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

Tzu Yin Chen, Ke Li Tsai, Tzu Ying Lee, Chuang Chin Chiueh, Wen Sen Lee, Chin Hsu

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)160-165
Number of pages6
JournalStroke
Volume41
Issue number1
DOIs
Publication statusPublished - Jan 2010

Fingerprint

Thioredoxins
Brain Injuries
Estradiol
Iron
Caudate Nucleus
Neuroprotective Agents
Nitrobenzoates
Estrogen Receptors
Small Interfering RNA
Thioredoxin-Disulfide Reductase
Forelimb
Cerebral Hemorrhage
Brain
Craniocerebral Trauma
Sex Characteristics
Free Radicals
Capsules
Sprague Dawley Rats
monoferrous acid citrate
Neuroprotection

Keywords

  • Caudate nucleus
  • Estrogen
  • Ferrous citrate
  • Hemorrhagic stroke
  • Thioredoxin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Advanced and Specialised Nursing

Cite this

Sex-specific role of thioredoxin in neuroprotection against iron-induced brain injury conferred by estradiol. / Chen, Tzu Yin; Tsai, Ke Li; Lee, Tzu Ying; Chiueh, Chuang Chin; Lee, Wen Sen; Hsu, Chin.

In: Stroke, Vol. 41, No. 1, 01.2010, p. 160-165.

Research output: Contribution to journalArticle

Chen, Tzu Yin ; Tsai, Ke Li ; Lee, Tzu Ying ; Chiueh, Chuang Chin ; Lee, Wen Sen ; Hsu, Chin. / Sex-specific role of thioredoxin in neuroprotection against iron-induced brain injury conferred by estradiol. In: Stroke. 2010 ; Vol. 41, No. 1. pp. 160-165.
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abstract = "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.",
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AU - Lee, Wen Sen

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N2 - 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.

AB - 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.

KW - Caudate nucleus

KW - Estrogen

KW - Ferrous citrate

KW - Hemorrhagic stroke

KW - Thioredoxin

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