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. 2022 Sep 1;77(9):1784-1788.
doi: 10.1093/gerona/glac101.

Losartan Mitigates Oxidative Stress in the Brains of Aged and Inflamed IL-10-/- Mice

Nazaneen Saleh  1 , Caglar Cosarderelioglu  2   3 , Ramya Vajapey  4 , Jeremy Walston  2 , Peter M Abadir  2
Affiliations

Losartan Mitigates Oxidative Stress in the Brains of Aged and Inflamed IL-10-/- Mice

Nazaneen Saleh et al. J Gerontol A Biol Sci Med Sci. .

Abstract

Chronic inflammation, oxidative stress, and dysregulation of the renin-angiotensin system are closely linked, and their crosstalk commonly contributes to age-related physical and cognitive decline. The primary dementia-protective benefits of Angiotensin II type 1 receptor (AT1R) blockers are believed to arise from systemic effects on blood pressure. However, there is an independently regulated brain-specific renin-angiotensin system. Here, we examined the impact of 4 weeks of oral Losartan treatment on the brains of aged (100 weeks old) IL-10-/- mice, an animal model of chronic inflammation and frailty. Our data show that aged IL-10-/- mice have higher AT1R and Nitrotyrosine (oxidative stress marker) levels in their frontal cortex tissue but not in cerebellar or hippocampal tissue compared to age- and sex-matched wild type mice. Losartan treatment for 4 weeks is associated with lower AT1R protein level, Nitrotyrosine, and Tau protein in the frontal cortex of aged IL-10-/- mice. Our results highlight the impact of Losartan, an AT1R blocker commonly prescribed for treating high blood pressure, on the brain-specific angiotensin system and AT1R-linked downstream effects such as brain oxidative stress damage and Tau burden in a frailty mouse model.

Keywords: Angiotensin system; Brain; Inflammation; Losartan; Tau.

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Figures

Figure 1.
Figure 1.
Impact of aging with chronic inflammation on brain RAS receptors, oxidative stress, and Tau. Actin was used for normalization. Arbitrary units were shown in the figures. Data are presented with mean and standard error of the mean. Comparisons were conducted using the Student’s t-test. AT1R, for cortex WT n = 4, IL-10−/−n = 3; for cerebellum WT n = 4, IL-10−/−n = 4; and for hippocampus WT n = 5, IL-10−/−n = 5. AT2R, for cortex WT n = 4, IL-10−/−n = 4; for cerebellum WT n = 4, IL-10−/−n = 4; and for hippocampus WT n = 5, IL-10−/−n = 5. NT, for cortex WT n = 4, IL-10−/−n = 4; for cerebellum WT n = 4, IL-10−/−n = 4; and for hippocampus WT n = 5, IL-10−/−n = 5. Tau, for cortex WT n = 4, IL-10−/−n = 4; for cerebellum WT n = 4, IL-10−/−n = 4; and for hippocampus WT n = 5, IL-10−/−n = 5. AT1R = Angiotensin II type 1 receptor; AT2R = Angiotensin II type 2 receptor; IL-10−/− = IL-10 knockout mouse model, ns = nonsignificant; NT = nitrotyrosine; RAS = renin–angiotensin system; WT = wild type; *p ≤ .05; **p ≤ .01.
Figure 2.
Figure 2.
Effect of Losartan treatment on the main brain renin–angiotensin receptors, oxidative stress, and Tau. Actin was used for normalization. Arbitrary units were shown in figures. Data are presented with mean and standard error of the mean. Comparisons were conducted using the Student’s t-test. AT1R, for cortex IL-10−/−n = 3 IL-10−/− + Los n = 4; for cerebellum IL-10−/−n = 4 IL-10−/− + Los n = 3; and for hippocampus IL-10−/−n = 5 IL-10−/− + Los n = 5. AT2R, for cortex IL-10−/−n = 4 IL-10−/− + Los n = 4; for cerebellum IL-10−/−n = 4 IL-10−/− + Los n = 4; and for hippocampus IL-10−/−n = 5 IL-10−/− + Los n = 5. NT, for cortex IL-10−/−n = 4 IL-10−/− + Los n = 4; for cerebellum IL-10−/−n = 4 IL-10−/− + Los n = 4; and for hippocampus IL-10−/−n = 5 IL-10−/− + Los n = 5. Tau, for cortex IL-10−/−n = 4 IL-10−/− + Los n = 4; for cerebellum IL-10−/−n = 4 IL-10−/− + Los n = 4; and for hippocampus IL-10−/−n = 5 IL-10−/− + Los n = 5. AT1R = Angiotensin II type 1 receptor; AT2R = Angiotensin II type 2 receptor; IL-10−/− = IL-10 knockout mouse model; ns = nonsignificant; NT = nitrotyrosine; *p ≤ .05; **p ≤ .01; ***p ≤ .001.
Figure 3.
Figure 3.
Similarities and differences in the molecular mechanisms of chronic inflammation (IL-10−/−) and Losartan treatment mouse models within the frontal cortex, cerebellum, and hippocampus. AT1R = Angiotensin II type 1 receptor; AT2R = Angiotensin II type 2 receptor; NT = Nitrotyrosine.
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