Interação sinérgica entre nitrato dietético e exercício físico na promoção da melhoria neurovascular e cognitiva: de modelos pré-clínicos à prova de conceito

The overall goal of this proposal is to establish a novel approach based on lifestyle interventions to improve neurovascular and cognitive function associated with vascular cognitive impairment (VCI). Specifically, we aim to explore a potential synergic effect of dietary nitrate and exercise in affording neuroprotection and counteracting the cognitive decline in VCI (GRAPHICAL HYPOTHESIS attached). Dietary nitrate has been ascribed as an effective ergogenic supplement, increasing the tolerance to physical exercise. This has led us to the assumption that dietary nitrate may be able to boost the neuroprotective effects of physical exercise. In turn, physical exercise can create an optimal physiological environment for nourishing and potentiating the nitrate-nitrite-NO pathway. This may increase the potential of dietary nitrate to increase NO bioavailability and NO-dependent neurovascular coupling, which we recently demonstrated to mitigate cognitive impairment in VCI rodent models (PRELIMINARY RESULTS attached). Specific aims include: i. To test the beneficial effect of dietary nitrate and physical exercise on neurovascular function in VCI rodent models, as well as their impact on cognitive performance on basis of a quantitative/temporal association between vascular changes and neuronal functioning. ii. To explore the molecular mechanistic underpinning of the beneficial effects of the combined intervention with dietary nitrate and physical exercise, particularly focusing the neurogenesis and angiogenesis, neuroinflammation, and oxidative stress; iii. To provide insights into the crosstalk between the brain and peripheral and investigate plausible bloodborne components capable of mimicking the beneficial effects of dietary nitrate and physical exercise. iv. To explore the potential of transferable factors from exercised plasma to modulate of neurovascular and cognitive dysfunction in VCI rodent models mimicking the beneficial impact ascribed to the combined intervention in brain function. v. To attain information with relevant translational value regarding the impact of dietary nitrate and physical exercise and intervention by non-invasive imaging methods. vi. To provide a proof of concept in humans regarding the impact of combined intervention with dietary nitrate and physical exercise and in neurovascular function capable of supporting the translation of the intervention to a clinical cohort. Overall, this proposal tackles important challenges related to dementia prevention and management, particularly in VCI. This is a major challenge considering that reducing the burden of dementia is a major biomedical priority and VCI is the prevalent form of dementia in Portugal. It leverages lifestyle interventions with potential neuroprotective effects with ambitious goals that go beyond the current state of the art. While both dietary interventions and exercise have been separately studied for their potential cognitive benefits, this research plan seeks to integrate these approaches synergistically, which represents a novel and potentially groundbreaking concept. This will be accomplished by an interdisciplinary approach capable of pushing the boundaries of current knowledge in the field. By integration of preclinical and clinical research, which is both ambitious and potentially transformative, the initiative aims to provide proof of concept in humans regarding the impact of the combined intervention on neurovascular function.