17β‐Estradiol activates ICI 182,780‐sensitive estrogen receptors and cyclic GMP‐dependent thioredoxin expression for neuroprotection

Abstract

Clinical studies suggest that estrogen may improve cognition in Alzheimer's patients. Basic experiments demonstrate that 17beta-estradiol protects against neurodegeneration in both cell and animal models. In the present study, a human SH-SY5Y cell model was used to investigate molecular mechanisms underlying the receptor-mediated neuroprotection of physiological concentrations of 17beta-estradiol. 17beta-estradiol (<10 nM) concomitantly increased neuronal nitric oxide synthase (NOS1) expression and cell viability. 17beta-estradiol-induced neuroprotection was blocked by the receptor antagonist ICI 182,780, also prevented by inhibitors of NOS1 (7-nitroindazole), guanylyl cyclase (LY 83,583), and cGMP-dependent protein kinase (PKG) (Rp-8-pCPT-cGMPs). In addition to the expression of NOS1 and MnSOD, 17beta-estradiol increased the expression of the redox protein thioredoxin (Trx), which was blocked by the inhibition of either cGMP formation or PKG activity. The expression of heme oxygenase 2 and brain-derived neurotrophic factor was not altered. Estrogen receptor-enhanced cell viability against oxidative stress may be linked to Trx expression because the Trx reductase inhibitor, 5,5'-dithio-bis(2-nitrobenzoic acid) significantly reduced the cytoprotective effect of 17beta-estradiol. Furthermore, Trx (1 microM) inhibited lipid peroxidation, proapoptotic caspase-3, and cell death during oxidative stress caused by serum deprivation. We conclude that cGMP-dependent expression of Trx--the redox protein with potent antioxidative and antiapoptotic properties--may play a pivotal role in estrogen-induced neuroprotection.

The protective effects of Polygonum multiflorum stilbeneglycoside preconditioning in an ischemia/reperfusion model of HUVECs

“…The effect of PMS on NO production may play a central role in the mechanism for cell protection. Previously, we have observed that NO activates the cGMP-mediated signal transduction pathway to prevent oxidative stress-induced injury [35][36][37][38] . Estrogen induces NOS1/NO/cGMP/PKG to activate the signaling pathway and results in the expression of thioredoxin and MnSOD, crucial components of the estrogen-mediated multifaceted neuroprotective mechanisms [35] .…”

“…Previously, we have observed that NO activates the cGMP-mediated signal transduction pathway to prevent oxidative stress-induced injury [35][36][37][38] . Estrogen induces NOS1/NO/cGMP/PKG to activate the signaling pathway and results in the expression of thioredoxin and MnSOD, crucial components of the estrogen-mediated multifaceted neuroprotective mechanisms [35] . Cuong et al [36] reported that anoxic preconditioning induced iNOS expression and activated the NO/cGMP/PKG pathway, which may play an important role in maintaining mitochondrial K + ATP channels in an open state during A/R.…”

Involvement of PI3K/PKG/ERK1/2 signaling pathways in cortical neurons to trigger protection by cotreatment of acetyl-L-carnitine and α-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: Implications for Alzheimer's disease

“…Activation of PKG pathway results in the induction of antioxidative and antiapoptotic proteins (47). Recently, cGMP-dependent expression of thioredoxin, the redox protein with potent antioxidative properties, has been shown to play a pivotal role in neuroprotection against oxidative stress mediated by estrogen (48). Interestingly, a decrease in thioredoxin protein level was observed in AD brains as compared to normal controls (77).…”

Sex-Specific Role of Thioredoxin in Neuroprotection Against Iron-Induced Brain Injury Conferred by Estradiol

“…A recent in vitro study provided new evidence to support a possible role of thioredoxin (Trx) in mediating 17␤-estradiol-mediated neuroprotection against brain injury. 7 Although the underlying mechanism of ICH-induced brain injury is not fully elucidated, 8 one theory holds that the extensive lysis of extravascular red blood cells in the brain after ICH lead to overproduction of ferrous iron, which undergoes a redox cycle, including Haber-Weiss reaction and/or a Fenton reaction in the presence of oxygen, citric acid, and isocitric acids. 9 Redox cycling of iron complexes (ie, bidentate and tridentate ferrous citrate and hemoglobin) causes persistent conversion of oxygen into reactive oxygen species that lead to axonal dystrophy and cell death.…”