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Suppression of post-ischemic-induced fos protein expression by an antisense oligonucleotide to c-fos mRNA leads to
Y Zhang1, M A Widmayer, B Zhang
1Department of Neurosurgery, Baylor College of Medicine, Suite 944, 6560 Fannin Street, Houston, TX 77030, USA.
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.
Insights
Suppressing c-fos gene expression after stroke surprisingly increased brain infarct size. This suggests c-fos activation and Fos protein expression offer neuroprotection, potentially aiding functional recovery after focal cerebral ischemia.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Immediate early genes like c-fos are activated following neural injury, including focal cerebral ischemia (FCI).
- Fos protein, often dimerizing with Jun to form activator protein 1 (AP-1), regulates downstream gene expression.
- The precise role of c-fos activation in the brain's response to ischemic injury remains to be fully elucidated.
Purpose of the Study:
- To investigate the downstream consequences of c-fos expression following ischemic injury.
- To determine the neuroprotective or detrimental effects of c-fos activation in a rat model of focal cerebral ischemia.
Main Methods:
- Administration of antisense oligonucleotides (AO) targeting c-fos mRNA to suppress Fos protein translation in Long Evans rats.
- Induction of permanent focal cerebral ischemia via middle cerebral artery occlusion.
- Assessment of neurological function, infarct volume, and Fos-positive cell counts 24 hours post-occlusion.
Main Results:
- Antisense oligonucleotide administration significantly reduced Fos-positive cells by approximately 75% compared to controls.
- No significant differences in neurological scores were observed between AO-treated and control groups.
- Animals treated with AO developed significantly larger infarct volumes (40.1%) compared to mismatched AO (34.3%) or artificial cerebrospinal fluid (34.6%) controls.
Conclusions:
- c-fos activation and subsequent Fos protein expression appear to exert a neuroprotective effect following focal cerebral ischemia.
- This neuroprotection may be mediated by the upregulation of neurotrophins.
- The c-fos/Fos pathway contributes to brain adaptation and potential functional recovery after stroke.