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Dehydroepiandrosterone Modulates Nuclear Factor-B Activation in Hippocampus of Diabetic Rats

Department of Experimental Medicine and Oncology (M.A., R.M., G.R., M.P., O.D.) General Pathology Section, and Department of Clinical Pathophysiology (E.B., M.C., R.M., G.B.), University of Turin, Turin 10126, Italy

Address all correspondence and requests for reprints to: Prof. Giuseppe Boccuzzi, Department of Clinical Pathophysiology, Via Genova 3, University of Turin, Turin 10126, Italy. E-mail: giuseppe.boccuzzi{at}unito.it.

Oxidative stress induced by chronic hyperglycemia contributes to cerebrovascular complications in diabetes. Reactive oxygen species activate the transcription factor nuclear factor-B (NF-B), which in turn activates a variety of target genes linked to the development of diabetic complications. Dehydroepiandrosterone, an adrenal steroid, which possesses a multitargeted antioxidant effects, is also synthesized de novo by the brain. Normoglycemic and streptozotocin-diabetic rats were either treated with dehydroepiandrosterone (DHEA) for 7, 14, or 21 d (4 mg/d per rat) or left untreated. Oxidative state, antioxidant balance and activation of nuclear transcriptional redox-sensitive factor NF-B were evaluated in the hippocampus area. In streptozotocin-treated rats, besides the strong increase in oxygen reactive species, there is also a persistent activation of NF-B. The derangement of the oxidative balance in the brain induced by diabetes improves with DHEA. Moreover, DHEA completely counteracts NF-B activation, measured as DNA binding activity, and hinders the increase of IB- inhibitory subunit induced by oxidative stress. The time-lag of DHEA’s effects on NF-B activation parallels its effects on oxidative balance. Results indicate that DHEA might protect hippocampus from chronic activation of NF-B-dependent genes by reducing NF-B nuclear translocation. This could result in protection from diabetes-dependent brain damage.

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