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Superoxide dismutase mimetics protec...

Galvez, James Jason.

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Superoxide dismutase mimetics protect mitochondria during ischemia and reperfusion.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Superoxide dismutase mimetics protect mitochondria during ischemia and reperfusion./
Author:	Galvez, James Jason.
Description:	127 p.
Notes:	Source: Dissertation Abstracts International, Volume: 65-02, Section: B, page: 0673.
Contained By:	Dissertation Abstracts International65-02B.
Subject:	Health Sciences, Pharmacology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3123672
ISBN:	0496709836

Superoxide dismutase mimetics protect mitochondria during ischemia and reperfusion.
Galvez, James Jason.

Superoxide dismutase mimetics protect mitochondria during ischemia and reperfusion. - 127 p.

Source: Dissertation Abstracts International, Volume: 65-02, Section: B, page: 0673.

Thesis (Ph.D.)--Wake Forest University, The Bowman Gray School of Medicine, 2004.

Super-oxide (O2·-) is an important and ubiquitous free radical formed under basal conditions and during ischemia and reperfusion (I/R). Mitochondria are the principal source of intracellular O2·- generation during I/R which is presumably responsible for mitochondrial and cellular injury following I/R stress. The premise and focus of our hypothesis is that O2 ·- is an important free radical formed during I/R and at least one mechanism of damage results from targeting mitochondria. In these studies we have utilized manganese based, low molecular weight, synthetic enzymes with selective superoxide dismutase (SOD) activity, termed SOD mimetics. We tested the hypothesis that O2·- is a significant metabolite mediating I/R injury and that the generation of this free radical imparts mitochondrial injury during I/R. Due to the selective nature of the compounds used, we have begun to tease apart and gain insight into the importance of O2·- in the involvement of I/R injury. We exploited both isolated organ (ex vivo ) techniques and an in vivo model of I/R to examine the protective effects of the SOD mimetics M40403 and M40401 on the heart and, more specifically, on mitochondria. Both M40403 and M40401 are protective against I/R injury in the heart. Animals receiving M40403 showed significant protection against hemodynamic failure following global I/R. To support these findings, M40403 protected cellular and mitochondrial structure, assessed by electron microscopy, following I/R. Similar to M40403, M40401 significantly protected hemodynamic function following global I/R. In addition, mitochondrial function following I/R was preserved in the presence of M40401. Mitochondrial function was examined using whole tissue homogenate respiration ratios, analogous to respiratory control ratios (RCR) used in isolated mitochondria preparations, with a significant difference in respiration rates following I/R between M40401 treated hearts and untreated hearts seen during ADP-stimulated respiration. As with our isolated heart experiments, M40401 protected against in vivo I/R injury. M40401 significantly reduced infarct size and preserved creatine kinase (CK) activity, a measure of cellular integrity. Our results demonstrate that intervening at the level of O2·- during I/R structurally and functionally protects mitochondria. Data obtained strongly suggest that O 2·- is an important mediator of I/R injury and that mitochondria are targets of this free radical under conditions of I/R.

ISBN: 0496709836Subjects--Topical Terms:

1017717
Health Sciences, Pharmacology.

Superoxide dismutase mimetics protect mitochondria during ischemia and reperfusion.
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245 1 0 $a Superoxide dismutase mimetics protect mitochondria during ischemia and reperfusion.
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500 $a Source: Dissertation Abstracts International, Volume: 65-02, Section: B, page: 0673.
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502 $a Thesis (Ph.D.)--Wake Forest University, The Bowman Gray School of Medicine, 2004.
520 $a Super-oxide (O2·-) is an important and ubiquitous free radical formed under basal conditions and during ischemia and reperfusion (I/R). Mitochondria are the principal source of intracellular O2·- generation during I/R which is presumably responsible for mitochondrial and cellular injury following I/R stress. The premise and focus of our hypothesis is that O2 ·- is an important free radical formed during I/R and at least one mechanism of damage results from targeting mitochondria. In these studies we have utilized manganese based, low molecular weight, synthetic enzymes with selective superoxide dismutase (SOD) activity, termed SOD mimetics. We tested the hypothesis that O2·- is a significant metabolite mediating I/R injury and that the generation of this free radical imparts mitochondrial injury during I/R. Due to the selective nature of the compounds used, we have begun to tease apart and gain insight into the importance of O2·- in the involvement of I/R injury. We exploited both isolated organ (ex vivo ) techniques and an in vivo model of I/R to examine the protective effects of the SOD mimetics M40403 and M40401 on the heart and, more specifically, on mitochondria. Both M40403 and M40401 are protective against I/R injury in the heart. Animals receiving M40403 showed significant protection against hemodynamic failure following global I/R. To support these findings, M40403 protected cellular and mitochondrial structure, assessed by electron microscopy, following I/R. Similar to M40403, M40401 significantly protected hemodynamic function following global I/R. In addition, mitochondrial function following I/R was preserved in the presence of M40401. Mitochondrial function was examined using whole tissue homogenate respiration ratios, analogous to respiratory control ratios (RCR) used in isolated mitochondria preparations, with a significant difference in respiration rates following I/R between M40401 treated hearts and untreated hearts seen during ADP-stimulated respiration. As with our isolated heart experiments, M40401 protected against in vivo I/R injury. M40401 significantly reduced infarct size and preserved creatine kinase (CK) activity, a measure of cellular integrity. Our results demonstrate that intervening at the level of O2·- during I/R structurally and functionally protects mitochondria. Data obtained strongly suggest that O 2·- is an important mediator of I/R injury and that mitochondria are targets of this free radical under conditions of I/R.
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