Expression of c-fos in the rat cerebral cortex after focal ischemia and reperfusion

doi:10.1016/0361-9230(94)90234-8

Brain Research Bulletin

Volume 33, Issue 6, 1994, Pages 689-697

https://doi.org/10.1016/0361-9230(94)90234-8 Get rights and content

Abstract

Time-dependent changes in c-fos-like immunoreactivity (c-fos-LI) were studied in the rat during focal cerebral ischemia and reperfusion after middle cerebral artery (MCA) occlusion. In the permanent ischemia model, the levels of c-fos-LI increased for the first 30 min of ischemia in neuronal nuclei in the lesioned hemisphere. They reached a maximum at 60 min. The level in the parietal cortex (PC) diminished considerably after 120 min, and in the cingulate cortex (CC) it gradually decreased to near the control value at 180 min. Regional cerebral blood flow (rCBF) in the PC fell to 32% and that in the CC fell to 64% of pre-ischemic values after MCA occlusion. Reperfusion induced strong expression of c-fos-LI in the PC and CC after 6 h of reperfusion that followed 30 min of ischemia. The c-fos-LI was effectively reduced by preadministration of the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine (100 mg/kg, IP). These findings suggest that the expression of c-fos after ischemia may be immediately activated through NMDA receptors and may spread to surrounding regions in a manner sensitive to reductions in rCBF. Reperfusion after ischemia also appears to cause activation of expression of c-fos and of intracellular signal transduction.

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The immediate-early gene c-fos and its protein product Fos have been reliable indicators of cell activity and may play a role in both neuronal death and cell survival [3,23]. In adult focal ischemia models, immunocytochemical expression of Fos is generally observed in widespread regions of the ipsilateral cortex at early time points (2–6 h) [17,48,54]. The overall widespread cortical expression of c-fos has been attributed to the event of spreading depression [25,28].
Ischemia is a potent modulator of gene expression. Differential expression of transcription factors after focal ischemia may reflect the potential for neuronal recovery in peri-ischemic regions. Previously, we demonstrated that hypothermia reduces the volume of damage in a model of neonatal focal ischemia. In the present study, immunocytochemistry was used to assess the temporal and spatial profiles of the transcription factors Fos and pCREB under normal and hypothermic conditions in this neonatal model of focal ischemia. At 7 days of age, rat pups underwent a permanent middle cerebral artery occlusion (MCAo) coupled with a temporary 1-h occlusion of the common carotid artery (CCAo). They were maintained at 37 °C throughout ischemia and reperfusion (Normothermic), or given 1 h of hypothermic conditions (28 °C) either during the occlusion (Intraischemic Hypothermia) or during the second hour of reperfusion (postischemic hypothermia). In normothermic pups, Fos immunoreactivity peaked at early time points (4–8 h post-ischemia) in a narrow band in peri-ischemic regions. By later stages of reperfusion (12–24 h), there was a more widespread induction in peri-ischemic regions including the ipsilateral cortex. In contrast with Fos, the constitutive transcription factor pCREB was reduced in core regions at all time points examined. Both the c-fos induction in peri-ischemic regions and the reduction of pCREB in the core were attenuated by intraischemic hypothermia. Postischemic hypothermia altered the distribution of Fos immunoreactivity without significantly changing the number of Fos- and pCREB-immunoreactive cells compared to normothermic rats. Both intra- and postischemic hypothermia reduced the number of caspase-immunoreactive cells. Thus, focal ischemia in the P7 rat produces different distributions of Fos and pCREB than what has been observed in adult rats subjected to focal ischemia, and expression of these transcription factors can be altered by hypothermia.
Suppression of post-ischemic-induced Fos protein expression by an antisense oligonucleotide to c-fos mRNA leads to increased tissue damage
1999, Brain Research
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.
Primary cortical glial reaction versus secondary thalamic glial response in the excitotoxically injured young brain: Microglial/macrophage response and major histocompatibility complex class I and II expression
1999, Neuroscience
The excitatory amino acid analog,N-methyl-d-aspartate, was injected intracortically into nine-day-old rats. Resulting axon-sparing lesions in the developing sensorimotor cortex, which secondarily affect thalamic neurons that become deprived of cortical targets, provide an experimental model for the study of the glial response in distantly affected areas. The microglial/macrophage response was studied using tomato lectin histochemistry and major histocompatibility complex I and II immunocytochemistry. Blood-brain barrier integrity was evaluated. In the cortical lesion site, where blood-brain barrier breakdown occurs, the rapid microglial response was restricted to the degenerating area. Microglial changes were first seen at 4 h post-injection, peaking at days 3–5. Reactive microglia changed morphology, increased tomato lectin binding and expressed major histocompatibility complex I. Additionally, some cells expressed major histocompatibility complex II. In the secondarily affected thalamus, the microglial response was not as pronounced as in the cortex, was first seen at 10 h post-injection and peaked at days 3–5. Reactive microglia showed a bushy morphology, were intensely lectin positive and expressed major histocompatibility complex I.
The exceptional response of the nine-day-old brain to cortical lesions makes this model an interesting tool for studying the implications of microglial major histocompatibility factor expression in still enigmatic processes such as wound healing and plasticity.
Correlation between potentiation of AP1 DNA binding and expression of c- Fos in association with phosphorylation of CREB at serine133 in thalamus of gerbils with ischemia
1998, Brain Research
Protein biosynthesis is mainly under the control at the level of gene transcription in eukaryotes. Transcription factors are nuclear proteins with abilities to modulate the activity of RNA polymerase II which is responsible for the formation of messenger RNA from double stranded DNA in the cell nuclei. Binding of a radiolabeled oligonucleotide probe for the transcription factor activator protein-1 (AP1) was transiently potentiated 1 to 6 h after the recirculation of blood supply in the thalamus and striatum, but not in the entorhinal cortex, olfactory bulb, frontal cortex, cerebellar cortex and medulla-pons, in gerbils with transient global forebrain ischemia for 5 min, in addition to the hippocampal subregions. The ischemic insult not only increased the immunoreactivity with an antibody against cyclic AMP response element binding protein (CREB) phosphorylated at serine133, but also induced the expression of both c-Jun and c-Fos family proteins 3 h after the recirculation in the thalamus. Limited proteolysis by Staphylococcus aureus (S. aureus) V8 protease revealed the expression of different partner proteins of AP1 in response to ischemic signals in the thalamus. Moreover, ischemia for 2 min led to more prolonged elevation of AP1 binding in the thalamus at least up to 12 h after the reperfusion than that seen with ischemia for 5 min. These results suggest that potentiation of AP1 DNA binding may at least in part involve mechanisms associated with the expression of c-Fos protein through phosphorylation of CREB at serine133 in the thalamus of gerbils with ischemia.
Expression of Fos in the spinal motoneurons labelled by horseradish peroxidase following middle cerebral artery occlusion in rat
1998, Brain Research Bulletin
The study was aimed at the investigation of the rat corticospinal system both functionally and anatomically using as a functional marker the immediate early gene c-fos, combined with retrograde tracing with horseradish peroxidase (HRP). This was achieved by mapping c-fos induction immunocytochemically in the spinal cord as a result of occlusion of the middle cerebral artery (MCA). Following left-sided MCA occlusion, Fos-like immunoreactivity (Fos-LI) was localized in both the dorsal and ventral horn neurons at the lumbar segment of the spinal cord. Labelling was often bilateral but was generally more substantial ipsilaterally. In the ventral horn, some of the Fos-positive neurons were confirmed to be somatic motoneurons innervating the tibialis anterior muscle of the lower extremity contralateral to MCA occlusion, as shown by their retrograde labelling with horseradish peroxidase injected into the muscle. Fos-LI was absent in the ventral horn of the spinal cord at cervical, thoracic, and sacral segments in both experimental and sham-operated rats. These findings suggest that the expression of c-fos may be used as a sensitive transneuronal marker for the study of neuronal activity in the spinal cord elicited by brain damage, viz. focal cerebral ischaemia, and when coupled with injection of HRP as a retrograde tracer, the method may prove to be useful for the study of transneuronal effect of the damage of the corticospinal motor system. While the expression of c-fos in the spinal motoneurons was most probably attributable to transneuronal effect following MCA occlusion, the possibility of that c-fos can be induced by altered hindlimb activity after the cerebral ischaemic insult cannot be excluded.

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ArticleExpression of c-fos in the rat cerebral cortex after focal ischemia and reperfusion

Abstract

Brain Res.

Neurosci. Lett.

Neurosci. Lett.

J. Biol. Chemistry

Neuroscience

Brain Res.

Brain Res.

Brain Res.

Neurosci. Lett.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Effects of hypoxia-ischemia and seizures on neuronal and glial-like c-fos protein levels in the infant rat

Brain Res.

Thresholds in cerebral ischemia—The ischemic penumbra

Stroke

Hypoxia and vascular disorders of the central nervous system

Hypothermia but not the N-methyl-D-aspartate antagonist, MK-801, attenuates neuronal damage in gerbils subjected to transient global ischemia

J. Neurosci.

Expression of c-fos-like protein as a marker for neuronal activity following noxious stimulation in the rat

J. Comp. Neurol.

A model of focal ischemic stroke in the rat: Reproducible extensive cortical infarction

Stroke

Functional recovery of cortical neurons as related to degree and duration of ischemia

Annals of Neurology

Article
Expression of c-fos in the rat cerebral cortex after focal ischemia and reperfusion