Chronic Administration of the Angiotensin-Converting Enzyme Inhibitor, Ramipril, Prevents Fractionated Whole-Brain Irradiation-Induced Perirhinal Cortex-Dependent Cognitive Impairment

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.

The Current Utilization of Cognitive Tests in the Research of Radiation-Induced Cognitive Dysfunction in Rodent Models

“…A dosage of 20 Gy/5 f of which the BED is nearly equivalent to that of 10 Gy/1 f was also reported to be incapable of impairing recognition memory [38]. Other dosages of 40 Gy/8 f [18,46], 50 Gy/10 f [45], 20 Gy/1 f and 30 Gy/1 f [52] in various studies jeopardized recognition memory. In NLR, radiation-induced cognitive dysfunction was demonstrated by the decrease of exploration time in the novel location or decreased discrimination ratio.…”

“…Novel object recognition and novel location recognition: Time intervals post-irradiation utilized in NOR varied from half a month [53] to one year [18], among which most time intervals were less than half a year [46,61]. Time intervals of 3 months [18,42,44,45,52,62] and 6 months [18,38,52,61] were the most frequently utilized and 7 months [46] as well as 1 year were used in one study each [18].…”

“…Time intervals of 3 months [18,42,44,45,52,62] and 6 months [18,38,52,61] were the most frequently utilized and 7 months [46] as well as 1 year were used in one study each [18]. Time intervals post-irradiation in NLR ranged from 1 month [38] [50], among which 1 month was the most frequently utilized.…”

“…In NOR, the percentage exploration time in the novel object and discrimination ratio (novel object exploration time/total exploration time with both objects) are commonly used end points [44,45]. The time to explore familiar objects was used in Lee's research to indicate impaired memory recognition [46]. Radiation-induced cognitive dysfunction is demonstrated by the decrease of exploration time in the novel object and discrimination ratio.…”

Neurocognitive Effects Following Cranial Irradiation for Brain Metastases

“…Hippocampal neurogenesis seems to be unaffected in older rats with radiotherapy-induced cognitive impairment [61] but activated microglia appear to release pro-inflammatory cytokines that can directly inhibit NPC [62]. This may be relevant in a wider context because not all hippocampaldependent learning depends on neurogenesis [63] and deficits in non-hippocampal-dependent domains of cognitive function also occur [64].…”