17β-Estradiol Inhibits Subarachnoid Hemorrhage–Induced Inducible Nitric Oxide Synthase Gene Expression by Interfering With the Nuclear Factor κB Transactivation

Abstract

Background and Purpose-Previously, we showed that 17␤-estradiol (E 2 ) treatment prevented the subarachnoid hemorrhage (SAH)-induced cerebral vasospasm in male rats. The aim of this study was designed to further delineate the molecular mechanisms underlying E 2 -induced inhibition of inducible nitric oxide synthase (iNOS) upregulation and relief of vasospasm caused by SAH. Methods-The 2-hemorrhage SAH model was induced by 2 autologous injections of blood into the cisterna magna of adult male rats. The rats were then subcutaneously implanted of a Silastic tube containing corn oil with or without 17␤-estradiol benzoate and received daily intraperitoneal injections of various doses of ICI 182,780, a nonselective estrogen receptor (ER) antagonist, for 7 days after the first hemorrhage. Basilar arteries were then removed for protein extraction, RNA isolation, and gel mobility assay. The protein levels of iNOS, p65, and ER were examined by Western blot analysis, and that iNOS mRNA expression was evaluated by reverse-transcription polymerase chain reaction. Results-E 2 prevented the SAH-induced vasospasm and increases of the levels of iNOS protein and mRNA in basilar artery through an ER-dependent mechanism. Treatment of the SAH rat with E 2 did not affect the nuclear translocation of p65 subunit of nuclear factor B, but caused an increase of the association of p65/ER, and reversed the SAH-induced increase of the p65 binding on iNOS promoter. Conclusions-E

3,4-Dihydroxyphenylethanol alleviates early brain injury by modulating oxidative stress and Akt and nuclear factor-κB pathways in a rat model of subarachnoid hemorrhage

“…The nuclear transcription factor NF-κВ has been shown to be an important inflammatory mediator in brain tissue during the pathophysiological occurrence of cerebral vasospasm (35). NF-κВ is mainly expressed in vascular endothelial cells and cell nuclei of the outer membrane, and its expression level is positively correlated with the degree of vascular spasm (36).…”

Neurovascular Events After Subarachnoid Hemorrhage: Focusing on Subcellular Organelles

“…Furthermore, because of the association of p65 with the estrogen receptor, 17β-estradiol blocked the binding of p65 to the gene target inducible NOS (iNOS). Therefore, this hormone drug reduced iNOS and showed a neuroprotective effect on CVS [57]. The activation of NF-κB was biphasic in a single injection rabbit SAH model.…”

17β-Estradiol Activates Adenosine A2a Receptor After Subarachnoid Hemorrhage

“…was given for 7 d followed the first hemorrhage. Our previous study showed that pretreatment of the rat with the ICI182,780 (Tocris Bioscience, Ellisville, MO) dose-dependently reversed the E 2 -mediated prevention on the SAH-induced vasospasm with a maximal effect at a dose of 2 mg/kg ICI182,780 [9]. (Tocris) was dissolved in corn oil (Sigma) to make a final concentration of 20% solution.…”

“…Accumulating evidence suggests that estrogen affords neuroprotection against brain injury and neurodegenerative diseases both in animal and clinical studies [5,6]. Our previous study showed 17b-estradiol (E2) could attenuate experimental SAHinduced cerebral vasospasm by inhibiting endothelin-1 production [7], preventing the augmentation of iNOS expression by interfering with the nuclear factor k-B transactivation via an estrogen receptor (ER)-dependent mechanism [8,9], and preserving the normal eNOS expression after SAH [8].…”