Purpose-We hypothesized that administration of the angiotensin type 1 (AT 1 ) receptor antagonist, L-158,809, to young adult male rats would prevent or ameliorate fractionated whole-brain irradiation (WBI)-induced cognitive impairment. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Results-Administration of L-158,809 prior to, during, and for 28 or 54 weeks after fractionated WBI prevented or ameliorated the radiation-induced cognitive impairment observed 26 and 52 weeks post-irradiation. Moreover, giving L-158,809 prior to, during, and for only 5 weeks post-irradiation ameliorated the significant cognitive impairment observed 26 weeks post-irradiation. These radiation-induced cognitive impairments occurred without any changes in brain metabolites or gross histologic changes assessed at 28 and 54 weeks post-irradiation, respectively. Methods and Materials-Groups NIH Public AccessConclusions-Administering L-158,809 prior to, during, and after fractionated WBI can prevent or ameliorate the chronic, progressive, cognitive impairment observed in rats at 26 and 52 weeks post-irradiation. These findings offer the promise of improving the quality of life for brain tumor patients.

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.

To test the efficacy of magnetic resonance spectroscopy (MRS) in identifying radiation-induced brain injury, adult male Fischer 344 rats received fractionated whole-brain irradiation (40 or 45 Gy given in 5-Gy fractions twice a week for 4 or 4.5 weeks, respectively); control rats received sham irradiation. Twelve and 52 weeks after whole-brain irradiation, rats were subjected to high-resolution MRI and proton MRS. No apparent lesions or changes in T(1)- or T(2)-weighted images were noted at either time. This is in agreement with no gross changes being found in histological sections from rats 50 weeks postirradiation. Analysis of the MR spectra obtained 12 weeks after fractionated whole-brain irradiation also failed to show any significant differences (P > 0.1) in the concentration of brain metabolites between the whole-brain-irradiated and sham-irradiated rats. In contrast, analysis of the MR spectra obtained 52 weeks postirradiation revealed significant differences between the irradiated and sham-irradiated rats in the concentrations of several brain metabolites, including increases in the NAA/tCr (P < 0.005) and Glx/tCr (P < 0.001) ratios and a decrease in the mI/tCr ratio (P < 0.01). Although the cognitive function of these rats measured by the object recognition test was not significantly different (P > 0.1) between the irradiated and sham-irradiated rats at 14 weeks postirradiation, it was significantly different (P < 0.02) at 54 weeks postirradiation. These findings suggest that MRS may be a sensitive, noninvasive tool to detect changes in radiation-induced brain metabolites that may be associated with the radiation-induced cognitive impairments observed after prolonged fractionated whole-brain irradiation.

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Gilliam-Davis S, Payne VS, Kasper SO, Tommasi EN, Robbins ME, Diz DI. Long-term AT1 receptor blockade improves metabolic function and provides renoprotection in Fischer-344 rats. Am J Physiol Heart Circ Physiol 293: H1327-H1333, 2007. First published July 6, 2007; doi:10.1152 doi:10. /ajpheart.00457.2007 rats exhibit proteinuria and insulin resistance in the absence of hypertension as they age. We determined the effects of long-term (1 yr) treatment with the angiotensin (ANG) II type 1 (AT1) receptor blocker L-158,809 on plasma and urinary ANG peptide levels, systolic blood pressure (SBP), and indexes of glucose metabolism in 15-mo-old male F344 rats. Young rats at 3 mo of age (n ϭ 8) were compared with two separate groups of older rats: one control group (n ϭ 7) and one group treated with L-158,809 (n ϭ 6) orally (20 mg/l) for 1 yr. SBP was not different between control and treated rats but was higher in young rats. Serum leptin, insulin, and glucose levels were comparable between treated and young rats, whereas controls had higher glucose and leptin with a similar trend for insulin. Plasma ANG I and ANG II were higher in treated than untreated young or older rats, as evidence of effective AT1 receptor blockade. Urinary ANG II and ANG-(1-7) were higher in controls compared with young animals, and treated rats failed to show age-related increases. Protein excretion was markedly lower in treated and young rats compared with control rats (young: 8 Ϯ 2 mg/day vs. control: 129 Ϯ 51 mg/day vs. treated: 9 Ϯ 3 mg/day, P Ͻ 0.05). Long-term AT1 receptor blockade improves metabolic parameters and provides renoprotection. Differential regulation of systemic and intrarenal (urinary) ANG systems occurs during blockade, and suppression of the intrarenal system may contribute to reduced proteinuria. Thus, insulin resistance, renal injury, and activation of the intrarenal ANG system during early aging in normotensive animals can be averted by renin-ANG system blockade.angiotensin type 1 receptor blockade; glucose metabolosim; aging MANY NORMOTENSIVE RAT STRAINS exhibit increases in systolic blood pressure (SBP) (42), insulin resistance, body weight (13,30,31,41), and serum leptin (30, 39) as they age. Similar changes occur in the aging human population, and a clustering of these factors is consistent with the metabolic syndrome (MetS) (22, 41a). MetS, a collection of cardiovascular risk factors, is an intermediate state between normal metabolism and Type 2 diabetes (22,43). Clinical trials have shown that renin-angiotensin (ANG) system (RAS) blockade, either by ANG-converting enzyme (ACE) inhibitors (4, 57) or ANG II type 1 (AT 1 ) receptor blockers (17, 27), may substantially lower the risk for Type 2 diabetes in hypertensive subjects. However, the exact mechanism underlying this effect is unknown. Moreover, long-term ACE inhibition or AT 1 receptor blockade in rodents protects against most of these age-related changes, including the increase in blood pressure (5, 18), weight gain (11), and decline in cognitive, mitochondrial,...