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. 2012 Jul;178(1):46-56.
doi: 10.1667/rr2731.1. Epub 2012 Jun 12.

Chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, prevents fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment

Tammy C Lee  1 , Dana Greene-Schloesser, Valerie Payne, Debra I Diz, Fang-Chi Hsu, Mitra Kooshki, Rashida Mustafa, David R Riddle, Weiling Zhao, Michael D Chan, Mike E Robbins
Affiliations

Chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, prevents fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment

Tammy C Lee et al. Radiat Res. 2012 Jul.

Abstract

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.

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Figures

FIG. 1
FIG. 1
Administration of the angiotensin-converting enzyme-inhibitor, ramipril, to young adult male F344 rats before, during, and after fractionated whole-brain irradiation prevents radiation-induced perirhinal-cortex-dependent cognitive impairment measured by the perirhinal-cortex-dependent version of the novel object recognition task. Rats received either sham irradiation (Sham), 40 Gy of fractionated whole-brain irradiation (fWBI), sham irradiation + 15 mg/L of ramipril in the drinking water (Sham + Ram), or 40 Gy of fractionated whole-brain irradiation + ramipril (fWBI + Ram). Ramipril was continuously administered to the rats starting 3 days before the beginning of fractionated whole-brain irradiation. Cognitive function was assessed 26 weeks after completion of fractionated whole-brain irradiation. Data represent the mean ± SEM; n = 20/group; *P < 0.05.
FIG. 2
FIG. 2
Ramipril decreases radiation-induced microglial activation in the dentate gyrus of the hippocampus. The number of microglia/mm3 was unchanged after fractionated whole-brain irradiation (fWBI) (panel A). The percentage of activated microglia (panel B) increased after fractionated whole-brain irradiation. Administering ramipril prevented these increases. Rats received either sham irradiation (Sham), 40 Gy of fractionated whole-brain irradiation (fWBI), sham irradiation +15 mg/L of ramipril in the drinking water (Sham + Ram), or 40 Gy of fractionated whole-brain irradiation + ramipril (fWBI + Ram). Ramipril was continuously administered to the rats starting 3 days before the beginning of fractionated whole-brain irradiation. Data represent the mean ± SEM; n = 4 rats/group; **P < 0.01.
FIG. 3
FIG. 3
Fractionated whole-brain irradiation and/or ramipril treatment fails to alter total number of microglia (panel A) as well as microglial activation (panel B) in the perirhinal cortex. Rats received either sham irradiation (Sham), 40 Gy of fractionated whole-brain irradiation (fWBI), sham irradiation +15 mg/L of ramipril in the drinking water (Sham + Ram), or 40 Gy of fractionated whole-brain irradiation + ramipril (fWBI + Ram). Ramipril was continuously administered to the rats starting 3 days before the beginning of fractionated whole-brain irradiation. Data represent the mean ± SEM; n = 4 rats/group.
FIG. 4
FIG. 4
Ramipril does not prevent the fractionated whole-brain irradiation-induced decrease in hippocampal neurogenesis. The marked reduction in the number of immature neurons (DCX+) in the dentate gyrus after fractionated whole-brain irradiation determined 28 weeks after fractionated whole-brain irradiation was not modulated by continuous administration of ramipril. Rats received either sham irradiation (Sham), 40 Gy of fractionated whole-brain irradiation (fWBI), sham irradiation +15 mg/L of ramipril in the drinking water (Sham + Ram), or 40 Gy of fractionated whole-brain irradiation + ramipril (fWBI + Ram). Ramipril was continuously administered to the rats starting 3 days before the beginning of fractionated whole-brain irradiation. Data represent the mean ± SEM; n = 4 rats/group; **P < 0.01, ***P < 0.001.
FIG. 5
FIG. 5
Continuous administration of ramipril results in a significant increase in plasma Ang I and Ang-(1–7), but not Ang II. Panel A: Ang I levels; panel B: Ang II levels; panel C: Ang-(1–7) levels. Rats received either sham irradiation (Sham), 40 Gy of fractionated whole-brain irradiation (fWBI), sham irradiation +15 mg/L of ramipril in the drinking water (Sham + Ram), or 40 Gy of fractionated whole-brain irradiation + ramipril (fWBI + Ram). Ramipril was continuously administered to the rats starting 3 days before the beginning of fractionated whole-brain irradiation. Data represent mean ± SEM; n = 6 rats/group; * P < 0.05.
FIG. 6
FIG. 6
Continuous administration of ramipril does not significantly alter the levels of angiotensin peptides in the cerebral cortex. Panel A: Ang I levels; panel B: Ang II levels; panel C: Ang-(1–7) levels. Rats received either sham irradiation (Sham), 40 Gy of fractionated whole-brain irradiation (fWBI), sham irradiation +15 mg/L of ramipril in the drinking water (Sham + Ram), or 40 Gy of fractionated whole-brain irradiation + ramipril (fWBI + Ram). Ramipril was continuously administered to the rats starting 3 days before the beginning of fractionated whole-brain irradiation. Cognitive function was assessed 26 weeks after completion of fractionated whole-brain irradiation. Data represent mean ± SEM; n = 6 rats/group.
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