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PubMed1990

Intracellular distribution of the c-fos antigen during the cell cycle.

The subcellular localization of the c-fos proto-oncogene product was studied in the G1, S, G2, and mitotic phases of the cell cycle by indirect immunofluorescence. For these analyses c-fos transfected L6J1 rat skeletal myoblasts and adult rat aortic smooth muscle cells in secondary culture, and c-fos- and c-myc co-transfected mouse Swiss 3T3 fibroblasts were used. During G1, S, and G2, the c-fos protein was evenly distributed in the nucleus, with exclusion of the nucleoli. In mitotic prophase the c-fos antigen was dissociated from the condensed chromosomes and became diffusely distributed in the cell cytoplasm, where it remained until telophase, when, again, it appeared to be associated with chromatin in the re-assembling nucleus. When comparing the subnuclear distribution of the c-fos product with that of densely packed DNA, stained with the fluorochrome Hoechst, an inverse relationship was found. Dispersed chromatin regions with weak Hoechst DNA fluorescence showed a stronger fos immunofluorescence than regions that contained a higher concentration of DNA. The localization of c-fos antigen partially overlapped with that of antigens typical of small nuclear ribonucleoprotein complexes participating in transcription and splicing. To examine if the c-fos protein would bind preferentially to specific interphase chromosomes the nucleus was fragmented into micronuclei containing single, or groups of, chromosomes. Immunofluorescence analysis showed that the majority of micronuclei were fos-positive. Possible roles of the c-fos proto-oncogene product are discussed in relation to other nuclear antigens.

Animals↗
PubMed2002

c-Fos expression in the spinal cord after acute sacral segmental nerve stimulation.

AIMS: Sacral nerve stimulation (SNS) can provide subjective and objective relief of pelvic pain and chronic voiding symptoms, but its mechanism is poorly understood. It is well known that a noxious stimulus applied to one part of the body can reduce the response to a subsequent stimulus elsewhere in the body. This phenomenon, known as diffuse noxious inhibitory controls (DNIC), seems to be the mechanism by which pain can be reduced by concurrent noxious stimulation. METHODS: On the basis of the DNIC concept, we investigated the expression of a protein product of proto-oncogene c-Fos (c-Fos) in the rat spinal cord after acute electrical stimulation of the sacral segmental nerve with or without lower urinary tract irritation. Adult male Sprague-Dawley rats were treated either by sacral nerve stimulation (SNS) from the S1 sacral foramen or chemical irritation of the lower urinary tract (LUT) or both. Rats were perfused transcardially, and spinal cords were removed and processed for c-Fos immunohistochemistry. c-Fos expression in the central nervous system was detected by immunohistochemistry by using the avidin-biotin technique. The number of c-Fos-positive cells and their locations in the spinal cord were evaluated. RESULTS: SNS and LUT irritation resulted in significant increases in c-Fos-positive cells in L6 and S1 spinal segments. In the animals treated by SNS and LUT irritation, counts of c-Fos-positive cells in L6 and S1 segments were significantly smaller than expected. Distribution and number of c-Fos-positive cells in rats that received SNS and LUT irritation were almost the same as those induced by SNS alone in the S1 segment. CONCLUSIONS: SNS alone caused a near maximal response in c-Fos expression such that adding LUT irritation did not cause a linear increase in c-Fos. Subsequent LUT irritation could not induce additional expression of c-Fos within the spinal cord.

Animals↗
PubMed2002

Conditioned-fear stress increases Fos expression in monoaminergic and GABAergic neurons of the locus coeruleus and dorsal raphe nuclei.

Many studies have demonstrated that physical or psychological stress can increase Fos expression in brainstem monoaminergic nuclei. Little is known, however, about the extent to which stress increases the expression of Fos in monoaminergic and nonmonoaminergic neurons in the brainstem. We examined the effects of conditioned-fear (CF) stress following mild footshock (FS) as unconditioned stress on Fos expression in the monoaminergic and GABAergic neurons of the ventral tegmental area (VTA), locus coeruleus (LC), and dorsal raphe nucleus (DR) in rats. The CF stress significantly increased the number of Fos-positive (Fos+) cells in both the LC and DR, whereas it did not increase the number in the VTA. Using a double-labeling technique, we combined Fos immunostaining with that for tyrosine hydroxylase (TH), serotonin (5-HT), or GABA for histochemical identification of the CF stress-induced Fos+ neurons. The percentage of TH/Fos double-labeled cells resulting from CF stress was 63% of the Fos+ cells in the LC, whereas 52% of the Fos+ cells contained 5-HT in the DR. We also found that approximately 60% of the CF stress-induced Fos+ cells were GABAergic neurons in these brain regions. These results indicate that CF stress induces intense Fos expression in the noradrenergic LC and serotonergic DR neurons, but not in the dopaminergic VTA neurons. They also indicate that not only monoaminergic neurons but also GABAergic neurons within the LC and DR are activated by the stress.

Animals↗
PubMed1995

Developmental regulation of Fos-protein during proliferative growth of the otic vesicle and its relation to differentiation induced by retinoic acid.

This work studies Fos protein expression in the otic vesicle and the developing cochleovestibular ganglion (CVG), focusing on the possible role of Fos in the regulation of cell proliferation and differentiation during otic development. Fos was detected as a product of 56-62 kDa in otic vesicles and CVG lysates. Expression was transient and stage-dependent. Maximal levels occurred at stage 20 in the otic vesicle and at Day 4 in the CVG. Another wave of Fos expression occurred after Day 7 of development, out of the early proliferative period. Fos immunoreactivity was localized in cell nuclei of otic epithelium and CVG. Fos was readily induced by mitogens like serum and bombesin and this induction was inhibited by 25 nM retinoic acid, an inhibitor of cell proliferation in the otic vesicle.c-fos antisense oligonucleotides inhibited growth in the otic vesicle in parallel with a reduction in Fos expression. High levels of Fos protein were not sufficient, however, to sustain growth of isolated otic vesicles in the absence of mitogens. Incubation with retinoic acid (24 hr) induced differentiation of sensory hair-cells in parallel with inhibition of cell proliferation. Contrary to retinoic acid, Fos inhibition by antisense did not induce differentiation. The results suggest that Fos is part of the signaling mechanisms regulating normal development of the inner ear. Regulation of Fos may be required for controlling of the transition between cell proliferation and differentiation.

Animals↗
PubMed2000

Is Fos protein expressed by dying striatal neurons after immature hypoxic-ischemic brain injury?

The transient induction of mRNA for the immediate-early gene c-fos has been reported following hypoxic-ischemic brain injury in the immature brain. However, no studies have examined the temporal expression of Fos protein, which is the functionally relevant product of c-fos gene expression. Increased expression of Fos protein has been linked to cell death. We therefore examined whether Fos protein is expressed by dying neurons after immature hypoxic-ischemic brain injury. A well characterized immature rat model of hypoxic-ischemic injury at postnatal day (PN) 7 was used. Three hypoxic-ischemic and three normoxic control pups were studied per time point (i.e., 0, 2, 12, 24, 48, and 72 h posttreatment). Expression of Fos within striatal and other neurons was detected immunocytochemically. Fos protein was expressed within dying striatal neurons at 0-12 h after hypoxia-ischemia. However, detection was only seen in 2 of 17 hypoxic-ischemic pups. These 2 pups had >/=80% of their striatal neurons dying within their right, hypoxic-ischemic-exposed hemisphere. Fos protein expression after severe injury may, therefore, be a response to extraordinary or extreme stress. The absence of Fos protein expression in the majority of hypoxic-ischemic pups, which all exhibited striatal neuronal death, suggests that Fos expression is not necessary for cell death to occur. Therapies directed against Fos protein expression may therefore have limited usefulness in immature hypoxic-ischemic brain injury.

Animals↗
PubMed1999

C-Fos in enteric nerves after extrinsic denervation of guinea pig ileum.

BACKGROUND: Gastrointestinal function is controlled partly by an interaction between extrinsic (sympathetic, parasympathetic, sensory) and intrinsic (enteric) nerves. However, normal gut function occurs in the absence of extrinsic innervation as enteric nerves adapt to the loss of extrinsic nerves from the gut wall. Expression of the proto-oncogene product, c-Fos, is a signal for activity-dependent changes in gene expression and immunocytochemical detection of c-Fos is used as a marker for changes in neuronal activity. The purpose of this study was to determine if enteric neurons in guinea pig ileum respond to loss of extrinsic innervation by expressing c-Fos protein. MATERIALS AND METHODS: Fos protein was localized using immunohistochemical methods and an antiserum raised against synthetic Fos. Segments of ileum were extrinsically denervated by crushing the mesenteric nerves in anesthetized animals or by treating animals with 6-hydroxydopamine (6-OH-DA) or capsaicin to destroy sympathetic and extrinsic sensory nerves, respectively. RESULTS: One week after surgical extrinsic denervation of loops of ileum, 12 +/- 1 nuclei/submucosal ganglion and 114 +/- 6 nuclei/myenteric ganglion contained Fos immunoreactivity (ir). These values were greater (P < 0.05) than those from unoperated segments from the same animals (4 +/- 1 Fos-ir nuclei/submucosal ganglion and 13 +/- 4 Fos-ir nuclei/myenteric ganglion) or from sham-operated segments. Significantly more nuclei contained Fos-ir at 4, 7, 10, and 24 weeks after denervation. Finally, capsaicin or 6-OH-DA treatment increased the number of Fos-ir nuclei in enteric ganglia. CONCLUSIONS: These data suggest that Fos expression may be part of the adaptation of enteric nerves to extrinsic denervation.

Animals↗
PubMed1995

Circadian modulation in photic induction of Fos-like immunoreactivity in the suprachiasmatic nucleus cells of diurnal chipmunk, Eutamias asiaticus.

Photic induction of immediate early genes including c-fos in the suprachiasmatic nucleus (SCN) has been well demonstrated in the nocturnal rodents. On the other hand, in diurnal rodents, no data is available whether the light can induce c-fos or Fos in the SCN. We therefore examined whether 60 min light exposure induces Fos-like immunoreactivity (Fos-lir) in the SCN cells of diurnal chipmunks and whether the induction is phase dependent, comparing with the results in nocturnal hamsters. We also examined an effect of light on the locomotor activity rhythm under continuous darkness. Fos-lir was induced in the chipmunk SCN. The induction was clearly phase dependent. The light during the subjective night induced strong expression of Fos-lir. This phase dependency is similar to that in hamsters. However, unlike in hamsters, the Fos-lir was induced in some SCN cells of chipmunks exposed to light during the subjective day. In the locomotor rhythm, on the other hand, the light pulse failed to induce the phase shift at phases at which the Fos-lir was induced. These results suggest that the photic induction of Fos-lir in the diurnal chipmunks is gated by a circadian oscillator as well as in the nocturnal hamsters. However, the functional role of Fos protein may be different in the diurnal rodents from in the nocturnal rodents.

Animals↗
PubMed1997

Treadmill running induces striatal Fos expression via NMDA glutamate and dopamine receptors.

Several non-physiological stimuli (i.e. pharmacological or electrical stimuli) have been shown to induce Fos expression in striatal neurons. In this work, striatal Fos (i.e. Fos-like) expression was studied after physiological stimulation, i.e. motor activity (treadmill running at 36 m/min for 20 min). In rats killed 2 h after the treadmill session, Fos expression was observed in the medial region of the rostral and central striatum, and in the dorsal region of the caudal striatum. Fos expression was prevented by pretreatment with the non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist MK-801 (0.1 mg/kg) or the D1 dopamine receptor antagonist SCH-23390 (0.1 mg/kg), but not by pretreatment with the D2 receptor antagonist eticlopride (0.5 mg/kg). Thirty-six hours after 6-hydroxydopamine lesion, a considerable reduction in treadmill-induced Fos expression was observed in both sides; however, Fos expression in the lesioned striatum was higher than in the contralateral intact striatum. Several weeks after unilateral 6-hydroxydopamine lesion of the nigrostriatal system, treadmill-induced Fos expression was significantly, but not totally, reduced in the lesioned striatum. Corticostriatal deafferentation also led to considerable reduction in treadmill-induced Fos expression. The present results indicate that exercise induces striatal Fos expression and that, under physiological stimulation, concurrent activation of D1 and NMDA receptors is necessary for such expression to occur. Reduction of Fos expression is practically absolute after acute blockage of these receptors, but not after lesions, possibly due partially to compensatory changes.

Afferent Pathways↗
PubMed2003

Differential expression of c-fos and c-myc protooncogenes by estrogens, xenobiotics and other growth-stimulatory agents in primary rat hepatocytes.

Mechanism(s) of tumour promotion in liver by estrogens and other xenobiotics such as alpha-hexachlorocyclohexane (HCH), 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (DDT) and phenobarbital (PB), are not well understood although it is clear that growth stimulation is one important element in their action. To help in characterizing mechanisms of growth control by these compounds, their effects on the expression of immediate-early protooncogenes c- fos and c- myc have been examined and compared with other compounds that stimulate DNA synthesis in primary cultures of normal rat hepatocytes. Expression of c- fos was undetectable in cultures not exposed to growth factors. Although neither epidermal growth factor (EGF) nor 17beta-estradiol (E(2)) alone had marked effects on c- fos mRNA, the two acted synergistically to cause clear c- fos expression, maximal 1-2 h after growth factor addition and when test agents were added on the first day in culture. Neither insulin nor dexamethasone alone induced c- fos mRNA but stimulation of c- fos expression by EGF plus estradiol occurred earlier in the presence of insulin, and was augmented by preincubation of cells with dexamethasone. EGF + E(2)-induced c- fos mRNA was completely abolished by actinomycin D, suggesting that transcription is the major mechanism for c- fos induction by E(2) + EGF. Compounds that strongly stimulate hepatocyte DNA synthesis such as norepinephrine, pyruvate, prolactin, glutethimide, monensin, ammonium chloride, and normal rat serum when in combination with EGF, all failed (when added with EGF) to affect c- fos mRNA expression. Thus, induction of c- fos expression may be a component of estradiol's growth stimulatory effect in cultured hepatocytes but this is not the case for other compounds that strongly stimulate DNA synthesis. Unlike c- fos mRNA, c- myc mRNA was detectable in hepatocyte cultures without added growth factor, was augmented within 2 h of exposure to EGF, and was further increased by adding E(2), other estrogens or a variety of other stimulators of DNA synthesis in hepatocytes. This suggests that increased c- myc expression may be a common effect of many of these agents in combination with EGF.

Animals↗
PubMed2006

Vagus nerve stimulation preferentially induces Fos expression in nitrergic neurons of rat esophagus.

To identify neurochemical phenotypes of esophageal myenteric neurons synaptically activated by vagal preganglionic efferents, we immunohistochemically detected the expression of Fos, an immediate early gene product, in whole-mount preparations of the entire esophagus of rats following electrical stimulation of the vagus nerves. When electrical stimulation was applied to either the cervical left (LVN) or right vagus nerve (RVN), neurons with nuclei showing Fos immunoreactivity (IR) were found to comprise approximately 10% of the total myenteric neurons in the entire esophagus. These neurons increased from the oral toward the gastric end of the esophagus, with the highest frequency in the abdominal portion of the esophagus. A significant difference was not found in the number of Fos neurons between the LVN-stimulated and RVN-stimulated esophagus. Double-immunolabeling showed that nitric oxide synthase (NOS)-IR occurred in most (86% and 84% in the LVN-stimulated and RVN-stimulated esophagus, respectively) of the Fos neurons in the entire esophagus. Furthermore, the stimulation of either of the vagus nerves resulted in high proportions (71%-90%) of Fos neurons with NOS-IR, with respect to the total Fos neurons in each segment, in the entire esophagus. However, a small proportion (8% and 7% in the LVN-stimulated and RVN-stimulated esophagus, respectively) of the Fos neurons in the esophagus exhibited choline acetyltransferase (ChAT)-IR. The occurrence-frequency of Fos neurons with ChAT-IR was less than 4% of the total Fos neurons in any segment of the LVN-stimulated and RVN-stimulated esophagus. Some of the Fos neurons with ChAT-IR appeared to be innervated by numerous varicose ChAT-positive nerve terminals. The present results showing that electrical stimulation of the vagus nerves induces a high proportion of Fos neurons with NOS-IR suggests the preferential activation of NOS neurons in the esophagus by vagal preganglionic efferents. This connectivity between the vagal efferents and intrinsic nitrergic neurons might be involved in inhibitory actions on esophageal motility.

Animals↗
PubMed1996

Effect of acute stimulation on Fos expression in spinal neurons in the presence of persisting C-fiber activity.

Expression of the inducible transcription factor c-Fos has been examined in the lumbar spinal cord following noxious chemical stimulation (injection of 2% formalin) of the ankles or the ventral skin of the hindpaws of either normal rats, or monoarthritic rats during the chronic phase of the disease. In normal animals the basal expression of c-Fos was low. One day after induction of monoarthritis by an intra-articular injection of killed Mycobacterium butyricum (in complete Freund's adjuvant) there were numerous c-Fos labelled cells in the ipsilateral dorsal horn, and bilaterally in lamina VIII and in other areas of the ventral horn. Four weeks after induction of the arthritis, although marked inflammation of the ankle was still present, all the expression of c-Fos had returned to the basal levels. One hour after formalin stimulation of the ankle or hindpaw skin of normal rats expression of c-Fos was observed throughout the ipsilateral, but not contralateral dorsal horn. Formalin stimulation of the inflamed ankle in four-week arthritic rats induced a 3-to-6 fold increase in c-Fos expression in the ipsilateral dorsal horn compared to formalin stimulation of the ankle in normal rats. In addition, c-Fos expression was induced in the contralateral deep, but not superficial laminae, at a density similar to that produced ipsilaterally by formalin stimulation of the ankle of normal rats. Formalin stimulation of the contralateral ankle in monoarthritic rats (i.e. the non-inflamed ankle) induced an ipsilateral expression of c-Fos which was similar to that observed after stimulation of the arthritic ankle. This stimulation of the normal ankle also resulted in an expression of c-Fos in the contralateral deep, but not superficial laminae, that was similar to that induced ipsilaterally by stimulation of the arthritic ankle. Finally, formalin stimulation of the hindpaw skin (which was not inflamed) of the arthritic limb induced the same number of c-Fos labelled cells in the superficial laminae as did formalin stimulation of the skin of normal rats; but in the deep laminae there was a 1.6-fold increase in the number of labelled cells. These different observations show that the down-regulation of c-Fos expression observed in chronic monoarthritis is in fact associated with a sensitization and an extension of the field of its expression in response to an acute nociceptive stimulation.

Animals↗
PubMed1988

The c-Fos protein interacts with c-Jun/AP-1 to stimulate transcription of AP-1 responsive genes.

Cell lines stably transfected with metal inducible, MT-fos chimeric genes were used to study the ability of the c-fos gene product, Fos, to act as a transcriptional trans-activator. In 3T3MTfos cells, induction of Fos expression led to specific trans-activation of an AP-1 responsive reporter gene. Induction of Fos expression in F9MTfos cells, however, did not lead to trans-activation. Since, unlike NIH3T3 cells, F9 cells do not contain detectable levels of AP-1, we examined whether a c-Jun/AP-1 expression vector can restore the trans-activating effect of Fos in F9MTfos cells. Transfection with a functional c-Jun/AP-1 vector restored the specific trans-activating effect of Fos on AP-1 responsive constructs. When incubated with nondenatured cell extracts, anti-cFos antisera precipitated a protein complex composed of Fos and several Fos associated proteins (FAP). One of these, FAP p39, is structurally identical to c-Jun/AP-1. These results suggest that Fos is a trans-acting factor that is capable of stimulating gene expression not by direct binding to DNA but by interaction with the sequence-specific transcription factor AP-1. Therefore recognition of specific cis-elements by AP-1 is a prerequisite for Fos-mediated stimulation of gene expression.

Cell Line↗
PubMed1995

Fos protein immunoreactivity in the developing olfactory bulbs of normal and naris-occluded rats.

Immediate early genes such as c-fos may be a route through which extracellular events affect genomic expression. Expression of immediate early genes is important in the transcriptional regulation necessary for the normal development of the nervous system. Developmental patterns of Fos protein (the product of c-fos immediate early gene expression) were studied in the main olfactory bulb of the rat using immunocytochemistry. Embryonic Day 21 (E21, the last prenatal day), as well as Postnatal Day 0 (P0), P1, P5, P10, P15, P20 and P30 subjects were examined. Although staining was absent in the E21 bulb, there was a rapid onset of Fos synthesis within hours after birth. Distribution of Fos-immunoreactive (Fos-ir) nuclei corresponded to the sequence of bulb maturation: numerous mitral/tufted and granule cells were labeled on P0, followed by the appearance of Fos-ir in the nuclei of periglomerular cells and an increase in the number of stained granule cells with development. Surgical closure of an external naris on P1 resulted in a 70% reduction in the number of Fos-ir granule cell nuclei as early as 2 h after the manipulation. During the next 30 days, levels of Fos staining further diminished in experimental bulbs when compared to their contralateral controls. Nevertheless, electrical stimulation of the contralateral bulb in P20 pups resulted in a robust increase of Fos labeling in most main and accessory olfactory bulb mitral cells and in many granule and periglomerular neurons, suggesting that the experimental bulbs remain competent to express Fos protein.

Aging↗
PubMed1996

Peripherally and centrally administered bombesin induce Fos-like immunoreactivity in different brain regions in rats.

Bombesin (BBS) suppresses food intake when administered either peripherally or centrally to rats, but the brain systems involved in the anorectic action remain unclear. We addressed this question by examining Fos-like immunoreactivity (Fos-IR), a marker of neuronal activation, in rat brain following either intraperitoneal (i.p.) or 4th cerebroventricular (4V) administration of BBS. It was found that the hypothalamic paraventricular nucleus showed strong Fos-IR following either i.p. BBS in the dose range 20-80 micrograms/kg, or 4V BBS at a dose of 60 ng/rat. Additionally, different effects of i.p. and 4V BBS were observed in the following regions: (1) a strong Fos-IR was seen in the area postrema (caudal part) only following i.p. but not 4V BBS; (2) while i.p. BBS-induced Fos-IR was almost evenly distributed throughout the medial subdivision of the nucleus of the solitary tract, 4V BBS-induced Fos-IR was much stronger in the rostral part than in the caudal part of this region; (3) although the lateral parabrachial nucleus, the central nucleus of the amygdala and the bed nucleus of the stria terminalis showed strong Fos-IR following both i.p. and 4V BBS, subregional distribution of the Fos-IR was not the same. These sites were previously found to show strong Fos-IR after administration of either cholecystokinin (CCK) or dexfenfluramine (DF), but with different subregional distribution. The Fos-IR pattern induced by i.p. BBS was similar to that induced by CCK, and the Fos-IR pattern induced by 4V BBS was similar to that induced by DF.

Animals↗
PubMed1991

Dynorphin expression and Fos-like immunoreactivity following inflammation induced hyperalgesia are colocalized in spinal cord neurons.

Fos and Fos-related proteins are increased in spinal dorsal horn neurons following noxious stimulation. The laminar location of neurons that exhibit this increase is coincident with those that exhibit an increase in dynorphin in a rat model of peripheral inflammation and hyperalgesia. In order to determine whether the increase in Fos or related proteins and dynorphin occurs in the same dorsal horn neurons, two kinds of double-labeling methods were used: in situ hybridization histochemistry to label dynorphin mRNA autoradiographically, and immunocytochemistry to label Fos and Fos-related proteins, or a double immunocytochemical method that labeled Fos and Fos-related proteins and dynorphin peptide with distinct chromagens. With both methods more than 80% of the neurons in laminae I, II, V and VI exhibiting an increase in either dynorphin mRNA or peptide following peripheral inflammation also colocalized increased nuclear Fos-like immunoreactivity. However, the number of neurons displaying increased Fos-like immunoreactivity was substantially greater than the number of neurons colocalizing increased dynorphin. These data suggest that the activation of nuclear Fos and Fos-related proteins may be related to the induction of dynorphin gene expression in a subpopulation of spinal cord neurons following peripheral inflammation and hyperalgesia.

Animals↗
PubMed1996

Ketoprofen produces profound inhibition of spinal c-Fos protein expression resulting from an inflammatory stimulus but not from noxious heat.

This study assesses the anti-inflammatory/analgesic effects of ketoprofen a non-steroidal anti-inflammatory drug, using the method of c-Fos immunoreactivity at the spinal cord level in two models of noxious stimulation: carrageenan-induced inflammatory pain or acute noxious heat. Ketoprofen was pre-administered intravenously or orally 25 min before an intraplantar injection of carrageenan (6 mg in 150 microliters of saline) in hindpaw of the non-anaesthetised rat or before a single noxious heat (52 degrees C, 15 sec) stimulation of hindpaw of the anaesthetised rat. Three hours after carrageenan or 2 h after noxious heat, the number of spinal c-Fos protein-like immunoreactive (c-Fos-LI) neurons in L4-L5 segments and both the ankle and paw diameter, the indicator of peripheral oedema, were assessed. Pre-administered ketoprofen (1, 3 and 10 mg/kg i.v.) dose-dependently blocks the development of the carrageenan-induced spinal c-Fos protein expression and peripheral oedema, with the highest dose influencing in parallel both parameters (75 +/- 2% diminution of total number of c-Fos-LI neurons per L4-L5 section; 64 +/- 4% and 82 +/- 6% diminution of paw and ankle oedema, respectively). The effect of ketoprofen was significantly greater on the number of c-Fos-LI neurons in deep, as compared to superficial, laminae. Furthermore, the dose-dependent effects of ketoprofen on the carrageenan-induced spinal c-Fos protein expression and both the paw and ankle oedema were correlated. Oral pre-administration of ketoprofen (20 mg/kg) produced the blockage of development of the carrageenan-induced spinal c-Fos protein expression (65 +/- 3% diminution of total number of c-Fos-LI neurons per L4-L5 section) and peripheral oedema (20 +/- 3% and 59 +/- 10% diminution of paw and ankle oedema, respectively). In contrast, the same doses of both the intravenous and oral pre-administration of ketoprofen did not influence either the spinal c-Fos protein expression nor slightly enhanced paw diameter induced by a single noxious heat stimulation. This study suggests a predominant peripheral site, without excluding a central site of action of ketoprofen in the carrageenan-induced inflammation. The method of c-Fos protein-like immunoreactivity revealed ketoprofen to be more potent in comparison to members of other families of non-steroidal anti-inflammatory drugs, previously studied in the same experimental conditions of carrageenan-induced inflammatory pain.

Animals↗
PubMed1995

Haloperidol-induced Fos expression in striatum is dependent upon transcription factor cyclic AMP response element binding protein.

Haloperidol has been shown to induce rapid and transient expression of c-fos messenger RNA and Fos protein in striatal neurons via dopamine D2 receptors. Regulation of the c-fos gene by cyclic AMP and Ca2+ has been shown to be dependent on a DNA regulatory element within its promoter that binds the constitutively expressed transcription factor cyclic AMP response element binding protein. Cyclic AMP response element binding protein binds to an oligonucleotide containing the calcium/cyclic AMP response element of the c-fos promoter sequence in striatal cell extracts; the amount of binding is not regulated by haloperidol treatment. We have previously shown that haloperidol induces cyclic AMP response element binding protein phosphorylation in the striatum. Here we show by intrastriatal injection of antisense oligonucleotides that haloperidol-induced Fos expression is dependent on cyclic AMP response element binding protein. Intrastriatal injections of phosphorothioate oligonucleotides, in antisense orientation to cyclic AMP response element binding protein messenger RNA, reduce levels of cyclic AMP response element binding protein and completely prevent haloperidol-mediated induction of Fos. Oligonucleotides in sense orientation have no such effect. We observed a markedly different time course of the Fos protein inhibition by cyclic AMP response element binding protein antisense oligonucleotides compared to c-fos antisense oligonucleotides. This most likely reflects the different half-lives of c-fos and cyclic AMP response element binding protein messenger RNA and proteins. Neither cyclic AMP response element binding protein nor c-fos antisense oligonucleotide injection reduced c-Jun immunostaining in the striatum. We conclude that haloperidol induces Fos via transcription factor cyclic AMP response element binding protein.

Activating Transcription Factor 2↗
PubMed1996

c-Fos immunoreactivity in the sexually dimorphic area of the hypothalamus and related brain regions of male gerbils after exposure to sex-related stimuli or performance of specific sexual behaviors.

The sexually dimorphic area of the gerbil hypothalamus is essential for male sex behavior. To determine which aspects of mating activate its cells, or cells near or connected to it, we visualized c-Fos in the brains of male gerbils that had been exposed to various types of sex-related stimuli or that had displayed various aspects of sex behavior. Five groups of males were placed in familiar arenas containing sex-related odors. All subjects had previously mated in these arenas. For four groups, a female was introduced and remained with the male until he ejaculated, intromitted, mounted or sniffed her. Males in the fifth group remained in the arena alone. Males in a sixth group were placed in a clean arena in another room. These males were also familiar with this arena but had never encountered a female there. The seventh group remained in their home cages. The posterodorsal preoptic nucleus, the lateral part of the posterodorsal medial amygdala, the medial part of the sexually dimorphic area and the parvicellular part of the subparafascicular nucleus of the thalamus expressed c-Fos after ejaculation. Whether these cells triggered ejaculation or responded to it is not clear. The latter two areas also expressed c-Fos whenever males were exposed to the sex arena, but the sexually dimorphic area pars compacta did not express c-Fos under any condition. The medial core of the nucleus accumbens, the ventrolateral septum, the caudomedial bed nucleus of the stria terminalis, the medial/central part of the posterodorsal medial amygdala and the lateral part of the sexually dimorphic area also expressed c-Fos when males entered the sex arena. The ventrolateral part of the ventromedial nucleus of the hypothalamus expressed c-Fos whenever males were with females. None of the 31 areas studied responded to mounting or intromission, but the zona incerta, the amygdalohippocampal area, the lateral part of the sexually dimorphic area and the area lateral to the medial part of the sexually dimorphic area showed progressive increases in c-Fos expression as mating progressed. The area dorsal to the medial part of the sexually dimorphic area, the paraventricular nucleus of the hypothalamus, the ventral premammillary nucleus and the retrorubral field showed the same level of c-Fos expression when males were exposed to the non-sexual context as when they were exposed to the sexual one. While a projection to the retrorubral field from the sexually dimorphic area is critical for male sex behavior, the retrorubral field did not show a sex-related c-Fos response. The data suggest that brain regions involved in male sex behavior are involved in different aspects of it and that this can also apply to different subsets of cells in each area. The data also indicate that cells involved in mating do not necessarily show mating-related patterns of c-Fos expression. Thus, while c-Fos is useful for identifying areas involved in mating, or other behaviors, its characteristics could cause relevant areas to be overlooked.

Amygdala↗