The activation of the HPA axis is the endocrine measure of stress responsiveness that is initiated by corticotropin-releasing hormone (CRH). CRH exerts its effects via CRHR1 and CRH-R2 receptors coupled to the cAMP signaling system and this process involves transcription factor cAMP-responsive element-binding protein (CREB).This study investigated the role of CRH and the possible involvement of CREB in gene regulation of CRH receptor, under basal conditions and after stress application in the pituitary. We used wild type (wt +/+) controls and CRH knock-out (CRH-KO -/-) male mice. Using CRH-deficient mice, we were able to investigate the consequences of the lack of the CRH on the expression of CRH receptors and transcriptional regulation mediated by CREB. We estimated the effect of acute (IMO 1×) and repeated (IMO 7×) restraint stressors lasting 30 and 120 min on the expression of mRNA CREB, CRH-R1, and CRH-R2 by qPCR. We found very significant difference in the expression of these peptides under the effect of single and repeated stress in control and CRH-KO mice. Our results indicate that both CRH receptors and CREB might be involved in the regulation of stress response in the pituitary of mice. We propose that regulation of the stress response may be better understood if more were known about the mechanisms of CRH receptor signal transduction and involvement of CREB system.
- MeSH
- akutní nemoc MeSH
- hormon uvolňující kortikotropin biosyntéza nedostatek MeSH
- hypofýza metabolismus MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- protein vázající cAMP responzivní element biosyntéza MeSH
- psychický stres metabolismus psychologie MeSH
- receptory hormonu uvolňujícího kortikotropin biosyntéza MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Publikační typ
- abstrakt z konference MeSH
This review summarizes past and recent findings related to corticotropin releasing hormone (CRH, CRF) regulation and its involvement in the neuroendocrine, au-tonomic and behavioral stress reaction. CRH belongs to a larger family of neuropeptides that also includes uro-cortins with different affinity toward the two types of CRH receptors, CRH-R1 and CRH-R2. The new advances in the knowledge of mechanisms of CRH and its receptor sub-types effects show an involvement of CRH in stress and stress-related disorders, such as depression, anxiety and other psychiatric and physic diseases. This review lists some ligands and new drugs that act as agonists and anta-gonists on CRH receptor subtypes. Recent studies open up new possibilities for finding antidepressants that would also influence defensive stress mechanisms. Because CRH receptors are also located in the periphery, the use of CRH antagonists can have therapeutic potential in the treatment and prevention of organic diseases. Mainly non-peptide antagonists that have a potential for the therapeutic use in psychiatric, behavioral and other disorders are prospective in this respect. The aim of the current research is to find non-peptide ligands that penetrate the cerebrospinal barrier and, by binding to the respective CRH receptor, will have an anti-stress effect.
- MeSH
- adrenokortikotropní hormon * antagonisté a inhibitory chemie terapeutické užití MeSH
- lidé MeSH
- neuropeptidy terapeutické užití MeSH
- psychický stres MeSH
- výzkum MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
This review focuses on the research and new discoveries of signaling processes and on the importance of a remarkable system of G protein-coupled receptors (GPCR). GPCRs are the largest and the most diverse family of receptors involved in many physiological processes and represent attractive targets for pharmacological intervention to modify these processes in normal and pathological states. The new knowledge of the regulation of GPCR signaling enabled the synthesis of novel ligands with therapeutic use. Recipients of the 2012 Nobel Prize in chemistry, R. Lefkowitz and B. Kobilka, played a key role in the study of GPCR, arrestins, G-protein-coupled receptor kinases, and ligands functions, as a universal mechanism of receptor action and a molecular understanding of overall GPCR signaling. Their crystallographic studies of ligand-activated GPCRs allowed them to acquire the three-dimensional structures for a number of pharmacologically important receptors. Detailed analysis of the structure of GPCRs allowed the authors to create drug compounds with greater specificity of action and with reduced side effects, the drugs with therapeutic effects.
- MeSH
- lidé MeSH
- mapování interakce mezi proteiny MeSH
- objevování léků MeSH
- proteiny RGS * MeSH
- receptory spřažené s G-proteiny * MeSH
- výzkum MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Tong Luo Jiu Nao (TLJN), a modern formula of traditional Chinese medicine, has proven to be clinically efficacious in several vascular cerebral diseases but its specific effect is not known. In the present study we investigated the acute and persisting effects of TLJN on anxiety model in Wistar male rats. TLJN was administered intragastrically during three successive days (Days 1–3) and then, the double TLJN dose was given on Day 7. For the evaluation of anxiety-related behavior of animals, we used the open field (OF) and elevated plus maze (EPM) paradigms. Testing in the OF was performed on Days 1, 2, 3, 4, 8, 14 and 22; in the EPM on the Day 23. Two-way repeated-measures ANOVA revealed significant differences between control and TLJN treated animals in the open field model where TLJN induced increased exploratory activity, indicating reduced anxiety-like behavior. The effect persisted for several days after the treatment and was still present on Days 14 and 22. Reduced anxiety-like behavior was also observed on EPM 16 days after the last TLJN administration. The results demonstrate behavioral effects of intragastric administered TLJN, which indicate reduced anxiety. Persistence of the induced behavioral changes suggests prolonged duration of action.
- MeSH
- behaviorální symptomy klasifikace MeSH
- bludiště - učení MeSH
- cerebrovaskulární poruchy farmakoterapie MeSH
- chování zvířat účinky léků MeSH
- Gardenia MeSH
- Panax notoginseng MeSH
- potkani Wistar MeSH
- rostlinné extrakty * aplikace a dávkování MeSH
- tradiční čínská medicína * MeSH
- úzkostné poruchy * farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
OBJECTIVES: Oxytocin (OT) is a neuropeptide acting both as a peripheral hormone and in the brain as neurotransmitter and neuromodulator. In addition to its well-known effects on milk-ejection and uterine contraction, OT was shown to exert neuroendocrine regulation of heart functions. The aim of this study was to investigate the expression of mRNA of OT receptors (OTR) in rat hearts by real-time quantitative PCR (qPCR). The study was performed in Sprague-Dawley (SD) and Lewis (LE) rat strains, the latter having lower activity of HPA axis. METHODS: We used adult male SD and LE rats. OTR mRNA expression was detected in all heart chambers by comparing their threshold cycle values (CT) to CT of reference gene β-actin. The relative expression ratios were calculated using the 2-ΔΔCT method. The specificity of reaction of primary antibody with OTRs was tested by Western Blot and localization of OTR in the heart compartments was performed by immunofluorescence with commercial OTR specific antibodies. RESULTS: We found expression of OTR mRNA in all heart compartments. The expression of OTR mRNA in both atria (LA, RA) was much higher than in the ventricles (RV, LV). By using two-way ANOVA we found no statistical differences between corresponding compartments of SD and LE rats. Immunohistochemical studies showed that OTR staining is not related to neuronal tissue and findings from left atrium indicate that prevalent localization of OTR is on cell membranes of cardiomyocytes. CONCLUSIONS: The finding of expression of OTR mRNA by real-time qPCR and proof of OTR staining by immunohistochemistry in all heart compartments indicate that OT and its receptors may have function as a cardiovascular hormone. The differences in the HPA axis activity, as is exemplified in Sprague-Dawley and Lewis rat strain, do not project in the expression of OTR mRNA under basal condition. The effect of activity of HPA on OTR expression should be studied under stimulated conditions as it was performed in the behavioral studies.
- MeSH
- krysa rodu rattus MeSH
- messenger RNA metabolismus MeSH
- myokard cytologie metabolismus MeSH
- oxytocin metabolismus MeSH
- potkani inbrední LEW MeSH
- potkani Sprague-Dawley MeSH
- receptory oxytocinu genetika metabolismus MeSH
- systém hypofýza - nadledviny fyziologie MeSH
- systém hypotalamus-hypofýza fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The neuropeptide galanin has been recognized as a possible neurotransmitter/neuromodulator, and in addition has been implicated in anxiety- and depression-related behaviors. The present study demonstrates increased locomotion and rearing after galanin (0.3mg/kg) that was given intraperitoneally (i.p.) to intact Wistar rats which were tested 1h later in the open field (OF). These effects, which suggest an anxiolytic-like action, were blocked by i.p. administered peptidic galanin antagonist M40. Further, the locomotion increase caused by galanin and the inhibitory effect of M40 persisted for 48h without additional treatment. Rats exposed to restraint stress (lasting 60min) for three consecutive days and tested 1h after stress termination exhibited reduced locomotion and exploration in the OF. Galanin (0.3 and 1.0mg/kg) given immediately after each stress exposure prevented the decrease of locomotion and exploration induced by stress in all trials. When the test was repeated 6 days later without stress and galanin treatment the reduction of locomotion produced by stress persisted; the anti-stress behavioral effects of both galanin doses were also present. Testing performed on the 12th day after the last stress and galanin treatment with 0.3mg/kg revealed an increased locomotion compared with unstressed and stress-exposed rats. Our results demonstrate that behavioral effects of the peptide galanin are evident even after i.p. administration. These results also suggest that galanin elicits stress-modulatory action, and support the notion that the galaninergic system may serve as a drug target in stress-related conditions.
- MeSH
- anxiolytika antagonisté a inhibitory farmakologie MeSH
- čas MeSH
- časové faktory MeSH
- chování zvířat účinky léků fyziologie MeSH
- fyzické omezení škodlivé účinky psychologie MeSH
- galanin antagonisté a inhibitory metabolismus fyziologie MeSH
- krysa rodu rattus MeSH
- lékové transportní systémy MeSH
- modely nemocí na zvířatech MeSH
- pátrací chování účinky léků fyziologie MeSH
- pohybová aktivita účinky léků fyziologie MeSH
- potkani Wistar MeSH
- psychický stres metabolismus patofyziologie prevence a kontrola MeSH
- úzkostné poruchy metabolismus patofyziologie prevence a kontrola MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
