Sex-specific role of thioredoxin in neuroprotection against iron-induced brain injury conferred by estradiol.
OBJECTIVE
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 muL) into the right caudate nucleus. Beta-estradiol 3-benzoate (E(2)) 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 E(2)-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. E(2) treatment reduced FC-induced brain injury in both sexes. E(2) 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 E(2) against FC-induced injury. The protein and mRNA levels of estrogen receptor alpha, but not estrogen receptor beta, were more abundant in the caudate nucleus of female rats.


CONCLUSIONS
Increase of brain Trx activity might play an important role in the E(2)-mediated neuroprotective effect against FC-induced brain injury in female rats. Understanding of the sex differences in the Trx-mediated neuroprotective effect by E(2) might help in improving treatment of brain dysfunction after hemorrhagic stroke and/or head trauma.
Chen
Tzu-Yin
TY
Department of Physiology, Kaohsiung Medical University, Taiwan.
Tsai
Ke-Li
KL
Lee
Tzu-Ying
TY
Chiueh
Chuang Chin
CC
Lee
Wen-Sen
WS
Hsu
Chin
C
D000818:Animals; D001930:Brain Injuries / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D019343:Citric Acid; D004958:Estradiol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D005296:Ferrous Compounds / Q000633:toxicity*; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D013879:Thioredoxins / Q000096:biosynthesis / Q000502:physiology*
D005296:Ferrous Compounds; D018696:Neuroprotective Agents; C074283:estradiol 3-benzoate; D019343:Citric Acid; C016600:ferrous citrate; D004958:Estradiol; D013879:Thioredoxins