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PubMed1998

Olfactory contribution to Fos expression during mating in inexperienced male hamsters.

Male hamsters are very dependent on chemosensory cues for normal mating behavior. We have previously reported that central, vomeronasal pathways are intensely and selectively activated during mating or pheromonal stimulation. The contribution of main olfactory sensory input to the patterns of c-fos activation was investigated in this study. Sexually inexperienced male hamsters were either made anosmic by intranasal infusion of zinc sulfate or remained intact. Fos protein immunoreactivity was analyzed in main olfactory and vomeronasal pathways of the zinc sulfate-treated, anosmic animals after mating with receptive females for 45 min, and compared with Fos patterns seen in intact mating animals, some of which have been described in a previous publication. The zinc sulfate-treated anosmic males described here all mated when given access to receptive females. Whether mated or unstimulated, anosmic males had little or no Fos expression in main olfactory pathways; significantly less even than in unstimulated intact animals. Mating did not increase Fos expression in main olfactory pathways of intact animals over that of unstimulated intact controls. However, Fos expression in central vomeronasal pathways was significantly higher in mating anosmic males, as in intact males, compared with appropriate non-mating controls. Fos expression was significantly different between intact and zinc sulfate-treated anosmic mating males in only one area studied. The rostral anterior medial amygdala, known to receive a small olfactory terminal field, had significantly lower Fos expression in zinc sulfate-treated anosmic males that mated when compared with intact-mating animals. Thus, functional main olfactory input to the rostral vomeronasal amygdala can be demonstrated but does not appear to be critical for mating behavior in previously inexperienced male hamsters with intact vomeronasal organs. Other main olfactory input appears to have a negligible contribution to Fos-patterns in such animals.

Animals↗
PubMed1990

Coupled and uncoupled induction of fos and jun transcription by different second messengers in cells of hematopoietic origin.

The nuclear oncoproteins fos and jun are associated as a heterodimer which binds to TPA (PMA or TPA: phorbol 12-myristate 13-acetate)- responsive promoter elements (TRE), the recognition site for the transcription factor AP-1. The fos/jun heterodimer has a higher affinity to the TRE and stimulates transcription of responsive genes more than the jun homodimer. The association of these two oncoproteins may play a central role in signal transduction and regulation of cell proliferation and differentiation. We further defined the regulation of fos and jun by studying their inducibility by second messengers in cells of hematopoietic origin. In THP-1 monocytic leukemia cells fos and jun mRNA levels are regulated in a coupled manner by second messengers activated after membrane phospholipid turnover. Addition of phospholipase C to cells, as well as stimulation of protein kinase C and release of intracellular Ca2+, caused a rapid induction of fos and jun mRNA levels, but the induction of jun mRNA showed a more persistant and less transient pattern than fos. In contrast to the phosphoinositol system, stimulation of the adenylate cyclase pathway in THP-1 cells induced only fos transcription whereas jun mRNA levels remained unchanged. A similar uncoupling of fos and jun inducibility was found after phorbol ester addition to the human erythroleukemia cell line HEL and the human promyelocytic cell line HL-60. The uncoupling of fos and jun levels might predispose cells to the formation of combinatorial transcription complexes of a different composition and activity than the fos/jun heterodimer. Indeed, nuclear extracts from THP-1 cells before or after activation of the phosphinositol or adenylate cyclase second messenger pathways revealed a correlation in fos and jun expression and specific binding of the heterocomplex to a TRE sequence.

Calcimycin↗
PubMed1991

Difference in transcriptional regulatory function between c-Fos and Fra-2.

Fra-2, one of the Fos-related antigens, is promptly expressed after the growth stimulation of fibroblasts, but its induction peak is later than that of c-Fos. In this report, we examined biochemical properties of Fra-2 and compared them with those of two other Fos family proteins, c-Fos and Fra-1. Like c-Fos and Fra-1, Fra-2 formed stable heterodimers with c-Jun, JunB or JunD in vitro and all these complexes had specific DNA-binding activity to AP-1-binding sites (AP-1 sites) or related sequences. When transiently introduced into a mouse embryonic carcinoma cell line, F9, with reporter genes containing the AP-1 site from the collagenase gene, fra-2 plus c-jun suppressed the transactivation by c-jun alone. This property of Fra-2 is in clear contrast to that of c-Fos, which stimulates the transcriptional activity of c-Jun by forming a stable heterodimer. Analysis of chimeric proteins between c-Fos and Fra-2 indicated that this difference is mainly attributable to their C terminal-half regions. Interestingly, this suppressive effect of Fra-2 was not observed in the combination with JunD: fra-2 plus junD, like c-fos plus junD, had higher transcriptional activity than junD alone. Fra-1 showed essentially the same transcriptional regulatory properties as Fra-2. These differential properties greatly expand the potential range of regulatory functions of the Fos family proteins.

Animals↗
PubMed1993

Hydrogen peroxide-induced c-fos expression is mediated by arachidonic acid release: role of protein kinase C.

We found previously that stimulation of c-fos and c-myc mRNA expression are early events in hydrogen peroxide-induced growth in rat aortic smooth muscle (RASM) cells. In the present study, we investigated the role of phospholipase A2 (PLA2) and protein kinase C (PKC) in mediating hydrogen peroxide-induced c-fos mRNA expression in RASM cells. Mepacrine and p-bromophenacylbromide, potent inhibitors of PLA2 activity, blocked hydrogen peroxide-induced c-fos mRNA expression. Arachidonic acid, a product of PLA2 activity, stimulated the expression of c-fos mRNA with a time course similar to that of hydrogen peroxide. PKC down-regulation attenuated both hydrogen peroxide and arachidonic acid-induced c-fos mRNA expression by 50%. Nordihydroguaiaretic acid (a lipoxygenase-cytochrome P450 monooxygenase inhibitor) significantly inhibited both hydrogen peroxide and arachidonic acid-induced c-fos mRNA expression, whereas indomethacin (a cyclooxygenase inhibitor) had no effect. Together, these findings indicate that 1) hydrogen peroxide-induced c-fos mRNA expression is mediated by PLA2-dependent arachidonic acid release, 2) both PKC-dependent and independent mechanisms are involved in hydrogen peroxide-induced expression of c-fos mRNA and 3) arachidonic acid metabolism via the lipoxygenase-cytochrome P450 monooxygenase pathway appears to be required for hydrogen peroxide-induced expression of c-fos mRNA.

Animals↗
PubMed2003

Cytoplasmic versus nuclear localization of Fos-related proteins in the frog, Rana esculenta, testis: in vivo and direct in vitro effect of a gonadotropin-releasing hormone agonist.

Evidence has been accumulated indicating that GnRH-like peptides are present in a variety of extrabrain areas of mammalian and nonmammalian vertebrates. A pioneer study carried out in the frog, Rana esculenta, demonstrated that testicular GnRH induced spermatogonial proliferation. Recently, we have shown that in proliferating spermatogonia (SPG) of frogs, a change of localization of the oncoprotein Fos, from the cytoplasm to the nucleus, occurs. This leads to the hypothesis that one or more testicular GnRH peptides may regulate SPG proliferation through Fos family proteins. Therefore, in vivo experiments in intact R. esculenta and in vitro incubations of testis fragments have been carried out using GnRH agonist (GnRHa; buserelin) and GnRH antagonist (D-pGlu(1),D-Phe(2),D-Trp(3,6)-GnRH). Cytoplasmic and nuclear Fos-like protein localization has been found by Western blot analysis in testicular extracts. Immunocytochemistry confirmed that cytoplasmic immunostaining was restricted to SPG; change of localization into the nuclear compartment was observed after GnRHa treatment. Northern blot analysis showed that treatments of testis fragments with GnRHa did not modify testicular c-fos mRNA expression. On the contrary, a Fos-like protein of 52 kDa, while not affected in vivo, disappeared from testicular cytosolic extracts after in vitro treatment with GnRHa. Contemporaneously, a 55-kDa Fos-related signal appeared in nuclear extracts. The GnRH antagonist counteracted the effects of GnRHa. Furthermore, in vivo treatments showed that GnRHa acted negatively on a 43-kDa nuclear Fos-related signal and that gonadotropins caused the decrease of 52-kDa cytoplasmic signal. In conclusion, we show, to our knowledge for the first time, that Fos is regulated by GnRHa directly (not through the pituitary) at the testicular level. The main effect appears to be related to Fos translocation from cytoplasmic to nuclear compartments of SPG.

Animals↗
PubMed1992

Role of [Ca2+]i in induction of c-fos, c-jun, and c-myc mRNA in rat PTE after oxidative stress.

Oxidative stress plays an important role in various types of cell injury and tumor promotion. Cells respond to oxidative stress in many ways including changes in membrane organization, ion movements, and altered gene expression, all of which contribute to the subsequent fate of affected cells. In this study, we investigated the expression of the proto-oncogenes c-fos, c-myc, and c-jun, which play a key role in proliferation and differentiation, using primary cultures of rat proximal tubular epithelium exposed to oxidative stress generated by the xanthine/xanthine oxidase system. This system generates superoxide and H2O2 in the extracellular space stimulating the release of active oxygen species from inflammatory cells. c-fos mRNA was expressed within 15 min, peaked at 30 min, and returned to constitutive levels by 3 h. c-jun mRNA began to rise after 30 min, peaked at 120 min, and remained above the constitutive levels up to 180 min. c-myc mRNA expression was less affected by the treatment, with levels increasing gradually over the 180 min period. The expression of c-fos was inhibited by superoxide dismutase but not by catalase and was super-induced by cycloheximide. H2O2 alone did not induce any c-fos mRNA in this system. Chelation of extracellular ionized calcium by EGTA or of intracellular ionized calcium by Quin 2/AM resulted in a marked decrease of c-fos expression. Two protein kinase C inhibitors, H-7 and staurosporine, partly diminished the expression of c-fos, whereas a third, 2-aminopurine, which has a broader spectrum of inhibiting protein kinases, almost completely abolished it. A poly ADP-ribosylation inhibitor, 3-aminobenzamide, had no effect on c-fos expression in this system. Our results show that oxidative stress provokes sequential expression of c-fos, c-jun, and c-myc, mRNA in this order. This c-fos expression appears to be largely controlled by calcium ion movement, which could include protein kinase C activation. Another protein kinase or kinases also appear to play an important role.

Alkaloids↗
PubMed1998

Electroacupuncture decreases c-fos expression in the spinal cord induced by noxious stimulation of the rat bladder.

PURPOSE: The present study investigated the effects of noxious stimulation of the lower urinary tract on neuronal fos protein expression in the spinal micturition center of rats and also examined the effects of electroacupuncture (EA) on fos expression induced by noxious stimulation of the lower urinary tract. MATERIALS AND METHODS: Experiments were conducted on 21 female Sprague-Dawley rats divided into four groups. Group 1 rats (n = 5) served as normal controls. Group 2 rats (n = 5) received EA at the Sanyinjiao acupoint. Group 3 animals (n = 6) were catheterized through the urethra and instilled with 1% acetic acid, and group 4 (n = 5) animals received EA 1 hour before 1% acetic acid instillation. All animals underwent arterial perfusion, laminectomy, and spinal cord removal. Spinal cords were sectioned and processed for immunohistochemical staining for fos protein. RESULTS: No fos protein was detected in any spinal neurons in normal control animals, and either none or few (0 to 4 cells/section) fos-immunoreactive (fos-IR) cells were seen in animals treated with EA. Noxious stimulation of the lower urinary tract with 1% acetic acid drastically increased the number of fos-IR neurons (30 to 127 cells/L6 section, mean 76.17+/-13.98; 28 to 77, cells/S1 section, mean 59+/-8.30; 7 to 35 cells/S2 section, mean 19.83+/-4.10). However, EA administered 1 hour before 1% acetic acid instillation significantly decreased the number of fos-IR neurons resulting from chemical irritation (0 to 50 cells/L6 section, mean 19.8+/-9.33; 0 to 47 cells/S1 section, mean 13.2+/-9.12; 0 to 37 cells/S2 section, mean 13.6+/-7.31). CONCLUSIONS: Our study demonstrates that bladder instillation with 1% acetic acid induces fos protein expression in the spinal micturition center of the rat and that electroacupuncture can reduce this expression. These results suggest a link between electroacupuncture and reduction in spinal neuronal cell activity.

Acetic Acid↗
PubMed1999

Expression and changes of Fos protein in the rat forebrain after gamma knife irradiation targeted to the caudate putamen.

OBJECTIVE: Forebrain expression and changes of Fos protein immunoreactivity were investigated in rats subjected to gamma knife irradiation (dose, 100 Gy), focusing on the right caudate nucleus. METHODS: Serial cryostat forebrain sections were processed with Fos protein antiserum and then by avidin-biotin-peroxidase complex immunohistochemistry after gamma knife irradiation. RESULTS: Some neurons, glial cells, and endothelial cells were positive for Fos-like immunoreactivity (LI). Fos-LI was mainly distributed in the target area of irradiation, as well as in white matter surrounding lateral ventricles, cortex, hippocampus, and certain nuclei reportedly implicated in the regulation of stress responses. From 0.5 hour to 30 days after irradiation, expression of Fos-LI displayed two peaks. The first peak arose from 3 hours to 24 hours, with cell nuclei being positive for Fos-LI. The second peak was noticeable at the 14th day postirradiation. Subsequently, three types of Fos-LI-positive cells were identified during the period between 14 and 30 days: in the first type, only the nucleus was positive; in the second type, the cytoplasm was stained; and in the third type, the cells were positive in both the nucleus and the cytoplasm. CONCLUSION: During the early stages after gamma knife irradiation, a specific stress response (significant Fos expression with two peaks) is observed not only in the target region but also in the surrounding forebrain regions. The characteristics and significance of two types of Fos-LI-positive cells are discussed in the context of this investigation.

Animals↗
PubMed2000

Fos expression in the rat brain and spinal cord evoked by noxious stimulation to low back muscle and skin.

STUDY DESIGN: Acute noxious stimulation delivered to lumbar muscles and skin of rats was used to study Fos expression patterns in the brain and spinal cord. OBJECTIVES: The present study was conducted to determine the differences in Fos expression in the brain and spinal cord as evoked by stimuli delivered to lumbar muscles and skin in rats. SUMMARY OF BACKGROUND DATA: Patients with low back pain sometimes show psychological symptoms, such as quiescence, loss of interest, decreased activities, appetite loss, and restlessness. The pathway of deep somatic pain to the brain has been reported to be different from that of cutaneous pain. However, Fos expression has not been studied in the central nervous systems after stimulation of low back muscles. METHODS: Rats were injected with 100 L of 5% formalin into the multifidus muscle (deep pain group; n = 10) and into the back skin of the L5 dermatome (cutaneous pain group; n = 10). Two hours after injection, the distribution of Fos-immunoreactive neurons was studied in the brain and spinal cord. RESULTS: Fos-immunoreactive neurons were observed in laminae I-V in the spinal cord in the cutaneous pain group, but they were not seen in lamina II in the deep pain group. In the brain, Fos-immunoreactive neurons were significantly more numerous in the deep pain group than in the cutaneous pain group in the piriform cortex, the accumbens nucleus core, the basolateral nucleus of amygdala, the paraventricular hypothalamic nucleus, the ventral tegmental area, and the ventrolateral periaqueductal gray. CONCLUSION: The finding that Fos-immunoreactive neurons were absent from lamina II of the spinal cord in the deep pain group is similar to that of the projection pattern of the visceral pain pathway. Fos expression in the ventrolateral periaqueductal gray in the deep pain group may represent a reaction of quiescence and a loss of interest, activities, or appetite. Furthermore, the detection of large numbers of Fos-immunoreactive neurons in the core of accumbens nucleus, basolateral nucleus of amygdala, paraventricular hypothalamic nucleus, and ventral tegmental area in the deep pain group may suggest a dominant reaction of dopaminergic neurons to stress, and a different information processing pathway than from that of cutaneous pain.

Animals↗
PubMed1988

Fos and Jun bind cooperatively to the AP-1 site: reconstitution in vitro.

The protein products of the fos (Fos) and jun (Jun) proto-oncogenes have been shown to associate with a DNA element known as the transcription factor activator protein-1 (AP-1) binding site. Jun (previously known as the Fos-binding protein p39) and Fos form a protein complex in the nucleus. To investigate the nature of the association of Fos and Jun with the AP-1 site, and to determine the role of protein complex formation in DNA-binding, we have reconstituted the protein-protein and protein-DNA interactions in vitro using Fos and Jun synthesized in reticulocyte lysates. The Fos-Jun complex formed extremely rapidly in vitro and possessed similar, though not identical, chromatographic and sedimentation properties to the complex isolated from cell extracts. Jun exhibited a low level of AP-1 binding activity; however, this was evident only at high concentrations of DNA. Fos did not bind to the AP-1 site on its own; however, it acted cooperatively with Jun to give enhanced DNA-binding activity. The increased affinity of the Fos-Jun complex for DNA resulted from a stabilization of the protein-DNA complex. These data demonstrate a cooperative interaction between the protein products of two proto-oncogenes with a DNA element involved in transcriptional regulation.

Allosteric Regulation↗
PubMed2004

Cytoplasmic c-Fos induced by the YXXQ-derived STAT3 signal requires the co-operative MEK/ERK signal for its nuclear translocation.

A STAT3 (signal transducer and activator of transcription 3)- and a MEK/Erk-mediated signal can be activated by cytokines, including IL-6 (interleukin-6), PDGF, and EGF. Recently, STAT3 and an ERK-signal were shown to co-operatively activate the c-fos gene. Activation of a truncated form of the IL-6 receptor subunit, gp130, that had only one YXXQ motif, induced both c-Fos and JunB in NIH3T3 cells through STAT3 without an apparent increase in the AP-1 (activator protein-1) activity. In contrast, concomitant stimulation of the STAT3 signal and a MEK/Erk-signal markedly increased AP-1 activity with enhanced c-Fos expression. Surprisingly, the c-Fos induced by the YXXQ-signal alone was localized to the cytoplasm, from which it translocated into the nucleus following TPA (12-O-tetradecanoyl-phorbol 13-acetate) treatment in a MEK/Erk-dependent manner. c-Fos that was expressed from a constitutive promoter localized to the nucleus and did not move into the cytoplasm in response to the YXXQ-signal. Rather, the YXXQ-signal was required during c-Fos production for it to be retained in the cytoplasm. Thus, the YXXQ-signal induces c-Fos expression through STAT3 and anchors the new c-Fos in the cytoplasm. In addition, the YXXQ-signal and an Erk signal co-operatively cause c-Fos activation in the nucleus.

Active Transport, Cell Nucleus↗
PubMed2005

Sex differences in Fos protein expression in the neonatal rat brain.

Sex differences in the brain and behaviour are mostly a result of transient increases in testosterone during the perinatal period. Testosterone influences brain development primarily through aromatization to oestradiol and subsequent binding to oestrogen receptors. Although some studies report that steroid hormones regulate the expression of the inducible transcription factor, Fos, in developing brain, it is not known if there is a sex difference in Fos expression. Changes in Fos protein can be used as an indicator of neuronal/genomic activity. Thus, it provides a useful tool to identify brain regions responding directly or indirectly to steroid hormones. In a first experiment, we examined Fos protein expression in the developing male and female rat brain using western immunoblotting. Dissections were taken from male and female rat pups on the day of birth (postnatal day 0; PN 0), PN1, PN5, PN11 or PN20. Although there was no difference on PN 0, males expressed significantly greater levels of Fos protein on PN1, PN5 and PN20. In a second experiment, we localized the sex difference in Fos protein expression using immunocytochemistry. We found that males expressed significantly higher levels of Fos within a variety of brain regions. These data indicate a sex difference in Fos protein expression during brain development, suggesting a potential role for Fos in differentiating male from female rat brain.

Age Factors↗
PubMed1990

Characterization of fos-induced osteogenic tumours and tumour-derived murine cell lines.

Osteogenic tumours from c-fos (MT-c-fos-LTR)-transgenic mice and from mice infected with the v-fos-bearing FBR murine osteosarcoma virus (FBR MSV) showed close morphological and neoplastic similarities. Fos mRNA expression was elevated in both types of tumours, and expression of several genes characteristic of differentiated bone cells was either lower, enhanced, or not detectable in comparison to that in normal bone. Tumour-derived cell lines showed variable levels of exogenous fos expression; bone-cell-specific genes were similarly expressed in both primary tumours and tumour-derived cell lines. Upon transplantation the tumour cells formed fibrosarcomas, some of which contained areas of focal osseochondrous differentiation. Non-tumorigenic cell lines established from bone tissue of normal and MT-c-fos-LTR transgenic mice showed osteoblastic characteristics, whereas no parathyroid hormone (PTH) response was observed in transgenic tumour cell lines in spite of high alkaline phosphatase activity. These data indicate that deregulated fos expression interferes with terminal osteogenic differentiation in v-fos- and c-fos-induced bone tumours.

Alkaline Phosphatase↗
PubMed1995

Thermal sensitivity in NIH 3T3 fibroblasts transformed by the v-fos oncogene. Correlation with reduced accumulation of 68-kDa and 25-kDa stress proteins after heat shock.

The effect of v-fos transformation on the cellular response to heat shock has been investigated. NIH 3T3 fibroblasts were transfected with the FBR p75gag-fos gene fusion under the control of the long terminal repeat (LTR) promoter of Finkel-Biskin-Reilly (FBR) murine sarcoma virus and with the gene encoding hygromycin resistance. Several hygromycin-resistant clone isolates, that expressed various levels of p75gag-fos oncoprotein, were analyzed as they displayed properties of transformed cells, such as altered morphology, shorter doubling time, serum-independent growth and foci formation in soft agar. The thermal response of these clones was compared to that of the control cells expressing the hygromycin-resistance gene only. Here, we report that the v-fos-transformed clones displayed an enhanced thermosensitivity which resulted in a reduced tolerance to thermal stress. Heat-treated v-fos-transformed cells displayed a decreased expression and accumulation of the major stress proteins Hsp68 (68-kDa heat-shock protein) and Hsp25 which probably resulted of a reduced accumulation of the corresponding mRNAs. This effect was particularly intense at the level of Hsp25. These alterations in cell survival and stress-protein expression appeared correlated to the level of p75gag-fos. At least for Hsp68, the transcription of this gene was not found altered by v-fos expression suggesting that this oncogene increases the turn-over of Hsp68 mRNA. After the heat-shock treatment, v-fos transformation also reduced the time period during which the constitutively expressed stress protein Hsc70 redistributes inside the nucleus. Since Hsp68 and Hsp25 are molecular chaperones that in vivo protect cells against the deleterious effects of heat shock, it is conceivable that their reduced accumulation and altered cellular distribution following heat shock may contribute, at least in part, to the thermosensitivity of v-fos-transformed NIH 3T3 fibroblasts.

3T3 Cells↗
PubMed1996

Differences in c-fos gene product expression in cancers of the gall-bladder and biliary tract.

The c-fos gene encodes a 55 kDa nuclear protein product that complexes to a cellular protein, p39. The pattern of expression of c-fos is particularly complex with increased expression of the protein observed in undifferentiated cultured cells while reduced expression is found during terminal differentiation. The expression of c-fos gene was studied by immunohistochemistry in carcinoma of the gall-bladder (n = 13), biliary tract (n = 5) and ampulla of Vater (n = 9). Non-malignant conditions investigated include chronic cholecystitis (n = 11), gall-bladder dysplasia (n = 3) and adenoma (n = 1), and ampullary carcinoma in situ (n = 3). Strong positive granular cytoplasmic immunostaining for c-fos oncoprotein was present in most gall-bladder adenocarcinomas (n = 11; 85%). The single gall-bladder adenoma and only one of the dysplasia cases were positive. Most of the cases of chronic cholecystitis showed either absent or only focal to patchy and weak to moderate c-fos immunoreactivity in the deeper glands and Rokitansky-Aschoff sinuses but not in the superficial epithelium. None of the biliary tract and ampullary tumors showed immunostaining for c-fos. The difference in c-fos immunoreactivity between gall-bladder carcinoma and chronic cholecystitis was statistically significant (P = 0.0002; chi 2 test with continuity correction). In conclusion, c-fos protein may be important in the development of gall-bladder neoplasia with increased c-fos immunoreactivity in gall-bladder carcinoma but not in chronic cholecystitis, biliary tract and ampullary neoplasms. These findings suggest that gall-bladder carcinoma may arise from a different genetic basis compared to biliary tract and ampullary cancers.

Adenoma↗
PubMed1995

Glutamate induces c-fos proto-oncogene expression and inhibits proliferation in oligodendrocyte progenitors: receptor characterization.

The effect of glutamate on c-fos expression in oligodendrocyte progenitors was investigated by Northern blot analysis. Glutamate caused rapid and transient induction. Both 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) and 6,7-dinitroquinoxaline-2,3-dione (DNQX), two competitive non-NMDA ionotropic receptor antagonists, reduced glutamate-induced c-fos expression, whereas the NMDA antagonist MK-801 was ineffective. In addition, the glutamate receptor agonists (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrobromide (AMPA) and kainate strongly induced c-fos. However, the metabotropic receptor agonist trans-(+/-)-1-amino-(1S,3R)-cyclopentanedicarboxylic acid (trans-(+/-)-ACPD) did not increase c-fos mRNA level and the antagonist L-(+)-2-amino-3-phosphonopropionic acid did not block glutamate-induced c-fos mRNA. These findings indicate that c-fos induction in oligodendrocyte progenitors is mediated through the AMPA/kainate receptors, while NMDA and metabotropic receptor subtypes are not involved. Chelation of extracellular calcium by EDTA prevented glutamate-induced c-fos expression. Similarly, the protein kinase C inhibitor 1-(5-isoquinoline-sulphonyl)-2-methylpiperazine dihydrochloride (H7) and down-regulation of protein kinase C by prolonged exposure to phorbol-12-myristate 13-acetate blocked c-fos induction. These results suggest that induction of c-fos through AMPA/kainate receptors is dependent on extracellular calcium influx and involves downstream activation of phorbol ester-sensitive protein kinase C. The effect of glutamate on oligodendrocyte progenitor proliferation was assessed by [3H]thymidine incorporation. Glutamate and the agonists kainate and AMPA, but not trans-(+/-)-ACPD, caused a dose-dependent decrease in [3H]thymidine incorporation. All these pharmacological agents were not toxic to oligodendrocyte progenitors. CNQX reversed the inhibitory effects produced by glutamate and the various agonists. These results suggest that glutamate may modulate the growth and differentiation of oligodendrocytes in the central nervous system.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1997

Prevention of kainic acid-induced limbic seizures and Fos expression by the GABA-A receptor agonist muscimol.

Fos oncoprotein expression has been shown to be a sensitive marker for sequential neuronal activation in response to a specific stimulus. The present study investigated the effect of the gamma-aminobutyric acid (GABA)-A receptor agonist muscimol on kainic acid (KA)-induced limbic seizures and Fos expression in the rat forebrain. One hour after KA injection, a substantial Fos expression was observed in the hippocampal dentate gyrus, whereas only a low level of Fos induction was seen in CA1-3 fields. Six hours post-injection a prominent increase of Fos expression occurred in most forebrain structures, including the whole hippocampus. Following 0.5 mg/kg muscimol treatment a remarkable decrease of Fos expression occurred but only in the caudate putamen and core of the accumbens nucleus. Treatment with 1 mg/kg muscimol led to further significant decreases of Fos expression in CA1-3 pyramidal neurons and the disappearance of Fos induction in the cerebral cortex above the rhinal fissure, reticular thalamic nucleus, claustrum, fundus striati, ventral pallidum, septal nucleus, lateral habenular nucleus, and lateral amygdaloid nucleus. When 2 mg/kg muscimol was injected, animals exhibited "absence seizures' instead of limbic seizures, and Fos expression in the hippocampus was effectively blocked. These results suggest that a reduction of GABAergic inhibition plays a crucial role not only in limbic seizure genesis in the dentate gyrus, but also in the seizure spread mechanism in many brain structures, among which the hippocampal CA1-3 fields are most markedly involved, less marked in the cerebral cortex and some other structures, and least marked in the caudate putamen and core of the accumbens nucleus.

Animals↗
PubMed2005

CGRP release and c-fos expression within trigeminal nucleus caudalis of the rat following glyceryltrinitrate infusion.

Neuropeptide release and the expression of c-fos like immunoreactivity (c-fos LI) within trigeminal nucleus caudalis neurons (TNC) are activation markers of the trigeminal nerve system. Glyceryltrinitrate (GTN) is believed to stimulate the trigeminal nerve system, thereby causing headache. We examined the effects of a 30 min NO-donor infusion on CGRP release in jugular vein blood and c-fos LI within TNC of the rat. GTN (2 and 50 microg/kg/min) or NONOate infusion (25 nmol/kg/min) did not cause any CGRP release during and shortly after infusion, whereas administration of capsaicin resulted in strongly increased CGRP levels. GTN infusion (2 microg/kg/min for 30 min) did not lead to enhanced c-fos LI after 2 h and 4 h, whereas capsaicin infusion caused a time- and dose-dependent expression of c-fos LI within laminae I and II of the TNC. Surprisingly, GTN attenuated capsaicin-induced c-fos expression by 64%. The nitric oxide synthase (NOS) inhibitor L-NAME (5 and 50 mg/kg) reduced capsaicin-induced c-fos LI dose dependently (reduction by 13% and 59%). We conclude that GTN may lead to headaches by mechanisms independent of CGRP release from trigeminal nerve fibres. GTN doses comparable to those used in humans did not activate or sensitize the trigeminal nerve system. Both GTN and L-NAME reduced capsaicin-induced c-fos LI. This is most likely due to a feedback inhibition of nitric oxide synthases, which indicates that the c-fos response to capsaicin within TNC is mediated by NO dependent mechanisms.

Animals↗