Role of signal transducer and activator of transcription-3 in estradiol-mediated neuroprotection

Suzan Dziennis, Taiping Jia, Oline Ronnekleiv, Patricia D. Hurn, Nabil Alkayed

Research output: Contribution to journalArticle

80 Scopus citations

Abstract

Estradiol is protective in experimental cerebral ischemia, but the precise mechanisms remain unknown. Signal transducer and activator of transcription-3 (STAT3) is a transcription factor that is activated by estrogen, translocates to the nucleus, and induces the transcription of neuroprotective genes, such as bcl-2. We determined whether estradiol increases STAT3 activation in female rat brain after focal cerebral ischemia and whether STAT3 activation contributes to estradiol-mediated neuroprotection against ischemic brain injury. Ovariectomized (OVX) female rats with and without estradiol replacement were subjected to 2 h of middle cerebral artery occlusion (MCAO), and phosphorylated STAT3 (P-STAT3) and total STAT3 (T-STAT3) were quantified by Western blot analysis at 3 and 22 h of reperfusion. STAT3 activation was colocalized with neuronal and survival markers microtubule-associated protein 2 (MAP2) and Bcl-2 using immunohistochemistry. Infarct size was measured at 22 h after MCAO in estradiol-treated OVX animals in the presence and absence of STAT3 inhibitor cucurbitacin I (JSI-124) using 2,3,5-triphenyltetrazolium chloride staining. Estradiol increased P-STAT3 in the ischemic cortex cytosolic fraction at 3 h after MCAO without affecting T-STAT3. This was associated with increased P-STAT3 in the nuclear fraction, which remained elevated at 22 h after MCAO. The nuclear P-STAT3 colocalized with MAP2 and Bcl-2 within the peri-infarct zone. The P-STAT3 inhibitor JSI-124 abolished the protective effect of estradiol without affecting infarct size in untreated OVX rats. We conclude that estradiol increases STAT3 phosphorylation in neurons after MCAO and that STAT3 activation plays an important role in estradiol-mediated neuroprotection.

Original languageEnglish (US)
Pages (from-to)7268-7274
Number of pages7
JournalJournal of Neuroscience
Volume27
Issue number27
DOIs
Publication statusPublished - Jul 4 2007

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Keywords

  • Estrogen
  • Ischemia
  • JSI-124 (cucurbitacin I)
  • MCAO
  • Neuroprotection
  • STAT3

ASJC Scopus subject areas

  • Neuroscience(all)

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