Abstract:
: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 mitochondrial 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, mitochondrial oxidative stress were significantly altered in I/R mice compared to sham. We also observed alteration in mitochondrial transition pore, ATP production and O2 consumption in the ischemic brain as compared to sham. Further, elevated matrix metalloproteinases-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 hyper-methylation 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.
journal_name
Neurochem Intjournal_title
Neurochemistry internationalauthors
Mondal NK,Behera J,Kelly KE,George AK,Tyagi PK,Tyagi Ndoi
10.1016/j.neuint.2018.11.015subject
Has Abstractpub_date
2019-01-01 00:00:00pages
120-138eissn
0197-0186issn
1872-9754pii
S0197-0186(18)30376-0journal_volume
122pub_type
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