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, due to 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 AGE (advanced glycated end-product)/AGE-receptor interaction and on down-stream signaling in the hippocampus of streptozotocin rats. Data show that, in diabetic rats, level of prooxidant compounds increase while level of antioxidant compound fall. RAGE and galectin-3 content and polyol flux increase while glyceraldehyde-3-phosphate dehydrogenase activity is impaired. Moreover, NFkB (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 DHEA was administered to diabetic rats, the improved oxidative imbalance and the marked reduction of AGE-receptors paralleled the reduced activation of NFkB and the reduction of S-100 levels, reinforcing the suggestion that oxidative stress plays a role in diabetes-related neuronal damage.