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RADIATION-INDUCED BRAIN INJURY AND THE RENIN-ANGIOTENSIN SYSTEM

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title
RADIATION-INDUCED BRAIN INJURY AND THE RENIN-ANGIOTENSIN SYSTEM
author
Lee, Tammy
abstract
Fractionated partial or whole-brain irradiation (WBI), widely used in the treatment of primary and metastatic brain tumors, leads to progressive cognitive impairment in ≥50% of adult patients surviving ≥6 months postirradiation. One of the most successful approaches to reduce the severity of late radiation-induced injury in the lung, kidney and CNS has been pharmacologic suppression of the reninangiotensin system (RAS). The brain has its own intrinsic RAS which has effects beyond cardiovascular and fluid homeostasis including learning, cognition and memory. Although the pathogenesis of radiation injury remains unclear, we hypothesize that WBI may up-regulate the brain RAS and lead to a neuroinflammatory response associated with an increase in the number of activated microglia; an established inhibitor of neurogenesis in the adult rodent hippocampus. The aim of this study was to determine if the angiotensin-converting enzyme (ACE) inhibitor, ramipril, could prevent radiation-induced cognitive impairment. Eighty young adult male, 12-14 weeks old, Fischer 344 rats were randomized to 4 groups: 1) fractionated WBI (40 Gy, 8 fractions of 5 Gy, twice/week for 4 weeks); 2) shamirradiation; 3) WBI plus ramipril (15mg/L drinking water) starting 3 days prior, during and for 28 weeks postirradiation; and 4) sham-irradiation plus ramipril. Cognitive function was assessed 26 weeks after WBI using the novel object xv recognition task. WBI led to a significant reduction in cognitive function (p < 0.05) compared with the age-matched sham-irradiated controls. This WBI-induced reduction in cognitive function was prevented in the rats receiving ramipril. The neuroinflammatory response in these animals was evaluated by determining the total number of microglia (Iba1+ cells) and activated microglia (ED1+ cells) in the dentate gyrus of the hippocampus at 28 weeks post-irradiation. Our results showed a significant increase in the density of activated microglia in rats receiving WBI (p<0.01) which was prevented by ramipril (p<0.01). The total number of microglia was relatively unchanged 6 months post-irradiation. In contrast, WBI significantly increased the fraction of the microglia population that was activated (p<0.01); ramipril prevented the increase in fraction of activated microglia (p<0.001). The fraction of activated microglia can influence the neuronal microenvironment. These data suggest that microglia are responding to persistent radiation-induced changes or alterations to the microenvironment which can be modified by the ACE inhibitor, ramipril. This study suggests that the brain RAS plays a pivotal role in the progression of cognitive impairment and brings us closer to improving the quality of life (QOL) of brain cancer survivors.
subject
Whole-Brain Irradiation
Renin-Angiotensin System
Cognitive impairment
ACE inhibition
Ramipril
contributor
Brosnihan, K. Bridget (committee chair)
Robbins, Mike (committee member)
L, Richard (committee member)
date
2009-10-06T14:55:11Z (accessioned)
2010-06-18T18:58:59Z (accessioned)
2009-10-06T14:55:11Z (available)
2010-06-18T18:58:59Z (available)
2009-10-06T14:55:11Z (issued)
degree
Molecular Medicine (discipline)
identifier
http://hdl.handle.net/10339/14814 (uri)
language
en_US (iso)
publisher
Wake Forest University
rights
Release the entire work for access only to the Wake Forest University system for one year from the date below. After one year, release the entire work for access worldwide. (accessRights)
type
Thesis

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