title: Suppression of post-ischemic-induced fos protein expression by an antisense oligonucleotide to c-fos mRNA leads to increased tissue damage.
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 approximately 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.
authors.affiliation: Department of Neurosurgery, Baylor College of Medicine, Suite 944, 6560 Fannin Street, Houston, TX 77030, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: M A
authors.initials: MA
authors.lastname: Widmayer
authors.forename: B
authors.initials: B
authors.lastname: Zhang
authors.forename: J K
authors.initials: JK
authors.lastname: Cui
authors.forename: D S
authors.initials: DS
authors.lastname: Baskin
mesh_terms: D000818:Animals; D002544:Cerebral Infarction / Q000378:metabolism* / Q000473:pathology; D003864:Depression, Chemical; D007150:Immunohistochemistry; D002546:Ischemic Attack, Transient / Q000378:metabolism* / Q000473:pathology; D008297:Male; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D020318:Rats, Long-Evans
chemical_list: D016376:Oligonucleotides, Antisense; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger