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Up-Regulation of Advanced Glycated Products Receptors in the Brain of Diabetic Rats Is Prevented by Antioxidant Treatment

Department of Experimental Medicine and Oncology (M.A., R.M., F.R., O.D.), General Pathology Section, Department of Anatomy, Pharmacology, and Forensic Medicine (N.P.), and Department of Analytical Chemistry (C.M.), University of Turin, 10125 Turin; and Department of Clinical Pathophysiology (M.G.C., G.B.), University of Turin, 10126 Turin, Italy

Address all correspondence and requests for reprints to: Dr. Manuela Aragno, Department of Experimental Medicine and Oncology, General Pathology Section, University of Turin, Corso Raffaello 30, 10125 Turin, Italy. E-mail: manuela.aragno{at}unito.it.

Diabetics have at least twice the risk of stroke and may show performance deficit in a wide range of cognitive domains. The mechanisms underlying this gradually developing end-organ damage may involve both vascular changes and direct damage to neuronal cells as a result of overproduction of superoxide by the respiratory chain and consequent oxidative stress. The study aimed to assess the role of oxidative stress on the aldose reductase-polyol pathway, on advanced glycated end-product (AGE)/AGE-receptor interaction, and on downstream signaling in the hippocampus of streptozotocin-treated rats. Data show that, in diabetic rats, levels of prooxidant compounds increase, whereas levels of antioxidant compounds fall. Receptor for AGE and galectin-3 content and polyol flux increase, whereas glyceraldehyde-3-phosphate dehydrogenase activity is impaired. Moreover, nuclear factor B (p65) transcription factor levels and S-100 protein are increased in the hippocampus cytosol, suggesting that oxidative stress triggers the cascade of events that finally leads to neuronal damage. Dehydroepiandrosterone, the most abundant hormonal steroid in the blood, has been reported to possess antioxidant properties. When dehydroepiandrosterone was administered to diabetic rats, the improved oxidative imbalance and the marked reduction of AGE receptors paralleled the reduced activation of nuclear factor B and the reduction of S-100 levels, reinforcing the suggestion that oxidative stress plays a role in diabetes-related neuronal damage.

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