Suppression of post-ischemic-induced Fos protein expression by an antisense oligonucleotide to c-fos mRNA leads to increased tissue damage

Yi Jonathan Zhang, Marsha A. Widmayer, Benxiao Zhang, Jian Kun Cui, David S. Baskin

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Activation of c-fos, an immediate early gene, and the subsequent upregulation of Fos protein expression occur following neural injury, including focal cerebral ischemia (fci). Fos and Jun form a heterodimer known as activator protein 1, which regulates the expression of many late effector genes. To study the downstream effects of c-fos expression following ischemia, we suppressed the translation of c-fos by administering an antisense oligonucleotide (AO) to c-fos mRNA. Eighteen hours prior to fci, male, Long Evans (LE) rats received intraventricular injections of AO, mismatched AO (MS) or artificial cerebrospinal fluid (aCSF). Fci was induced by permanent right middle cerebral artery occlusion. At 24-h post-occlusion, neurological function was assessed, and the animals were sacrificed. The brains were removed and stained with triphenyltetrazolium chloride for infarct volume determination. Fos immunohistochemistry was performed in separate animals to determine the effects of treatment on Fos expression number of Fos positive cells. AO administration reduced the number of cells with fci-induced Fos expression by ~ 75%. No differences in neurological scores existed between any of the groups. AO-treated LE developed larger infarcts (40.1 ± 1.0%, mean ± S.D., p < 0.001) than MS- or aCSF-treated controls (34.3 ± 1.0%, 34.6 ± 1.0%, respectively). These results suggest that c-fos activation and subsequent Fos protein expression exerts a neuroprotective effect, which is likely via upregulation of neurotrophins, following focal cerebral ischemia. This response, among others, may contribute to brain adaptation to injury that underlies functional recovery after stroke.

Original languageEnglish (US)
Pages (from-to)112-117
Number of pages6
JournalBrain Research
Volume832
Issue number1-2
DOIs
StatePublished - Jun 19 1999

Keywords

  • Antisense oligonucleotide
  • c-fos
  • Cerebral infarction
  • Cerebral ischemia
  • Immediate early gene

ASJC Scopus subject areas

  • Neuroscience(all)

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