Effects of acute exercise and voluntary freewheel exercise in mice on pro-inflammatory cytokines and markers of apoptosis in the hippocampus
Pervaiz Munir, Nabeel
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Introduction: Alzheimer’s disease (AD) and dementias constitute a significant public health burden and it is estimated that one in 85 people may be living with AD by 2050. Dementias are a spectrum of diseases with common traits including amyloid protein growth, neurodegradation, neurofibrillary plaque and tangle formation, and which may be influenced by pro- and anti- inflammatory immune mechanisms. Even a modest delay in onset could result in significant reductions in the social and economic burdens of dementias. An important lifestyle factor identified in risk reduction is physical activity (PA). Although the association between dementia risk and PA has been established, the exact physiological mechanisms through which protection occurs are not known. This research consists of two experiments that were designed to explore the effects of physical activity on pro- and anti-inflammatory cytokines and apoptosis in the mouse hippocampus, a brain region implicated in learning, memory, and cognition. Methods: Study #1: Female C57BL/6 mice, 4-5 months of age, were divided into three groups: sedentary controls (NOTREAD) (n = 22), treadmill exercise with immediate sacrifice (TREAD-Imm) (n = 21), or treadmill exercise with sacrifice after 2 hours (TREAD-2h) (n = 20). TNF-α, IL-6, and IL-1β expression in the hippocampus and intestinal lymphocytes were measured by Western blot analysis. Percentages of hippocampal cells undergoing apoptosis (Annexin+) or necrosis (Propidium Iodide+) were determined through flow cytometry. Plasma levels of 8-isoprostane and corticosterone were measured using commercially available EIA kits. Study # 2: Female C57BL/6 mice, 3-4 weeks of age, were assigned to wheel running (WR; n = 20) or a control condition (No WR; n = 22) and sacrificed after the 16 weeks. Data collected included measures of training status (running volume, body weight, run-to-exhaustion time, and skeletal muscle cytochrome c oxidase activity), flow cytometric analysis of hippocampal cell phenotypes and apoptosis (CD45+, CD11b+, Annexin+, Annexin+/PI+, PI+), and cytokine concentrations (TNF-α, IL-1β, IL-12, IL-6, IL-1ra, and IL-10) in cell lysates. Results: Study #1: Acute treadmill exercise lead to significant decreases in TNF-α (p<0.05) and increases in IL-6 (p<0.05) expression in the hippocampus of healthy mice. No effects of acute exercise on the apoptotic status of hippocampal cells were observed. In intestinal lymphocytes, the exercise bout lead to significant increases in TNF-α (p<0.05), IL-6 (p<0.05), and IL-1β (p<0.05). Acute exercise was associated with a significant increase in both plasma 8-isoprostane (p<0.05) and corticosterone (p<0.05) levels. Study #2: WR mice had measurable training effects and significantly lower TNF-α (p<0.05) and higher IL-6 (p<0.05), IL-1ra (p<0.05) and IL-12 (p<0.05) expression in the hippocampus compared to controls. IL-1β, IL-10, and the percent of apoptotic, dead cells, and cell phenotypes did not change due to training. Conclusion: Exercise chronicity (acute vs. chronic), stress characteristics of the exercise (forced vs. voluntary) and tissue location (systemic vs. central) emerged as important variables with effects on both cytokine concentrations and plasma levels of stress hormones. Physical activity may protect the hippocampus against inflammatory damage caused by TNF-α, and the suppression of this cytokine may be due to increased glucocorticoid secretion during acute exercise. It is also proposed that elevated IL-6 expression (central and systemic) may mediate this protection by creating an anti-apoptotic environment in the hippocampus. Less apoptosis may also contribute to maintenance of cognitive function during acute and long-term physical activity.