Magnetic resonance imaging biomarkers of exercise‐induced improvement of oxidative stress and inflammation in the brain of old high‐fat‐fed ApoE^−/− mice

Abstract

Vascular brain lesions, present in advanced atherosclerosis, share pathological hallmarks with peripheral vascular lesions, such as increased inflammation and oxidative stress. Physical activity reduces these peripheral risk factors, but its cerebrovascular effect is less documented, especially by non-invasive imaging. Through a combination of in vivo and post-mortem techniques, we aimed to characterize vascular brain damage in old ApoE mice fed a high-cholesterol (HC) diet with dietary controlled intake. We then sought to determine the beneficial effects of exercise training on oxidative stress and inflammation in the brain as a treatment option in an ageing atherosclerosis mouse model. Using in vivo magnetic resonance imaging (MRI) and biological markers of oxidative stress and inflammation, we evaluated the occurrence of vascular abnormalities in the brain of HC-diet fed ApoE mice >70 weeks old, its association with local and systemic oxidative stress and inflammation, and whether both can be modulated by exercise. Exercise training significantly reduced both MRI-detected abnormalities (present in 71% of untrained vs. 14% of trained mice) and oxidative stress (lipid peroxidation, 9.1 ± 1.4 vs. 5.2 ± 0.9 μmol mg ; P < 0.01) and inflammation (interleukin-1β, 226.8 ± 27.1 vs. 182.5 ± 21.5 pg mg ; P < 0.05) in the brain, and the mortality rate. Exercise also decreased peripheral insulin resistance, oxidative stress and inflammation, but significant associations were seen only within brain markers. Highly localized vascular brain damage is a frequent finding in this ageing atherosclerosis model, and exercise is able to reduce this outcome and improve lifespan. In vivo MRI evaluated both the neurovascular damage and the protective effect of exercise.

Exercise Does Not Protect against Peripheral and Central Effects of a High Cholesterol Diet Given Ad libitum in Old ApoE−/− Mice

“…The observed consequences were neurological symptoms and mortality within the 12 weeks of follow-up (25 and 16% in EX and SED ApoE −/− , respectively). This clinical aggravation was observed despite a regular physical activity, which was supposed to induce protection and counteract neuroinflammation and oxidative stress, as previously described when the food quantity was limited to 20 g/week in both sedentary and exercise mice (Chirico et al, 2016 ). In this context of limited access to the HC diet, exercise training, possibly via its oxidative stress and inflammation lowering capabilities, reduced brain macrophage infiltration, limited inflammation, and oxidative stress in the brain, and also improved insulin sensitivity.…”

“…Analysis of longitudinal data showed that these features, present in old ApoE −/− mice (Chirico et al, 2016 ), evolved during the 12-weeks training in EX ApoE −/− mice, as confirmed by the significant increase in post-gadolinium T1 score ( p = 0.02, Figure 3A–B ), when there was no significant change in SED ApoE −/− mice. After-training, focal periventricular areas of signal loss were observed on T2 * maps in both EX and SED ApoE −/− mice (Figure S3 ), but there were no significant T2 and T2 * scores changes after the follow-up period.…”

“…In addition to the vascular risk per-se , an increasing number of studies are reporting various locations of BBB permeability and hippocampal inflammation as a direct consequences of obesity and high fat consumption (Badaut et al, 2012 ; Thaler et al, 2012 ; Lee et al, 2013 ; Erion et al, 2014 ; Van der Donckt et al, 2015 ). In an atherosclerosis mouse model under high fat diet, we and others have recently shown that exercise can limit brain inflammation (Yi et al, 2012 ; Auer et al, 2015 ; Chirico et al, 2016 ).…”

Alogliptin improves survival and health of mice on a high‐fat diet

“…To select optimum dose of alogliptin, we firstly performed the dose–response experiment in apolipoprotein E null (ApoE −/− ) mice on high‐fat diet. Naturally, ApoE −/− mice exhibited shorter lifespan compared with C57BL/6 mice (Chirico et al, ; Honma et al, ). Cohorts of one‐year‐old male ApoE −/− mice were provided with high‐fat diet (60% of calories from fat, HFD) for the remainder of their lives.…”

Cultivating a healthy neuro‐immune network: A health psychology approach

“…Studies using animal models have also characterized effects of physical activity on inflammation in the CNS. More specifically, exercise appears to shift microglia from an inflammatory to a neuroprotective phenotype (Chirico et al, ; Parachikova, Nichol, & Cotman, ; Ryan & Kelly, ), the latter of which has been linked to better cognitive function and neurogenesis in aged mice (Chirico et al, ; Kohman, DeYoung, Bhattacharya, Peterson, & Rhodes, ). In addition, exercise following spinal cord injury reduces microglia activation during recovery and mitigates development of pain in a rodent model (Chhaya, Quiros‐Molina, Tamashiro‐Orrego, Houle, & Detloff, ).…”