Dehydroepiandrosterone modulates nuclear factor-kappaB activation in hippocampus of diabetic rats.
Oxidative stress induced by chronic hyperglycemia contributes to cerebrovascular complications in diabetes. Reactive oxygen species activate the transcription factor nuclear factor-kappaB (NF-kappaB), 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-kappaB 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-kappaB. The derangement of the oxidative balance in the brain induced by diabetes improves with DHEA. Moreover, DHEA completely counteracts NF-kappaB activation, measured as DNA binding activity, and hinders the increase of IkappaB-alpha inhibitory subunit induced by oxidative stress. The time-lag of DHEA's effects on NF-kappaB activation parallels its effects on oxidative balance. Results indicate that DHEA might protect hippocampus from chronic activation of NF-kappaB-dependent genes by reducing NF-kappaB nuclear translocation. This could result in protection from diabetes-dependent brain damage.
Department of Experimental Medicine and Oncology, General Pathology Section, University of Turin, Turin 10126, Italy.
Manuela
M
Aragno
Raffaella
R
Mastrocola
Enrico
E
Brignardello
Maria
M
Catalano
Gaia
G
Robino
Roberta
R
Manti
Maurizio
M
Parola
Oliviero
O
Danni
Giuseppe
G
Boccuzzi
D000447:Aldehydes / Q000032:analysis; D000818:Animals; D000975:Antioxidants / Q000032:analysis / Q000494:pharmacology; D001665:Binding Sites; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins; D003687:Dehydroepiandrosterone / Q000008:administration & dosage / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000032:analysis; D020672:I-kappa B Proteins; D015227:Lipid Peroxidation; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
D000447:Aldehydes; D000975:Antioxidants; D015415:Biomarkers; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D017382:Reactive Oxygen Species; C462359:tert-4-hydroxy-2-nonenal; D000072000:NF-KappaB Inhibitor alpha; D003687:Dehydroepiandrosterone; D004247:DNA; D006861:Hydrogen Peroxide