Journal
BRITISH JOURNAL OF NUTRITION
Volume 113, Issue 11, Pages 1667-1676Publisher
CAMBRIDGE UNIV PRESS
DOI: 10.1017/S0007114515000884
Keywords
Hydroxytyrosol; db/db Mice; Mitochondrial function; Oxidative stress; AMP-activated protein kinase pathway; Reactive oxygen species
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Funding
- National Basic Research Program [2015CB553602, 2014CB548200]
- Fundamental Research Funds for the Central Universities [08143008]
- National Natural Science Foundation of China [81201023, 31370844]
- National 'Twelfth Five-Year' Plan for Science & Technology Support [2012BAH30F03]
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Hydroxytyrosol (HT) is a major polyphenolic compound found in olive oil with reported anti-cancer and anti-inflammatory activities. However, the neuroprotective effect of HT on type 2 diabetes remains unknown. In the present study, db/db mice and SH-SY-5Y neuroblastoma cells were used to evaluate the neuroprotective effects of HT. After 8 weeks of HT administration at doses of 10 and 50mg/kg, expression levels of the mitochondrial respiratory chain complexes I/II/IV and the activity of complex I were significantly elevated in the brain of db/db mice. Likewise, targets of the antioxidative transcription factor nuclear factor erythroid 2 related factor 2 including p62 (sequestosome-1), haeme oxygenase 1 (HO-1), and superoxide dismutases 1 and 2 increased, and protein oxidation significantly decreased. HT treatment was also found to activate AMP-activated protein kinase (AMPK), sirtuin 1 and PPAR gamma coactivator-1 alpha, which constitute an energy-sensing protein network known to regulate mitochondrial function and oxidative stress responses. Meanwhile, neuronal survival indicated by neuron marker expression levels including activity-regulated cytoskeleton-associated protein, N-methyl-D-aspartate receptor and nerve growth factor was significantly improved by HT administration. Additionally, in a high glucose-induced neuronal cell damage model, HT effectively increased mitochondrial complex IV and HO-1 expression through activating AMPK pathway, followed by the prevention of high glucose-induced production of reactive oxygen species and declines of cell viability and V-O2 capacity. Our observations suggest that HT improves mitochondrial function and reduces oxidative stress potentially through activation of the AMPK pathway in the brain of db/db mice.
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