ABC | Volume 115, Nº2, August 2020

Review Article Trombetta et al. BDNF in cardiovascular protection and exercise Arq Bras Cardiol. 2020; 115(2):263-269 derived from NADPH oxidase (NOX) by TrkB receptor signal transduction, probably via Akt activation , resulting in the migration of endothelial cells. 8 The study suggests that: TrkB ⇒ NADPH oxidase 2 (Nox2) ⇒ ROS ⇒ Phosphoinositide 3-kinase (PI3K)/Akt. 8 In fact, BDNF has been consistently implicated in the angiogenesis and maintenance of vascular integrity. Specifically in the endothelium, besides the binding of BDNF to its high affinity receptor TrkB, 25,46 there is also the expression of the p75 receptor, of which binding to the pro-BDNF has been related to vascular smooth muscle apoptosis. 47,48 Considering the conjugated localization of BDNF-TrkB and pro-BDNF-p75 in the endothelium and due to the antagonistic physiological action between BDNF and pro-BDNF, it is important to take into account the balance between plasticity/survival and apoptosis in peripheral blood flow through the BDNF/pro-BDNF ratio. More recently, the link between this neurotrophic and cardiovascular protection was evidenced in the study by Okada et al, 49 conducted with conditional BDNF-knockout mice, in which BDNF expression was systemically reduced. In this study, the authors demonstrated that a mechanism mediated by the Central Nervous System is involved in the regulation of cardiac function after myocardial infarction. Ischemic insults are transmitted from the heart to the Central Nervous System through afferent cardiac fibers after the myocardial infarction, thereby increasing BDNF neuronal expression. An increase in circulating BDNF promotes the survival of cardiomyocytes and is associated with increased expression of pro-angiogenic factors. Comparatively, knockout animals had greater myocardial damage after the experimental infarction compared to wild-type mice. 49 In this context, the Val66Met polymorphism can affect serum concentrations of BDNF and, consequently, influence the activity of tissues containing TrkB receptors, be they neurons or even peripheral tissues, such as vascular endothelial cells. BDNF and Cognitive Effects of Exercise There is much evidence that physical exercise, especially aerobic exercise, has a beneficial effect on cognitive domains, particularly on executive and memory functions and reduces hippocampal atrophy in late adulthood, with BDNF being heavily involved. 11,50-57 Epidemiological and intervention studies reinforce the idea of using physical activity as a strategy to increase neuroplasticity in pathological conditions. 58 Several studies have shown that exercise not only causes structural changes in the brain, but also protects against aging-related cognitive decline. 57,59 Physical exercise activates molecular and cellular cascades that promote neuronal plasticity and neurogenesis, inducing expression of the gene encoding BDNF. 10,60 Peripheral concentrations of BDNF increase in both acute and chronic aerobic exercise, and the magnitude of this increase seems to be dependent on exercise intensity. 61 In addition, greater cognitive benefits are obtained when the duration of the program and the exercise session are longer, individuals are older, with greater benefits for women than for men. 56 The difference between genders regarding BDNF levels in cerebrospinal fluid in favor of women may be due to hormonal effects, 23 since estrogen receptors are located in cells expressing BDNF and its TrkB receptor, so that estrogen regulates the expression of BDNF. 62 Interestingly, this benefit of exercise occurs even in young adult men. This was evidenced in a cohort study of young Swedish men enlisted in military service at age 18 (n=1,221,727), 50 in which a significant positive association was found between cardiovascular fitness and cognitive performance after adjusting for relevant confounders. Largely, the benefits of exercise on the production of BDNF and neuronal plasticity are related to increased cerebral and muscle vascularization. In fact, in a recent review 63 the authors have shown that the cognitive benefits of good cardiovascular fitness are related to increased cerebral circulation and angiogenesis. This important adaptation allows increased flow and upregulation of neurotrophins in the neurogenic niche of the hippocampus, a phenomenon that occurs even after acute exercise sessions. 63 Specifically, studies on the acute and chronic effects of exercise on serum BDNF concentration still yield controversial results. For example, in a study comparing the chronic and acute effects of physical exercise on the serum concentrations of BDNF, it was demonstrated that a single exercise session was able to induce a transient increase in BDNF levels, but the same results were not achieved after a longer period of training. 64 On the other hand, in another study where the sample was submitted to 6 months of training, a trend in an increase in serum BDNF concentration was found, in addition to an improvement in cognitive function. 65 A similar result was found in a longitudinal study with the elderly, which resulted in an increase in the volume of hippocampal parts and, according to the authors, this fact is related to the increase in BDNF levels. 51 These apparently controversial results may be dependent on the duration of the exercise benefits, specifically on post- exercise BDNF plasma levels, i.e., whether they occur soon after a single session of acute exercise, after a session of a regular exercise program (showing changes in BDNF release after repeated exercise sessions) or changes in resting BDNF levels after a regular exercise program. 66 Indeed, this was evidenced in the recent meta-analysis on the effects of exercise on serum BDNF, 66 which concluded that regular exercise intensified the effect of an exercise session on BDNF levels (Hedges’ g =0.59; P =0.02). However, the results indicated a lower effect of regular exercise on resting BDNF levels (Hedges’ g =0.27; P =0.005). There is reliable evidence from human studies indicating that each exercise episode results in a BDNF dose response and that the magnitude of this response can be increased over time through regular exercise. 66 There is a large body of evidence that demonstrates that exercise works on several powerful neuroprotective pathways that can converge to promote continued brain health into senescence. These benefits occur either in response to acute activities or in regular practice and occur both in response to high-intensity exercises and in moderate-intensity aerobic exercises, increasing levels of circulating neurotrophic factors and neurotransmission, exerting beneficial effects on mood and cognitive functions in individuals of all ages. 265