期刊
NEUROCHEMISTRY INTERNATIONAL
卷 122, 期 -, 页码 120-138出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuint.2018.11.015
关键词
Hyperhomocysteinemia; Oxidative stress; Extracellular matrix remodeling; Tight junction protein; Blood brain barrier; Epigenetic DNA methylation
资金
- National Institutes of Health (NIH) [HL-107640, AR-067667]
The objectives of this study are to identify the mechanism of mitochondrial dysfunction during cerebral ischemic/reperfusion (I/R) injury and the therapeutic potential of tetrahydrocurcumin (THC) to mitigate mitochondria] dysfunction in experimental stroke model. In our study, 8-10 weeks old male C57BL/6 wild-type mice were subjected to middle cerebral artery occlusion (MCAO) for 40 min, followed by reperfusion for 72 h. THC (25mg/kg-BW/day) was injected intraperitoneally once daily for 3 days after 4 h of ischemia. The experimental groups were: (i) sham, (ii) I/R and (iii) I/R + THC. We noticed that THC treatment in ischemic mice significantly improved the functional capacity and motor co-ordination along with reduced neuroscore, infarct volume, brain edema and microvascular leakage in brain parenchyma. The study revealed that level of total homocysteine (tHcy), homocysteine metabolizing enzymes, mitochondria] oxidative stress were significantly altered in I/R mice compared to sham. We also observed alteration in mitochondria' transition pore, ATP production and O-2 consumption in the ischemic brain as compared to sham. Further, elevated matrix metallo-proteinases-9 (MMP-9) activity and reduced tight junction protein expressions intensified the brain vascular impairment in I/R mice compared to sham. Interestingly, we found that levels of mitophagy markers, fusion and fission proteins were significantly altered. However THC treatment in I/R mice almost normalized the above functional and molecular changes. Mechanistic study demonstrated that DNA Methyltransferase 1 (DNMT1) expression was higher and was associated with reduced mitochondrial tissue inhibitor of metalloproteinases 2 (TIMP-2) expression through hyper-methylation of CpG island of TIMP-2 promoter in I/R mice compared to sham. However, administration of epigenetic inhibitor, 5-Azacytidine (5-Aza) abrogated I/R induced hypermethylation of TIMP-2 promoter and maintaining the extracellular matrix (ECM) integrity. In conclusion, this study suggests that THC epigenetically ameliorates mitochondrial dysfunction in brain vasculature during Ischemic Stroke.
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