Chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, prevents fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment.
We hypothesized that chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, to young adult male rats would prevent/ameliorate fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment. Eighty 12-14-week-old young adult male Fischer 344 rats received either: (1) sham irradiation, (2) 40 Gy of fractionated whole-brain irradiation delivered as two 5 Gy fractions/week for 4 weeks, (3) sham irradiation plus continuous administration of 15 mg/L of ramipril in the drinking water starting 3 days before irradiation, or (4) fractionated whole-brain irradiation plus ramipril. Cognitive function was assessed using a perirhinal cortex-dependent version of the novel object recognition task 26 weeks after irradiation. Microglial activation was determined in the perirhinal cortex and the dentate gyrus of the hippocampus 28 weeks after irradiation using the ED1 antibody. Neurogenesis was assessed in the granular cell layer and subgranular zones of the dentate gyrus using a doublecortin antibody. Fractionated whole-brain irradiation led to: (1) a significant impairment in perirhinal cortex-dependent cognitive function, (2) a significant increase in activated microglia in the dentate gyrus but not in the perirhinal cortex, and (3) a significant decrease in neurogenesis. Continuous administration of ramipril before, during, and after irradiation prevented the fractionated whole-brain irradiation-induced changes in perirhinal cortex-dependent cognitive function, as well as in microglial activation in the dentate gyrus. Thus, as hypothesized, continuous administration of the angiotensin-converting enzyme inhibitor, ramipril, can prevent the fractionated whole-brain irradiation-induced impairment in perirhinal cortex-dependent cognitive function.
Department of Molecular Medicine and Translational Science, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA.
Tammy C
TC
Lee
Dana
D
Greene-Schloesser
Valerie
V
Payne
Debra I
DI
Diz
Fang-Chi
FC
Hsu
Mitra
M
Kooshki
Rashida
R
Mustafa
David R
DR
Riddle
Weiling
W
Zhao
Michael D
MD
Chan
Mike E
ME
Robbins
D000803:Angiotensin I / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001835:Body Weight; D002540:Cerebral Cortex / Q000502:physiology / Q000528:radiation effects*; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control*; D016371:Cranial Irradiation / Q000009:adverse effects*; D019583:Dose Fractionation, Radiation; D000089662:Doublecortin Protein; D008297:Male; D011833:Radiation Injuries, Experimental / Q000517:prevention & control*; D017257:Ramipril / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344
D000806:Angiotensin-Converting Enzyme Inhibitors; C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D000803:Angiotensin I; D017257:Ramipril