Brain BDNF levels are dependent on cerebrovascular endothelium‐derived nitric oxide

Abstract

Scientific evidence continues to demonstrate a link between endothelial function and cognition. Besides, several studies have identified a complex interplay between nitric oxide (NO) and brain-derived neurotrophic factor (BDNF), a neurotrophin largely involved in cognition. Therefore, this study investigated the link between cerebral endothelium-derived NO and BDNF signaling. For this purpose, levels of BDNF and the phosphorylated form of endothelial NO synthase at serine 1177 (p-eNOS) were simultaneously measured in the cortex and hippocampus of rats subjected to either bilateral common carotid occlusion (n = 6), physical exercise (n = 6) or a combination of both (n = 6) as experimental approaches to modulate flow-induced NO production by the cerebrovasculature. Tropomyosin-related kinase type B (TrkB) receptors and its phosphorylated form at tyrosine 816 (p-TrkB) were also measured. Moreover, we investigated BDNF synthesis in brain slices exposed to the NO donor glyceryl trinitrate. Our results showed increased p-eNOS and BDNF levels after exercise and decreased levels after vascular occlusion as compared to corresponding controls, with a positive correlation between changes in p-eNOS and BDNF (r = 0.679). Exercise after vascular occlusion did not change levels of these proteins. Gyceryl trinitrate increased proBDNF and BDNF levels in brain slices, thus suggesting a possible causal relationship between NO and BDNF. Moreover, vascular occlusion, like exercise, resulted in increased TrkB and p-TrkB levels, whereas no change was observed with the combination of both. These results suggest that brain BDNF signaling may be dependent on cerebral endothelium-derived NO production.

Oxidative Stress in Cognitive and Epigenetic Aging: A Retrospective Glance

“…BDNF regulates post-synaptically the production of NO in the hippocampal neurons at the dendrites and the soma through TrkB and TrkC based signaling (Kolarow et al, 2014). Reduced BDNF levels in the brain has been studied in the context of downstream result of deregulated NO synthesis, and also resulting cognitive impairment (Canossa et al, 2002;Banoujaafar et al, 2016). In the cortex and the hippocampus, NO shows gradual decline with aging (Reckelhoff et al, 1994;Lima-Cabello et al, 2016).…”

“…Therapeutic strategies may be devised using multiple approaches to curb the effects of oxidative stress, this could be in the form of caloric restriction (Martins, 2017c) coupled with exercise. Physical exercise has been shown to increase the levels of blood flow in the brain vasculature and also to influence BDNF based neuroplasticity (Banoujaafar et al, 2016). Other approaches could involve nutrition therapy to supplement key players that help in epigenetic regulation with amino acids such as L-arginine, diet with Sirt1 activators, or downstream metabolites such as NAD + , or through quinone reductase inhibitors.…”

The Migraine Attack as a Homeostatic, Neuroprotective Response to Brain Oxidative Stress: Preliminary Evidence for a Theory

“…Endothelium‐derived nitric oxide contributes to synaptic plasticity and long‐term potentiation in the brain, in part because the blood vessel endothelium, in the presence of active (phosphorylated) eNOS, releases BDNF into the brain . Indeed, the blood vessel endothelium is a major source of cerebral BDNF, with endothelial cells producing BDNF at 50 times the rate of neurons .…”

“…Platelets and presumably the DRN release serotonin that, via 5-HT 2B receptors in the blood vessels, activate endothelial nitric oxide synthase (eNOS), increasing the production of nitric oxide. In turn, eNOS 40 and platelet activation 41 likely cause release of brainderived neurotrophic factor (BDNF) from the endothelium and platelets, respectively.…”

The Cerebral Brain-Derived Neurotrophic Factor Pathway, Either Neuronal or Endothelial, Is Impaired in Rats with Adjuvant-Induced Arthritis. Connection with Endothelial Dysfunction

“…However, even though our ex vivo experiments support a causal link between decreased endothelial NO production and BDNF production in AIA, a contribution of other factors cannot be excluded. In addition, whether neuronal BDNF expression, which is mainly controlled by neuronal activity (Balkowiec and Katz, 2000 ), is dependent on endothelial-derived BDNF remains an open question (Banoujaafar et al, 2016 ). An unresolved point concerns the role of pro-inflammatory in AIA-induced changes in BDNF.…”