The neuroprotective role of rosiglitazone in advanced glycation end product treated human neural stem cells is PPARgamma-dependent |
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| Institution: | 1. PIT Bioinformatics Group, Eötvös University, H-1117 Budapest, Hungary;2. Uratim Ltd., H-1118 Budapest, Hungary;1. Department of Nuclear Medicine, Aalborg University Hospital, Aalborg, Denmark;2. Department of Clinical Medicine, Aalborg University, Aalborg, Denmark;3. Department of Clinical Physiology, Viborg Hospital, Viborg, Denmark;4. Department of Health Science and Technology, Aalborg University, Aalborg, Denmark;5. Department of Urology, Viborg Hospital, Viborg, Denmark;6. Department of Nuclear Medicine, Regional Hospital West Jutland, Herning, Denmark;7. Department of Clinical Physiology and Nuclear Medicine, Randers Hospital, Randers, Denmark;1. Department of Neuroscience, Ohio State University, Columbus, OH 43210, USA;2. Neuroscience Graduate Studies Program, Ohio State University, Columbus, OH 43210, USA;3. Center for Brain and Spinal Cord Repair, Ohio State University, Columbus, OH 43210, USA |
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| Abstract: | Hyperglycemia is accompanied by an accelerated formation rate of advanced glycation end products (AGEs), which is associated with the pathogenesis of diabetic neuronal deficits. Peroxisome proliferator-activated receptor gamma (PPARγ) belongs to a family of ligand-activated nuclear receptors and its ligands are known to control many physiological, pathological and inflammatory pathways. Weinvestigated the hypothesis that the PPARγ agonist (rosiglitazone) would abrogate AGEs-mediated neurotoxic effects on human neural stem cells (hNSCs), by whichAGEs may play a role in diabetic-related neuronal impairment. Here, we show that rosiglitazone treatment increases cell viability of hNSCs via downregulation of caspase 3 activity. These rescue effects were extended in our studies showingrosiglitazone-mediated activation of PPARγ reversed the expression levels of two neuroprotective factors (Bcl-2 and PGC1α) that were downregulated in hNSCs exposed to AGEs alone. The stimulation of mitochondrial function and anti-oxidative stress by rosiglitazone was associated with activation of the PGC1α pathway by up-regulation of mitochondrial (NRF-1 and Tfam) and oxidative defense (SOD1, SOD2 and Gpx1) genes. Moreover, rosiglitazone significantly normalized the inflammatory responses (TNF-α and IL-1β), NF-κB (p65), and inflammatory genes (iNOS and COX-2) in the hNSCs treated with AGEs. This neuroprotective effect of rosiglitazone was effectively blocked by PPARγ-specific antagonist (GW9662), demonstrating that the action of rosiglitazone was mediated by at PPARγ-dependent pathway. Collectively, these novel findings show AGEs induce neurotoxic effects in hNSCs, and provide important mechanistic insights that may explain the increased risk of neuronal impairment deficits in diabetic patients. More importantly, these data show rosiglitazone-mediated activation of PPARγ-dependent signaling is neuroprotective in AGE-treated hNSCs, and suggests PPARγ ligands may be useful in the therapeutic management of patients with neurodegenerative diseases |
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| Keywords: | PPARγ hNSCs AGEs Neuroprotection |
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