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The Role of Agmatine and Arginine Decarboxylase in Ischemic Tolerance After Transient Cerebral Ischemia in Rat Models

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The Role of Agmatine and Arginine Decarboxylase in Ischemic Tolerance After Transient Cerebral Ischemia in Rat Models The role of agmatine and arginine decarboxylase in ischemic tolerance after transient cerebral ischemia in rat models Jin Young Jung Department of Medicine The Graduate School, Yonsei University The role of agmatine and arginine decarboxylase in ischemic tolerance after transient cerebral ischemia in rat models Directed by Professor Seung Kon Huh The Doctoral Dissertation submitted to the Department of Medicine, the Graduate School of Yonsei University in partial fulfillment of the requirements for the degree of Doctor of Philosophy Jin Young Jung May 2007 This certifies that the Doctoral Dissertation of Jin Young Jung is approved. __________________________________ Thesis Supervisor: Seung Kon Huh __________________________________ Jong Eun Lee: Thesis Committee Member #1 __________________________________ Jin Woo Chang: Thesis Committee Member #2 __________________________________ Duck Sun Ahn: Thesis Committee Member #3 __________________________________ Ji Cheol Shin: Thesis Committee Member #4 The Graduate School Yonsei University May 2007 Acknowledgements Some may consider this short section of the thesis trivial but for me it is a chance to express my sincerest gratitude to those that I am truly thankful. First of all, I would like to express my deepest gratitude to my thesis supervisor and mentor Professor Seung Kon Huh. He has inspired me when I was troubled and always gave me a warm heart. I would also like to thank Professor Jong Eun Lee who shared her valuable time on the execution and interpretation of this study, Professor Jin Woo Chang who always inspiring me with passion and discerning insight. Professor Duck Sun Ahn whose insightful comments were essential in completing this thesis, Professor Ji Cheol Shin for the excellent suggestion for improvement in this thesis. I wish to special thanks to Jae Hwan Kim for his many advises concerning the experiment, Yong Woo Lee who gave me a great help for completing this thesis. I am deeply indebted to my parents, who always provided a solid foundation for me to go my way. I feel a deep sense of gratitude for my companion and wife, Ho Jung Kang and my lovely son, Jae Yoon Jung who is the hope of my life. May 2007 Jin Young Jung TABLE OF CONTENTS ABSTRACT---------------------------------------------------------------------- 1 I. INTRODUCTION-------------------------------------------------------------- 3 II. MATERIALS AND METHODS-------------------------------------------- 4 1. Animals and experimental protocols------------------------------------- 4 2. Induction of ischemic preconditioning and focal ischemia------------ 4 3. Morphometric measurement of brain edema and infarct volume----- 5 4. Agmatine analysis with HPLC-------------------------------------------- 6 4-1.Sample preparation ---------------------------------------------------- 6 4-2. Apparatus and chromatographic conditions------------------------ 6 5. Immunostaining for ADC, NOSs, phosphoERK1/2, and BMP-7-----6 6. Immunoblotting of ADC, Erk1/2 ----------------------------------------- 7 7. Statistical analysis----------------------------------------------------------- 7 III. RESULTS--------------------------------------------------------------------- 7 1. rCBF responses to experimental control group and ischemic preconditioning group in MCAO models-------------------------------- 7 2. Brain edema and infarct volume after ischemic injury----------------- 8 3. The level of agmatine after ischemic injury----------------------------- 11 4. Assessment for level of ADC---------------------------------------------- 13 5. Assessment for level of nNOS and iNOS ------------------------------- 14 6. Assessment for level of ERK1/2, phosphoERK1/2, and BMP-7----- 17 IV. DISCUSSION----------------------------------------------------------------- 20 V. CONCLUSION---------------------------------------------------------------- 22 Ⅵ. REFERENCES---------------------------------------------------------------- 23 ABSTRACT (IN KOREAN) --------------------------------------------------- 28 i LIST OF FIGURES Figure 1 Experimental protocol---------------------------------- 5 Figure 2 rCBF of experimental control group and ischemic preconditioning group in MCAO--------------------- 8 Figure 3 Preconditioning reduces infarct size in a model of MCAO --------------------------------------------------- 9 Figure 4 Brain edema after ischemic injury with or without preconditioning------------------------------------------ 11 Figure 5 Level of agmatine in rat brain tissue------------------ 12 Figure 6 Western blots of arginine decarboxylase------------- 13 Figure 7 Immunohistochemistry of arginine decarboxylase- 14 Figure 8 Immunohistochemistry of neuronal nitric oxide synthase in ischemic injured rat brain---------------- 15 Figure 9 Immunohistochemistry of inducible nitric oxide synthase in ischemic injured rat brain---------------- 16 Figure 10 Western blots of ERK1/2 in ischemic injured rat brain------------------------------------------------------- 17 Figure 11 Immunohistochemistry of phosphoERK1/2 in ischemic injured rat cerebral cortex------------------ 17 Figure 12 Immunohistochemistry of phosphoERK1/2 in ischemic injured rat striatum-------------------------- 18 Figure 13 Immunohistochemistry of BMP-7 at post- reperfusion 1hr------------------------------------------ 19 LIST OF TABLES Table 1. Infarct volume after ischemic injury------------------ 10 Table 2. Level of agmatine after ischemic injury-------------- 12 ii LIST OF ABBREVIATIONS ADC Arginine decarboxylase BMP-7 Bone morphogenetic protein-7 EC Experimental control group ERK1/2 Extracellular signal-regulated kinase1/2 HPLC high performance liquid chromatography IP Ischemic preconditioning group MCAO Middle cerebal artery occlusion NO Nitric oxide nNOS Neuronal nitric oxide synthase iNOS Inducible nitric oxide synthase rCBF Regional cerebral blood flow iii Abstract The role of agmatine and arginine decarboxylase in ischemic tolerance after transient cerebral ischemia in rat models Jin Young Jung Department of Medicine The Graduate School, Yonsei University (Directed by Professor Seung Kon Huh) Agmatine is an endogenous clonidine-displacing substance, an agonist for the α2- adrenergic and imidazoline receptors, and an antagonist at N-methyl-D-aspartate (NMDA) receptors. Agmatine was shown to protect neurons against glutamate toxicity and this effect was mediated through NMDA receptor blockade, with agmatine interacting at a site located within the NMDA channel pore. Furthermore, this protection is associated with decreased nitric oxide synthase (NOS) activity and expression, as well as NO generation. Preconditioning describes a powerful sublethal treatment, which induces neurons to become more resistant to a subsequent ischemic insult. Ischemic preconditioning is one of the most important endogenous mechanisms for protecting cells against ischemic and reperfusion injury. In this study, the association of agmatine with ischemic preconditioning and ischemic tolerance was investigated. The data obtained here have demonstrated that the endogenous neuroprotective mechanisms are facilitated by ischemic preconditioning through increasing ischemic tolerance by agmatine. The level of agmatine was increased during the ischemic preconditioning and the increased level of agmatine also facilitates the agmatine production during the ischemic injury. However, expression of arginine decarboxylase (ADC) in preconditioning group was not demonstrable during the 1 ischemic injury and reperfusion injury. Being structurally similar to L-arginine, agmatine has been considered as a nitric oxide synthase (NOS) inhibitor, especially neuronal NOS. To investigate the relationship between elevating levels of agmatine during ischemic preconditioning and NOS expression, immunostaining against NOSs was performed. Results indicated that the agmatine has a ischemic preconditioning decreased the expression of nNOS in the cerebral cortex and striatum at 1 hr and 23 hr reperfusion following 1 hr ischemia. The level of ERK which regulates various cellular processes such as cell growth and differentiation was determined in ischemic brain with or without ischemic preconditioning. The protein expression of ERK was increased in ischemic preconditioning group than the experimental control group. The expression of BMP-7 was also investigated in this study. The level of BMP-7 was induced in preconditioning group under MCA occlusion. Induced level of agmatine may act by increasing the expression of BMP-7 and ERK which are involved in cell survival. These results indicated that neuroprotective mechanism of ischemic preconditioning might be related with elevated level of agmatine and increasing BMP-7, ERK expression. ______________________________________________________________________ Key words: agmatine, arginine decarboxylase, ischemic tolerance, preconditioning 2 The role of agmatine and arginine decarboxylase in ischemic tolerance after transient cerebral ischemia in rat models Jin Young Jung Department of Medicine The Graduate School, Yonsei University (Directed by Professor Seung Kon Huh) I. INTRODUCTION Agmatine, formed by the decarboxylation of L-arginine by arginine decarboxylase (ADC), was first discovered in 1910. It is hydrolyzed to putrescine and urea by agmatinase 1. Recently, agmatine, ADC, and agmatinase were found in mammalian brain 2. Agmatine is an endogenous clonidine-displacing substance, an agonist for the α2-adrenergic and imidazoline receptors, and an antagonist at N-methyl-D-aspartate
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