enzyme acting as a rate-limiting enzyme in the final phase of glycolysis, in the regulation of glial activation and brain damage of intracerebral hemorrhage (ICH).
Methods:
Western blotting and immunofluorescence were performed to investigate PKM2 expression, terminal deoxynucleotidyl transferase deoxyurinary triphosphate (dUTP) nick end labeling staining, hematoxylin and eosin staining, and behavioral tests were employed to evaluate the brain damage of ICH mice, and RNA-seq and bioinformatic analyses were performed to detect gene expression changes in ICH mice treated with TEPP-46.
Results:
Increased PKM2 levels in perihematomal brain tissue were found starting from 3 days following ICH and peaked at 5 and 7 days post ICH. The increased expression of PKM2 was mainly co-localized with glial fibrillary acidic protein (GFAP)+ astrocytes and ionized calcium binding adaptor molecule-1 (IBA-1)+ microglia. Furthermore, we observed a notable increase in the nuclear translocation of PKM2 in glial cells following ICH. TEPP-46 treatment significantly reduced PKM2 nuclear translocation, and effectively attenuated glial activation and brain injury, and improved functional recovery of mice with ICH. RNA-seq data indicated that 91.1% (205/225) of differentially expressed genes (DEGs) were down-regulated in the TEPP-46 treated groups compared with the vehicle-treated groups in ICH brains. Furthermore, bioinformatic analyses revealed that these down-regulated DEGs were involved in a variety of biological processes, including autophagy and metabolic processes. In addition, the majority of these downregulated DEGs had a primary high expression in neurons, with subsequent expression seen in endothelial cells, microglia, and astrocytes.
Conclusions:
These results indicate that increased PKM2 nuclear translocation promotes the activation of glial cells after ICH, hence aggravating ICH-induced brain damage, and aggravates the brain injury induced by ICH. This highlights a potential therapeutic target for inhibiting glial activation to attenuate brain injury after ICH.
Insights
Pyruvate kinase M2 (PKM2) nuclear translocation promotes glial activation and brain damage after intracerebral hemorrhage (ICH). Inhibiting PKM2 may offer a therapeutic strategy for reducing ICH-induced injury.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Intracerebral hemorrhage (ICH) leads to brain damage.
- Glial activation plays a role in ICH-induced brain injury.
- Pyruvate kinase M2 (PKM2) is a key glycolytic enzyme.
Purpose of the Study:
- To investigate PKM2's role in glial activation and brain damage following ICH.
- To explore TEPP-46's effects on PKM2 and ICH outcomes.
Main Methods:
- Western blotting and immunofluorescence for PKM2 expression.
- Histological staining (TUNEL, H&E) and behavioral tests for brain damage assessment.
- RNA-sequencing and bioinformatic analysis to identify gene expression changes.
Main Results:
- PKM2 levels and nuclear translocation increased in glial cells post-ICH.
- TEPP-46 treatment reduced PKM2 nuclear translocation, glial activation, and brain injury, improving functional recovery.
- RNA-seq revealed TEPP-46 down-regulated genes involved in autophagy and metabolism, primarily in neurons and glial cells.
Conclusions:
- Increased PKM2 nuclear translocation exacerbates ICH-induced brain damage by promoting glial activation.
- Inhibiting PKM2 nuclear translocation presents a potential therapeutic target for mitigating brain injury after ICH.
