Item Details

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

Lee, Tammy (author)

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)

title

RADIATION-INDUCED BRAIN INJURY AND THE RENIN-ANGIOTENSIN SYSTEM

type

Thesis