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

Abstract

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.

Oxidative Stress Impairs Skeletal Muscle Repair in Diabetic Rats

“…Moreover, antioxidants prevent the decrease of MCK transcription in skeletal muscle cells (15). It has been shown that dehydroepiandrosterone (DHEA), a multifunctional steroid secreted by the adrenal gland and brain (16), possesses a multitargeted antioxidant effect (17,18) and prevents tissue damage induced by acute and chronic hyperglycemia (19).…”

Suppressive effects of dehydroepiandrosterone and the nuclear factor-κB inhibitor parthenolide on corticotroph tumor cell growth and function in vitro and in vivo

“…PRT is known to exert an anti-NF-B effect by inactivating inhibitory kB (IkB) kinase (Kwok et al 2001). DHEA, in contrast, may inhibit NF-B through its antioxidant effect by altering the intracellular redox state (Gao et al 2005, Kabe et al 2005, through inhibition of I B ubiquitination is shown in diabetic rats (Aragno et al 2002), or through activation of PPAR (Kochan & Karbowska 2004). Thus, we assume that the combined effects of the two drugs are caused, at least partly, by their inhibitory effects on NF-B function, although the effects on other signaling pathway(s) are not ruled out.…”

“…95% ethanol mixed with 8 vol. mineral oil) (Aragno et al 2002) were administered subcutaneously for 21 days from 1 week after AtT20 cell injection. At the end of the experiment, mice were killed, and tumor weights were measured after their careful resection and the tumors and livers were used for quantitative RT-PCR assay.…”

“…Besides its effects as a prohormone, DHEA itself is suggested to have a variety of beneficial effects such as anti-tumor, anti-diabetic, antiatherosclerotic, and anti-aging effects (Aoki et al 2003). Some of these effects are thought to be mediated by its antioxidant properties via inhibition of nuclear factor-B (NF-B) (Aragno et al 2002, Iwasaki et al 2004, which is a transcription factor known to exert anti-apoptotic effects in neoplasia. DHEA is indeed reported to elicit cellular apoptosis in both tumor and non-tumor cells in vitro (Yang et al 2000, Liang et al 2004).…”

HSCARG Regulates NF-κB Activation by Promoting the Ubiquitination of RelA or COMMD1

“…Moreover, DHEA was found to potently inhibit NF-B activation by affecting NF-B itself and IB, at least partly through its effect on redox balance (23)(24)(25).…”