Aerobic training reduces microglial activation and TNFα release in the hypothalamus of hypertensive rats

Abstract

Spontaneously hypertensive rats (SHR) exhibit autonomic imbalance and blood-brain barrier (BBB) dysfunction, a pathophysiological condition that can be corrected by exercise training. Although microglia cells are not part of the structure of the BBB itself, they modulate it function through the synthesis and release of cytokines. In hypertension condition, for instance, microglia are activated releasing pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNFα), which is able to break down different BBB constituents. Therefore, here we hypothesized that the benefit of exercise training to ameliorate BBB integrity of hypertensive rats could be due to the reduction in the release of TNFα by microglia at the hypothalamus level. Thus, our aim is to evaluate whether microglial activation, and consequent TNFα release, in the hypothalamus of SHR can be affected by aerobic exercise training. Wistar and SHR male rats (CEUA ICB/USP #3407080618) aged 90 days were divided into four groups: sedentary (W-S n=6) and trained Wistar (W-T n=6), sedentary (SHR-S n=6) and trained SHR (SHR-T n=6). Exercise trained animals were submitted to moderate intensity of aerobic training on a treadmill (50%-60% of maximum capacity, 1 h/day, 5 days/week, for 4 weeks). At the end of the 4th week of training, the hypothalamus, brainstem, and cortex of all groups were collected and processed for isolation of mononuclear cells, followed by flow cytometry analysis to evaluate the microglial labeling by CD45lowCD11b+, gated for TNFα+. All data as analyzed by two-way ANOVA followed by Bonferroni’s post-test. Trained animals showed performance gains compared to their control groups (Velocity: W-S: 1.07±0.23km/h vs. W-T: 1.7±0.36km/h, p<0.0001 and SHR-S: 1.25±0.17km/h vs. SHT-T: 1.95±0.16km/h, p<0.0001; Distance: W-S: 85±42m vs. W-T: 218±95m, p=0.0042 and SHR-S: 124±44m vs. SHT-T: 315±21m, p<0.001). Hypertensive animals present an elevated neuroinflammation degree compared to normotensive subjects, by increased microglia activation (W-S: 0.65±0.39% vs. SHR-S: 7.0±1.4%, p<0.0001) and TNFα release (W-S: 33.9±24.6% vs. SHR-S: 95.2±3.6%, p=0.0007). After training, hypertensive rats exhibited a reduction in hypothalamic microglial activation in a similar way to sedentary and trained Wistar (CD45lowCD11b+, SHR-T: 0.55±0.26%: vs. W-S:0.65±0.39% p=0.99; vs. W-T: 0.41±0.28% p=0.98; vs. SHR-S: 7.0±1.4% p<0.0001). TNFα release also reduced in hypothalamus of SHR-T (CD11b+TNFα+, SHR-T: 59.4±17.0%: vs. W-S: 33.9±24.6% p=0.15; vs. W-T: 41.9±4.6% p=0.6; vs. SHR-S: 95.2±3.6% p<0.01). SHR-S exhibit higher microglial activation and TNFα release in brainstem compared to W-S, but 4 weeks of training was not enough to reduce this condition. No difference was observed in cortex. In conclusion, exercise training of moderate intensity is effcient to reduce microglia activation and consequently TNFα release in the hypothalamus of hypertensive animals, which could be one of the causes affecting the integrity of the BBB in hypertensive animals. FAPESP #2018/14544-6; #2022/07465-8. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.