Sex-specific role of thioredoxin in neuroprotection against iron-induced brain injury conferred by estradiol

BACKGROUND AND PURPOSE-: Accumulation of iron after intracerebral hemorrhage causes free radical formation and oxidative damage resulting in liquefaction. The aim of this study was the investigation of molecular mechanisms underlying estrogen-mediated neuroprotective effect against iron-induced brain injury in vivo. METHODS-: Age-matched male and female Sprague-Dawley rats were stereotaxically infused with either ferrous citrate (FC) or saline (10 μL) into the right caudate nucleus. Beta-estradiol 3-benzoate (E2) capsule was implanted subcutaneously at 24 hours before infusion of FC. The severity of brain injury and neurological deficits were measured by histological quantification and forelimb asymmetry test, respectively. The role of thioredoxin (Trx) in E2-mediated neuroprotective effect was examined by intrastriatal administration of a Trx reductase inhibitor, 5,5-dithiobis-(2- nitrobenzoic acid), and small interfering RNA. RESULTS-: FC induced greater brain injury in male rats than females. E2 treatment reduced FC-induced brain injury in both sexes. E2 significantly increased protein level and activity of Trx in the caudate nucleus of females but not males. Administration of female rats with 5,5-dithiobis-(2-nitrobenzoic acid) or Trx small interfering RNA to the caudate nucleus decreased the protective effect of E2 against FC-induced injury. The protein and mRNA levels of estrogen receptorα;, but not estrogen receptorβ, were more abundant in the caudate nucleus of female rats. CONCLUSIONS-: Increase of brain Trx activity might play an important role in the E2-mediated neuroprotective effect against FC-induced brain injury in female rats. Understanding of the sex differences in the Trx-mediated neuroprotective effect by E2 might help in improving treatment of brain dysfunction after hemorrhagic stroke and/or head trauma.