Mature BDNF binds with higher-affinity Trk family receptors (Villanueva
2013)—especially TrkB—increasing cell survival and differentiation, dendritic spine complexity, long-term potentiation (Lu et al.
2008; Messaoudi et al.
2002), synaptic plasticity (Kang and Schuman
1996), and the resculpting of neuronal networks (Lee et al.
2001). ProBDNF is also biologically active, it mediates its actions through binding to low-affinity p75Ntr, having antagonistic effect compared to matured BDNF: reducing spine complexity and density (Zagrebelsky et al.
2005) and promoting neuronal cell death (Teng et al.
2005).
BDNF in mood disorders
Numerous clinical studies confirm the involvement of BDNF in the pathophysiology of depression (Lee and Kim
2010). Reductions in serum and plasma mature BDNF have been demonstrated in patients suffering from depression (Lee et al.
2007; Yoshida et al.
2012) and in those who committed suicide (Birkenhager et al.
2012; Kim et al.
2007b). Significantly lower levels of serum BDNF were found in antidepressant-free patients with major depressive disorder compared with healthy controls (Shimizu et al.
2003), which findings were confirmed by a large cohort study (Molendijk et al.
2011) and by three meta-analyses as well (Bocchio-Chiavetto et al.
2010; Brunoni et al.
2008; Sen et al.
2008).
The regulatory background of BDNF in psychopathology is not totally clarified yet, but epigenetic mechanisms (chromatin remodeling, DNA methylation) have been implicated. Both in schizophrenia and in depression at the promoter I of BDNF DNA methylation at a specific CpG site is increased resulting in reduced BDNF gene transcription (Fuchikami et al.
2011; Ikegame et al.
2013).
Single nucleotide polymorphism in BDNF gene is a plausible candidate to be associated with the development of psychopathology. The Val
66Met polymorphism is characterized by an amino acid substitution of valine (Val) to methionine (Met) at amino acid residue 66. The presence of Met allele causes a failure in intracellular trafficking and packaging of proBDNF, which results in a 25% reduction of the activity-dependent secretion of mature BDNF (Egan et al.
2003). However, the role of Val
66Met polymorphism in psychiatric disorders is well studied but the results are inconsistent. Some studies reported that Met/Met patients have more severe symptoms of depression (Czira et al.
2012), whereas others showed that Val/Val genotype is associated with increased depressive symptoms (Jiang et al.
2013) or higher scores on the cognitive–affective factor of the Beck Depression Inventory-II test (Duncan et al.
2009).
BDNF and CV pathology
BDNF plays an important role during development of the CV system: it activates TrkB receptor leading to the survival of endothelial cells and the formation of the cardiac vasculature (Emanueli et al.
2014). Embryonic BDNF deficiency impairs the development of intramyocardial vessels and can also lead to cardiac hypercontractility (Donovan et al.
2000). BDNF functions as an angiogenic regulator, promoting angiogenesis (Kermani et al.
2005). It is expressed in a greater amount in the peripheral vessels, where it could influence vasoreactivity (Prigent-Tessier et al.
2013). BDNF is able to enhance vascular flow and can regulate revascularization of ischemic tissues (Kermani et al.
2005). Furthermore, it improves left-ventricular function in ischemic myocardium (Liu et al.
2006).
In CVD, the role of Val
66Met polymorphism is still unclear, but interestingly in a follow-up clinical study patients carrying Met allele were associated with a reduced risk of clinical CVD events and lower severity of coronary artery disease than Val/Val genotype (Jiang et al.
2017). However, further investigations are needed to clarify the genetic aspect of the link between BDNF and CVD.
How can BDNF influence blood pressure, potentially playing an important role in the development of hypertension? Axonal guidance is among the top pathways explaining the association between mood disorders and cardio-metabolic-disease risk (Amare et al.
2017). Mutant axonal guidance genes—including BDNF—followed by abnormal axonal guidance and connectivity can cause disorders primarily in the brain and subsequently in peripheral organs (Sasaki et al.
2014). During embryonic development, BDNF is found to be a target-derived survival factor for a large subset of nodose ganglion neurons, such as arterial baroreceptors (Brady et al.
1999) and is also involved in the development of chemoafferent sensory neurons innervating the carotid body (Conover et al.
1995; Erickson et al.
1996). Furthermore, postnatally BDNF is expressed by the nodose ganglion neurons themselves (Schecterson and Bothwell
1992; Wetmore and Olson
1995) and can be also released from these neurons by activity (Balkowiec and Katz
2000). BDNF is expressed in arterial baroreceptors and their central terminals in medial nucleus tractus solitarius in vivo. BDNF release from cultured nodose ganglion neurons is increased by electrical stimulation with patterns that mimic the in vivo activity of baroreceptor afferents (Martin et al.
2009). Thus it seems that BDNF is involved not only in the development of baroreceptors, but also in their normal functioning in adulthood.
During normal conditions when blood pressure increases, the activated baroreflex reduces heart rate and blood pressure by a negative feedback loop. In addition, elevated blood pressure activates inhibitory GABAergic neurons in the hypothalamus, reducing the secretion of the blood pressure-elevating hormone vasopressin (Marosi and Mattson
2015). But different pathophysiological changes can influence the mechanism of the baroreflex loop. It is already shown that high dietary salt intake can affect blood pressure through NT-mediated changes of the central homeostatic circuit. Choe et al. proved in an animal study that chronic high salt intake is able to decrease the baroreceptor-mediated inhibition of vasopressin neurons through a BDNF-dependent activation of TrkB receptors and through the downregulation of potassium/chloride co-transporter 2 expression, which prevents inhibitory of GABAergic signaling (Choe et al.
2015). Furthermore, reduced BDNF level in mice results in elevated heart rate, and infusion of this NT into the cerebral ventricles can restore this effect (Wan et al.
2014). In the same study, Wan et al. showed that GABAergic responses are increased in brainstem cardiovagal neurons of BDNF+/− mice, suggesting that BDNF increases the activity of the parasympathetic neurons to reduce heart rate (Wan et al.
2014). In summary, BDNF is required for normal carotid body innervation, baroreceptor function and heart rate regulation and these effects can be blunted in pathological conditions, such as high salt intake, which can lead to the development of hypertension.
Another pathway explaining the association between BDNF, CV function and susceptibility to mental diseases as well is the renin–angiotensin system (RAS). Increased central RAS activation is an indicator of many CV diseases, such as hypertension and heart failure (Biancardi et al.
2014; Zucker et al.
2012). On the other hand, data are accumulating about the newly discovered effects of the RAS related to neuroprotection, cognition and cerebral vasodilation. Angiotensin (AT) 1–7 also affects non-CV functions in the brain, such as learning, memory, and neuroprotection (Farag et al.
2017). Clinical studies have shown that AT II receptor type 1 (AT1R) blockers—independent of blood pressure-lowering effect—improve cognitive function in elderly hypertensive patients (Fogari et al.
2003; Hajjar et al.
2005). The background mechanism of this phenomenon was investigated in animal studies. Goel et al. showed the evidence that chronic neuroinflammation and memory impairment in hypertension—associated with increased apoptotic cell death and with amyloid beta deposition—can be prevented with candesartan treatment, suggesting partly to be explained by an increase of BDNF/CREB (cAMP response element binding protein) expression (Goel et al.
2017). Furthermore, the connection between RAS and TrkB signaling is proven in vitro (Becker et al.
2015) and in vivo as well, as Becker et al. demonstrated the mediator role of BDNF-TrkB signaling on Ang II-induced mean blood pressure and renal sympathetic nerve activity elevation in male rats (Becker et al.
2017). Thus probably RAS blockers restore BDNF through TrkB signaling pathway.
Cumulating data suggest the connection between endothelial dysfunction and BDNF as well. In an animal study, the protecting effect of the AT1R blocker candesartan after stroke was mediated by endothelial nitric oxide (NO) synthase and it was positively associated with BDNF expression (Alhusban et al.
2017). BDNF is probably indirectly associated with the NO-system as BDNF is secreted by endothelial cells (Zoladz and Pilc
2010), it increases vascular endothelial growth factor (VEGF) expression, which induces angiogenesis (Chen et al.
2005a; Lin et al.
2014) and VEGF also enhances the NO production of endothelial cells (Youn et al.
2009). The connection with endothelial dysfunction is also supported by the observation, that circulating BDNF level inversely correlates with vascular cell adhesion molecule-1 (Lee et al.
2012), which is an accepted biomarker of endothelial dysfunction (Burger and Touyz
2012).
Numerous data are available about the association between BDNF and CV health. In general population, a significant positive correlation was observed between plasma BDNF and diastolic blood pressure, and sexual differences were demonstrated in relation with different serum lipids (Golden et al.
2010). As it was a cross-sectional study, it is unclear if these associations observed are casual or elevated plasma BDNF represents a compensatory response of the disrupted lipid metabolism and hypertension, but the elevation of serum BDNF in hypertension was confirmed by our study as well (Nemcsik et al.
2016). Interestingly, in contrast, decreased endothelial BDNF expression was found in hypertension (Prigent-Tessier et al.
2013), so the source of higher BDNF serum and plasma levels in hypertension is probably not the endothelial cells. Increased BDNF expression was found in atherosclerotic coronary arteries in humans (Ejiri et al.
2005), and decreased plasma BDNF level was observed in patients with metabolic syndrome (Chaldakov et al.
2004), acute coronary syndrome (Lorgis et al.
2010; Manni et al.
2005) and in type 2 diabetes mellitus (Krabbe et al.
2007).
About obesity we found contradictory results in the literature. Previous studies showed that serum BDNF is generally lower in overweight and obese subjects (Celik Guzel et al.
2014; Corripio et al.
2012; El-Gharbawy et al.
2006). In contrary, others showed elevated serum BDNF level in obesity (Roth et al.
2013). This phenomenon has been explained by the fact that BDNF is also regulated by leptin, therefore leptin resistance—as one of the obesity-associated factors—shall be considered in future studies.
Serum BDNF level was diminished in smokers, compared to non-smokers (Bhang et al.
2010; Kim et al.
2007a). Furthermore, BDNF levels in chronic smokers were increased after smoking cessation (30).
In patients with angina pectoris Jiang at al. found that plasma BDNF was inversely associated with triglyceride and low-density lipoprotein (LDL)-cholesterol, male sex and age, while it was correlated positively with high-density lipoprotein (HDL)-cholesterol. In this cohort, low plasma BDNF was an independent predictor of future coronary events and mortality (Jiang et al.
2011). The predictive role of BDNF for future CV events and mortality was confirmed by other studies as well. Higher seBDNF was found to be associated with decreased risk of CV morbidity and mortality (Kaess et al.
2015). On contrary, decreased serum BDNF was found to be associated with increased risk of incident stroke/TIA (Pikula et al.
2013). In summary, these results suggest that BDNF is compensatory elevated in CV pathology and the lack of this elevation bears propensity for poor outcome.
Opportunities to restore BDNF level
Considering that BDNF is involved in CV physiology and through enhancing the neuroplasticity and neurogenesis, it increases the resistance of neurons to metabolic and excitotoxic stress (Marosi and Mattson
2014) a new therapeutic target of mood and CV disorders could be the restoration of BDNF level.
Lifestyle changes like physical activity, such as running and other types of aerobic exercise (Engesser-Cesar et al.
2007; Griffin et al.
2011) or calorie restriction (Marosi and Mattson
2014) could be cardioprotective through BDNF mediation.
Long-term treatment with various antidepressants can also normalize serum BDNF level (Duman and Monteggia
2006; Sen et al.
2008). In animal studies, antidepressants, including selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, and monoamine oxidase inhibitors elevate BDNF mRNA level in hippocampus (Huang et al.
2008). In psychiatry practice, BDNF level improvement can be evoked not only through medication, but also through electroconvulsive therapy (Brunoni et al.
2014). In relation with the CV pharmacology, the AT1R blocker candesartan is proven to restore BDNF (Alhusban et al.
2017) and the ACE-inhibitor perindopril has beneficial effects as well (Ali et al.
2016), but interestingly in case of ramipril this feature seems to be missing (Krikov et al.
2008). As we previously mentioned, RAS blockers probably restore BDNF through TrkB signaling pathway.
In the future, a possibility of BDNF restoration could be the inhibition of its degradation. The mechanism of BDNF degradation is not well investigated, in the literature there are only few studies about this process. More than 25% of synthesized BDNF is depredated by lysosomes. Soluble sortilin is a main protein, which directs the trafficking of BDNF. Sortilin binds to sorting motif of BDNF and facilitates BDNF allocation to the late endosome; hereby sortilin rescues BDNF from lysosomal degradation. Until now no pharmacological option exists to inhibit the degradation of BDNF. Modifying sortilin either with increasing its level or its binding action would be options to increase total BDNF levels through its decreased targeting to the lysosome (Evans et al.
2011).
As there is no agent that would reduce BDNF degradation, direct receptor (TrkB) activation via ligands/agonists or mechanisms of increasing the BDNF level would be also appropriate therapeutic applications. Based on the listed psychopathological and CV effects of BDNF, such a medication can potentially be beneficial for both systems.