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Signal transduction pathways involved in Na+/K+-ATPase inhibitor-induced hyperactivity in a rat model for bipolar disorder
DC Field | Value | Language |
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dc.contributor.advisor | 전용성 | - |
dc.contributor.author | 유현숙 | - |
dc.date.accessioned | 2017-07-14T01:41:37Z | - |
dc.date.available | 2017-07-14T01:41:37Z | - |
dc.date.issued | 2013-08 | - |
dc.identifier.other | 000000012895 | - |
dc.identifier.uri | https://hdl.handle.net/10371/122249 | - |
dc.description | 학위논문 (박사)-- 서울대학교 대학원 : 의과학과 의과학 전공, 2013. 8. 전용성. | - |
dc.description.abstract | Introduction: The possible involvement of sodium and potassium-activated adenosine triphosphatase (Na/K-ATPase) dysfunction has been suggested in the pathophysiology of bipolar disorder (BD) in clinical and genetic studies. Based on Na/K-ATPase dysfunction in BD, a potential animal BD model using ouabain, a specific Na/K-ATPase inhibitor, has been introduced. However, the biochemical mechanisms underlying the development of the behavioral changes caused by ouabain are not clearly understood. ERK, Akt, and PKC have been suggested to have important effects on Na/K-ATPase as signal transducers in vitro. In this study, in order to elucidate the mechanism of Na/K-ATPase involved in inducing behavioral changes in vivo, the roles of ERK, Akt, and PKC were investigated in brains from the rat BD model using ouabain
Methods: Sprague-Dawley rats were given intracerebroventricular (ICV) ouabain and the biochemical changes in rat brain related to the ouabain-induced hyperactivity were examined after measuring locomotor activity Results: A previous study indicated that ICV ouabain induces acute activation of the ERK1/2 signaling pathway, accompanied by hyperactivity in rats. Changes in the phosphorylation of tyrosine hydroxylase (TH) one of the downstream molecules of ERK1/2 were, investigated in the rat striatum. Ouabain induced significant increases in the phosphorylation of TH. Inhibition of ERK1/2 using an intrabrain MEK inhibitor attenuated the ouabain-induced increase in TH phosphorylation, as well as the hyperactivity of rats. Moreover, the phosphorylation of ERK1/2 and TH was increased consistently, up until 8 h after the ouabain treatment. Next, the persistent activation of the Akt/glycogen synthase kinase-3β (GSK-3β)/forkhead box, class O1 (FoxO1)/endothelial nitric oxide synthase (eNOS) pathways, was observed in the rat striatum and frontal cortex | - |
dc.description.abstract | this was accompanied by hyperactivity in rats up until 8 h after the ouabain injection. The Akt and ERK1/2 signal pathways cooperatively regulate the protein translation that is important in modifying neural circuits and behavior. Ouabain also induced persistent activation of the mammalian target of rapamycin (mTOR)/p70 ribosomal S6 kinase (p70S6K)/S6 protein translation pathway in the rat frontal cortex up until 8 h after treatment. In addition, the rate of protein synthesis measured by [3H]-leucine incorporation was increased in the cell-free extracts of frontal cortical tissues. mTOR activation is involved in the inactivation of AMP-activated kinase (AMPK), a key energy sensor regulating cellular metabolism to maintain energy homeostasis. In the rat striatum, ouabain decreased the phosphorylation of AMPK and its downstream acetyl CoA carboxylase (ACC) and increased the amount of PP2Cα. The activity of mitochondrial carnitine palmitoyl transferase 1a (CPT1a), a downstream target of ACC, was decreased. In addition, ouabain increased the activation of protein kinase C (PKC) in the rat striatum, and this was attenuated by anti- manic drugs, including haloperidol and verapamil.
Conclusions: These results indicate that the activity of the ERK, Akt, and PKC pathways is changed in the brain of rat model for mania of BD using ouabain, and suggest that they are associated with the behavioral changes observed in the animal model. Therefore, these findings could contribute to a better understanding of pathophysiology and therapeutic mechanism for BD. | - |
dc.description.tableofcontents | Introduction 1
Hypothetical and pharmacological rat model for bipolar disorder | - |
dc.description.tableofcontents | Na/K-ATPase dys-function 1
ERK, Akt, and PKC pathway and BD 4 The possible involvement of ERK, Akt, and PKC pathways involved in Na/K-ATPase signal transduction in a rat model for BD 6 Purpose of the study 13 Materials and Methods 14 Animals 14 ICV cannula placement 14 Experimental procedure 16 Measurement of locomotor activity 16 Sample preparations and immunoblot analysis 17 Sample preparation for cytosolic and membrane fractionations 17 PKC activity assay 18 Immunoprecipitation 19 Immunohistochemistry 19 Double labeled immunofluorescence 20 Translation assays in vitro 20 CPT1 activity assay 22 Statistical analysis 23 Results 26 1. Acute and chronic changes in locomotor activity after ICV injection of ouabain 26 2. Changes in the phosphorylation of TH pathway after ICV injection of ouabain | - |
dc.description.tableofcontents | ERK1/2 mediating TH phosphorylation 27
3. Changes in the phosphorylation of Akt pathway in the rat striatum and frontal cortex after ICV injection of ouabain 31 4. Changes in protein translation initiation in the rat frontal cortex after ICV injection of 1 mM ouabain 32 5. Changes in AMPK pathway in the rat striatum after ICV injection of 1 mM ouabain 36 6. Changes in PKC activity in the rat striatum after ICV injection of ouabain 38 Discussion 64 Conclusion 85 References 88 국문초록 124 | - |
dc.format | application/pdf | - |
dc.format.extent | 2219901 bytes | - |
dc.format.medium | application/pdf | - |
dc.language.iso | en | - |
dc.publisher | 서울대학교 대학원 | - |
dc.subject | bipolar disorder | - |
dc.subject | hyperactivity | - |
dc.subject | Na/K-ATPase inhibitor | - |
dc.subject | signal transduction pathway | - |
dc.subject | mania | - |
dc.subject.ddc | 610 | - |
dc.title | Signal transduction pathways involved in Na+/K+-ATPase inhibitor-induced hyperactivity in a rat model for bipolar disorder | - |
dc.type | Thesis | - |
dc.description.degree | Doctor | - |
dc.citation.pages | ⅹ, 125 | - |
dc.contributor.affiliation | 의과대학 의과학과 | - |
dc.date.awarded | 2013-08 | - |
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