Hydroxytyrosol improves mitochondrial function and reduces oxidative stress in the brain ofdb/dbmice: role of AMP-activated protein kinase activation

Abstract

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 50 mg/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 PPARg coactivator-1a, 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. The escalating epidemic of the metabolic syndromes, including obesity and diabetes, represents one of the most pressing and costly medical challenges in public health of the twentyfirst century. A recent study has reported that 336 million people had diabetes in 2011, and this number is expected to rise to 552 million by 2030(1) . Diabetes is recognised by hyperglycaemia and glucose intolerance due to insulin deficiency, impaired insulin sensitivity or both. Type 2 diabetes mellitus (T2DM) is predominant and accounts for 90 % of patients with diabetes (2) . It is well established that diabetes has been associated with slowly progressing brain damage that impaired cognitive function (3 -5) . Although there is some evidence for a relationship between T2DM and brain damage, the mechanisms driving it remain unknown. Clinical studies have indicated that cognitive dysfunction is correlated with brain atrophy in patients with diabetes (3,6,7) . Kumar et al.(8) reported smaller total brain grey matter volumes in patients with diabetes, and the decrease is more pronounced in the cortical grey matter of the temporal lobe (9) . Despite the limited knowledge on the underlying mechanisms for cognitive dysfunction during the progression of T2DM, mitochondrial dysfunction and oxida...

Hydroxytyrosol supplementation modulates the expression of miRNAs in rodents and in humans

“…Our transcriptomic analysis confirms previous results from our group [13] and those of other groups [23][24][25] pointing towards physiological effects of HT on oxidation-reduction processes. We now provide evidence that, in the small intestine, long-term HT supplementation also influences these pathways.…”

Hydroxytyrosol in the Prevention of the Metabolic Syndrome and Related Disorders

“…To counteract such effect and enhance oxidative metabolism, HT was supposed to be a good candidate. Although no clinical trial investigated the effect of HT supplementation, studies in obese- and diabetic-rendered rats and in doxorubicin-induced cardiotoxicity rats revealed that HT (0.5, 10 and 50 mg/kg/day) is able to increase mitochondrial function through an enhancement of mitochondrial complex subunit expression [65,105] and activity [105,106]. Enhanced mitochondrial activity was associated with an increase of uncoupling protein-2 protein expression (100 µM) [107].…”

Hydroxytyrosol and Cytoprotection: A Projection for Clinical Interventions

“…Accordingly, HT was shown to improve the mitochondrial electron transport chain in rats with cardiotoxicity induced by doxorubicin by increasing the levels of complex-II and complex-III that partially restore the respiratory chain activity [38]. This effect was also observed in diabetic mice after a 2-month treatment with HT at doses of 10 and 50 mg/kg, where the expression levels of complexes I, II, and IV and the activity of complex I were increased in the brain, improving mitochondrial function [15]. In agreement with these views, HT also stimulates mitochondrial biogenesis in ARPE-19 human retinal pigment epithelial cells subjected to OS, through enhancement in the expression of PGC1α that leads to an increased protein expression of mitochondrial transcription factor A, uncoupling protein 2 (UCP2) and mitochondrial complexes [40] (Table 1).…”

“…HT is known to improve mitochondrial function either by increasing the activity and/or expression of mitochondrial complexes I, II, III, IV, and V [15,38,59,60]. The 3T3-L1 adipocytes subjected to HT in the concentration range of 0.1–10 μM stimulated the expression and activity of peroxisome-proliferator activator receptor γ co-activator 1α (PGC1α), which promotes mitochondrial function by increasing the expression and activity of all complexes involved in the respiratory chain and oxidative phosphorylation [60].…”

“…In this context, hydroxytyrosol (HT) (3,4-Dihydroxyphenyl)ethanol; Figure 1) is a polyphenol mainly present in extra virgin olive oil (EVOO) [4] that has a potent antioxidant activity [5,6,7]. Moreover, HT provides other beneficial benefits that may be of importance for human health [8], namely anti-inflammatory [9] and anticancer [10] effects, enhancement of endothelial and vascular function [11], anti-steatotic [7,12] properties, and improvement of endoplasmic reticulum stress [13], autophagy [14] and mitochondrial function [15]. Interestingly, HT is the only polyphenol recognized by the European Food Safety Authority as a protector of low density lipoproteins (LDL) from oxidative damage [16], considering the finding that HT reduces the expression of adhesion molecules in endothelial cells, preventing the oxidation of LDL [17].…”