Digital Theses Archive


Tesi etd-03282023-121619

Type of thesis
Brain-Heart Axis Dysfunction Modeling: from Characterization to Nutraceutical Treatment
Scientific disciplinary sector
Istituto di Scienze della Vita - PHD IN MEDICINA TRASLAZIONALE
  • barley β-glucan
  • Brain-Heart Axis
  • obesity
  • oxidative stress
  • psychosocial stress
Exam session start date
Lifestyle-related risk factors, mainly obesity and work-related stress, hugely affect cardiac and brain health in Western societies, increasing susceptibility to concomitant disabling diseases such as myocardial infraction, stroke, dementia, mood and affective disorders. The in-depth study of the mechanisms that trigger these pathogenetic processes, aimed to identify prevention and treatment strategies, requires a translational animal model capable of mimicking dysfunctions and helping validate neuro- and cardioprotective non-invasive interventions, such as nutraceutical approaches. Nutraceutical supplementation, indeed, is becoming a subject of significant clinical interest, primarily because of its proven health benefits. Moreover, a notable advantage of nutraceuticals is the limited incidence of side effects compared to conventional pharmacological therapies.<br>To fill this gap, a Brain-Heart Axis dysfunction animal model was developed by subjecting 10-week-old C57BL/6J male mice to High-Fat Diet (HFD) for 18 weeks and psychosocial stress (PS) via Resident Intruder Paradigm (RIP) during the last 14 days of the dieting protocol [HFD+PS]. The nutraceutical supplementation was evaluated by adding 3% of barley β-glucan from the 8th week of HFD [HFDβ+PS]. Both model and treated animals were compared with normal-weight age-matched mice, fed standard diet and not undergoing PS [Ctrl]. In order to verify the safety of the sole compound intake on a healthy substrate, a further group of unstressed mice was fed standard diet enriched with β-glucan (3%) [Ctrlβ]. Functional in vivo characterization was performed through monitoring of metabolic parameters (weight and caloric intake), behavioral assessment (Y-maze for spatial memory evaluation and Elevated Plus Maze for anxiety-like traits detection) and echocardiography, while the morpho-functional post-mortem analysis were performed on perfused hippocampal slices and formalin-fixed paraffin-embedded myocardial sections. Moreover, a neurocardiac co-culture in vitro model was set up, by coexisting hippocampal and cardiac cells to delineate the H2O2-induced oxidative stress damage and test the potential protective effect of β-glucan treatment (3%).<br>Metabolically, dietary β-glucan supplementation mitigated HFD-induced weight gain in obese and stressed mice under conditions of equal caloric intake. During RIP, treated animals showed greater defensiveness against CD1 offense, suggesting the preservation of balanced mood, against the depressive-like manifestations observed in the model. The behavioral evaluation highlighted the efficacy of the compound in preventing the spatial memory deficit and the onset of anxiety-related traits, both detected in HFD+PS mice. The immunohistochemical investigation emphasized hippocampal pathological remodeling due to the synergy between HFD and PS; interestingly, levels of synaptic plasticity (PV+ interneurons), neurogenesis (BrdU+ cells) and astrogliosis (GFAP) comparable to the Ctrl group and statistically enhanced from the HFD+PS group were found in β-glucan-treated animals. In contrast, the dentate gyrus atrophy measured in the HFD+PS mice was not restored by the nutraceutical supplementation. The echocardiographic analysis revealed the left ventricular (LV) performance decline in obese stressed mice and a significative improvement in cardiac functionality referable to the compound. The heart tissue histological examination highlighted a relevant morphological alteration induced by the HFD/PS combination; noteworthy, dietary β-glucan enrichment prevented cardiomyocyte hypertrophy and decreased the number of apoptotic cardiac cells, compared to the HFD+PS group. Furthermore, the protective action of β-glucan in promoting hippocampal and cardiac cell survival was confirmed in vitro. The treatment has been shown to be effective in preventing HT22 and HL1 stress-induced mortality, by counteracting the oxidative stress load due to chronic exposure to H2O2.<br>Overall, our data demonstrated the neuro- and cardioprotective activity exerted by β-glucan in subjects at high cardio- and cerebrovascular risk, induced by chronic and synergistic exposure to HFD and PS. Our easily implementable nutraceutical approach constitutes an effective tool aimed at protecting the Brain-Heart Axis from an unbalanced Westernized lifestyle.