Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Earlier behavioural studies have shown that the expression of the immediate-early gene c-fos, as visualized by the immunohistochemical detection of Fos, in the inferior olive (IO) correlated closely with expression in related areas of the cerebellar nuclei. It has been speculated that the expression of c-fos within the cerebellar nuclei may be induced by enhanced spiking activity of the immunopositive neurons in the inferior olive. Two potential mechanisms may play a role in this process: a direct induction by way of the collaterals of the olivary climbing fibres to the cerebellar nuclei, or indirectly, by climbing fibre activity-induced depression of mossy fibre-parallel fibre-induced simple spike frequency of the Purkinje cells resulting in a subsequent disinhibition of the related parts of the cerebellar nuclei. In an attempt to distinguish between these possible mechanisms, we analysed Fos immunoreactivity in the olivocerebellar system of wild-type mice and in the mutant mouse Lurcher which lacks Purkinje cells. The tremorgenic agent harmaline, which is known to induce enhanced and rhythmic firing of olivary neurons was given intraperitoneally to anaesthetized mice of both genotypes. Harmaline application coincides with the induction of Fos-immunoreactive neurons in most areas of the IO in both wild-type and Lurcher mice. Both types of mice also showed enhanced expression in the larger neurons of the cerebellar nuclei. However, in the smaller, GABAergic nucleo-olivary neurons, increased c-fos expression was only observed in the wild-type mice. We conclude that: (i) increased olivary activity indeed may result in increased c-Fos expression in related areas of the cerebellar nuclei; (ii) because the indirect mode of induction is not operative in Lurcher mice, the olivary collateral innervation of the cerebellar nuclei is sufficient for c-fos induction in the larger nucleobulbar neurons in Lurcher and potentially also in wild-type mice; however (iii) for the nucleo-olivary cells an intact cerebellar cortical input is necessary to evoke increased expression of c-fos following harmaline application.
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PMID:Inferior olivary-induced expression of Fos-like immunoreactivity in the cerebellar nuclei of wild-type and Lurcher mice. 1058 70

The hypotheses that cerebral embolic events lead to repetitive episodes of cortical spreading depression (CSD) and that these propagating waves trigger the expression of c-fos, brain-derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP), and heat shock protein 70 (HSP70) mRNA were tested. Wistar rats underwent photochemically induced right common carotid artery thrombosis (CCAT) (n = 18) or sham (n = 8) procedures. In a subgroup of rats (n = 5), laser-Doppler flowmetry probes were placed overlying the right parietal cortex to record CSD-like changes in cortical blood flow during the initial 2-hour postinjury period. Rats were killed by decapitation at 2 or 24 hours after CCAT, and brains were processed for in situ localization of the gene expression. Two to five intermittent transient hyperemic episodes lasting 1 to 2 minutes were recorded ipsilaterally after CCAT. At 2 hours after CCAT, the widespread expression of c-fos and BDNF mRNAs was observed throughout the ipsilateral cerebral cortex. Pretreatment with the N-methyl-D-aspartate receptor blocker MK-801 (2 mg/kg) 1 hour before CCAT reduced the expression of BDNF mRNA expression at 2 hours. At 24 hours after CCAT, increased expression of GFAP mRNA was present in cortical and subcortical regions. In contrast, multifocal regions of HSP70 expression scattered throughout the thrombosed hemisphere were apparent at both 2 and 24 hours after injury. These data indicate that thromboembolic events lead to episodes of CSD and time-dependent alterations in gene expression. The ability of embolic processes to induce widespread molecular responses in neurons and glia may be important in the pathogenesis of transient ischemic attacks and may influence the susceptibility of the postembolic brain to subsequent insults including stroke.
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PMID:Thromboembolic events lead to cortical spreading depression and expression of c-fos, brain-derived neurotrophic factor, glial fibrillary acidic protein, and heat shock protein 70 mRNA in rats. 1061 98

These experiments examined the role of substance P-selective neurokinin 1 receptors in the restraint-induced activation of the rat locus coeruleus. Immunohistochemistry revealed high levels of neurokinin 1 receptor expression in the plasma membrane of tyrosine hydroxylase-positive locus coeruleus neurons. The selective neurokinin 1 receptor antagonists, RP 67580 (5 nmol) and L-760,735 (3.4 nmol), were administered intracerebroventricularly prior to restraint stress, and c-fos protein was measured as an index of locus coeruleus activation. Both antagonists attenuated the restraint-induced increase in locus coeruleus c-fos expression, whereas their inactive enantiomers were ineffective. These results suggest that neurokinin 1 receptors may mediate activation of locus coeruleus neurons during stress. Neurokinin 1 receptor antagonists may prove to be novel therapeutic compounds in the treatment of anxiety and depression.
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PMID:Stress-induced C-fos expression in the rat locus coeruleus is dependent on neurokinin 1 receptor activation. 1062 57

(1S, 2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606) is a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors containing the NR2B subunit. This compound was used to investigate the role of NR2B containing receptors in three responses to NMDA receptor activation in vivo. In mouse, CP-101,606 completely inhibited increases in fos-like immunoreactivity in dentate gyrus caused by a subconvulsant intraperitoneal dose of NMDA. In rat, the compound completely blocked cortical c-fos mRNA induction following focal injury in parietal cortex and the initiation and propagation of electrically induced cortical spreading depression. Inhibition of these responses by CP-101,606 indicates that c-fos induction and cortical spreading depression are dependent on activation of NMDA receptors containing the NR2B subunit. Since NMDA receptor dependent c-fos induction and cortical spreading depression may contribute to neuron loss after focal CNS injury, inhibition of these responses by CP-101,606 may contribute to the neuroprotective efficacy of the compound.
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PMID:CP-101,606, an NR2B subunit selective NMDA receptor antagonist, inhibits NMDA and injury induced c-fos expression and cortical spreading depression in rodents. 1076 Mar 58

Intrathecal administration(i.t.) of Dynorphin A1-17(Dyn) 1.25-20 nmol produced dose-dependent paralysis of hindlimbs and tail as well as inhibition of tail flick and foot flinch reflexes. The Dyn spinal neurotoxicity and antinociception involve two differential mechanisms: Enhancement of NMDA-Ca(2+)-NOS/NO pathway and c-fos over-expression in the ventral spinal cord for neurotoxicity, and depression of NMDA receptor and NOS activities in the dorsal spinal cord for antinociception. Both brain-derived constitutive NOS (predominant at early stage) and inducible NOS (at later stage) are detrimental, but endothelial constitutive NOS might be beneficial to Dyn spinal neurotoxicity. Dyn exerts a dualistic modulatory effect on [Ca2+]i of the cultured rat single spinal neurons, inducing sustained overload of intracellular free calcium via both NMDA and kappa receptor activation at higher concentrations, and producing significant inhibition of the depolarization-evoked calcium influx only via kappa receptor activation at lower concentrations. Dyn exposure for 1 h produced direct neurotoxicity in the cultured spinal neurons within an optimal range of concentrations.
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PMID:[Effects of dynorphin A1-17 on the activities, immunoreactivities and mRNA expression of cNOS and iNOS in rat spinal cord and their mechanisms]. 1092 Oct 77

Spreading depression (SD) is a wave of sustained depolarization challenging the energy metabolism of cells without causing irreversible damage. SD is a major mechanism of gene induction that takes place in cortical injury, including ischemia. We studied the role of oxygen radicals in SD-induced c-fos and cyclooxygenase-2 (COX-2) induction using transgenic (Tg) mice that overexpress copper/zinc-superoxide dismutase (SOD1). The frequency, amplitude and duration of SD waves were similar in the Tg mice and wild-type littermates. c-fos and COX-2 mRNAs were strongly induced 1 and 4 h after SD. The induction of both genes was slightly but significantly less at 4 h in the Tg mice. The results indicate that even a mild, noninjurious metabolic stimulation increases the concentration of oxygen radicals to the level that contributes to gene expression.
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PMID:Spreading depression-induced expression of c-fos and cyclooxygenase-2 in transgenic mice that overexpress human copper/zinc-superoxide dismutase. 1097 46

Unilateral, focal cerebrocortical lesion (FCL) and associated spreading depression (SD) increase immediate-early gene (IEG) expression throughout the ipsilateral hemisphere. Noradrenergic transmission is involved in the regulation of basal- and stimulation-induced expression of IEGs in cerebral cortex; and is modulated by both injury and SD. The present study further investigated the association between the noradrenergic system and cortical adaptive responses, by examining basal and FCL(SD)-induced cortical IEG expression following acute treatment with alpha(1)-, alpha(2)- and beta(1/2)-adrenoceptor (AR) agonists or antagonists. Activation of alpha(1)-ARs by NVI-085, or beta-ARs by salbutamol, increased cortical NGFI-A, c-jun and c-fos mRNA levels, whereas inhibition of alpha(1)-ARs by prazosin, or beta-ARs by propranolol, had no marked effect. The alpha(2)-AR agonists, clonidine and UK14304 also had no effect on basal IEG levels, while blockade of alpha(2)-ARs by methoxyidazoxan significantly increased NGFI-A and c-fos expression, but decreased c-jun mRNA levels. This latter effect confirms the complex and differential nature of IEG regulation in brain. In FCL(SD) rats, all AR agonists generally produced a supra-additive (synergistic) effect on expression of the examined IEGs, compared with drug-treatment or FCL alone. Prazosin reduced FCL(SD)-induced elevations of c-jun and c-fos, but not NGFI-A, mRNA. Methoxyidazoxan enhanced NGFI-A and c-fos mRNA expression after FCL(SD), but reduced c-jun. Propranolol enhanced all lesion-induced IEG levels. These results confirm that alpha(1)- and beta-ARs normally mediate a stimulatory, and alpha(2)-ARs a net inhibitory, influence on cortical cell activity (reflected by NGFI-A, c-fos expression); and demonstrate that alterations in noradrenergic tone modulate the level of cellular activation during and after SD, which is primarily elicited by K(+)/glutamate via NMDA receptors and Ca(2+)-associated mechanisms. In turn, noradrenergic transmission and interactions with excitatory systems are likely to be important in responses to brain injury, including regulation of IEGs and their downstream target genes.
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PMID:Differential modulatory effects of alpha- and beta-adrenoceptor agonists and antagonists on cortical immediate-early gene expression following focal cerebrocortical lesion-induced spreading depression. 1107 4

The effects of mild hypothermia on the apparent diffusion coefficient of water (ADC) and expression of c-fos and hsp70 mRNA were examined during acute focal cerebral ischemia. Young adult rats were subjected to 60-min middle cerebral artery occlusion under either normothermia (37.5 degrees C) or hypothermia (33 degrees C). Diffusion-weighted echo-planar magnetic resonance imaging was used to monitor changes in ADC throughout the ischemic period. Perfusion MRI with dysprosium contrast was used at the end of the ischemic period to verify that the occlusion was successful. C-fos and hsp70 mRNA expression were examined with in situ hybridization at the end of the ischemic period. The results indicate that the size of the region that exhibited reduced ADC was smaller during hypothermia than during normothermia. Hypothermia also decreased the frequency of occurrence of transient ADC reductions, especially in dorsal aspects of cortex. Expression of both c-fos and hsp70 mRNA were markedly reduced by hypothermia. Transient ADC reduction and c-fos expression are associated with spreading depression, which is believed to contribute to lesion expansion during acute focal ischemia. The results suggest that part of the neuroprotective effect of hypothermia may be due to a reduced incidence of spreading depression.
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PMID:Mild hypothermia decreases the incidence of transient ADC reduction detected with diffusion MRI and expression of c-fos and hsp70 mRNA during acute focal ischemia in rats. 1113 87

The effects of anesthetics on the generation of cortical spreading depression (CSD) were investigated. Volatile anesthetics halothane, isoflurane, sevoflurane (0.5, 1.0, and 2.0 MAC), and the intravenous anesthetic pentobarbital were studied. Cortical spreading depression was induced by 3M-KCl applied to a surface of brain cortex for 30 minutes. Direct current (DC) potential was recorded, and the number, amplitude, and duration of CSDs were observed. With increasing concentrations of each volatile anesthetic, there was a dose-related reduction in CSD frequency but not in CSD amplitude. At 2.0 MAC of sevoflurane the suppression of CSD was less than with the other volatile anesthetics. In addition, the influence of anesthetics on expression of c-fos mRNA was investigated. Additional animals anesthetized by isoflurane or sevoflurane were studied. Five CSDs were elicited by electric stimulation (0.5 mV, 1 second) in each animal. In situ hybridization with 35S-labeled oligonucleotides was used to evaluate the level of c-fos mRNA. The expression of c-fos was observed in the hemisphere in which CSD was elicited, but there was no difference in expression of c-fos among the groups. We conclude that volatile anesthetics can induce suppression of CSD elicitation in a dose dependent manner, but that at high concentrations sevoflurane is significantly less effective than other volatile agents. Pentobarbital has the least effect on KCl-induced CSD. These data suggest that the choice of anesthetics can impact the results of studies examining membrane depolarization and the ionic changes initiated by CSD.
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PMID:The effects of anesthetics on cortical spreading depression elicitation and c-fos expression in rats. 1114 74

The ability of the antagonists for the N-methyl-D-aspartate (NMDA) type of glutamate receptor to modulate locomotor activity were compared in alcohol-sensitive (or alcohol-nontolerant, ANT) and alcohol-insensitive (or alcohol-tolerant, AT) rat lines. Both rat lines showed altered locomotor activity after acute injections of a competitive antagonist (LY235959), a glycine-site antagonist (L-701,324), or noncompetitive antagonists [MK-801, phencyclidine (PCP), and ketamine] of the NMDA receptor. MK-801 at 0.5 mg/kg caused a strong increase in horizontal activity in both rat lines, the effect being significantly greater in the ANT rats. There was a subpopulation among AT rats that was almost completely unresponsive to MK-801. This insensitivity to MK-801 correlated with the lack of c-fos induction in the retrosplenial and cingulate cortices. Fos immunoreactive cells in these brain regions after MK-801 treatment were more numerous in ANT than AT rats, although c-fos induction in the inferior olivary nucleus was similar in all animals after MK-801. The ANT rats showed greater locomotor stimulation also after ketamine and LY235959, while stimulation induced by PCP and depression induced by L-701,324 did not differ between the rat lines. The data suggest that altered NMDA receptor-mediated processes may correlate with differences in innate alcohol sensitivity in the ANT/AT rat model.
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PMID:Enhanced locomotor stimulation by NMDA receptor antagonists in alcohol-sensitive ANT rats. 1116 70


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