Blood-brain barrier permeability and physical exercise

Abstract

In this narrative review, a theoretical framework on the crosstalk between physical exercise and blood-brain barrier (BBB) permeability is presented. We discuss the influence of physical activity on the factors affecting BBB permeability such as systemic inflammation, the brain renin-angiotensin and noradrenergic systems, central autonomic function and the kynurenine pathway. The positive role of exercise in multiple sclerosis and Alzheimer's disease is described. Finally, the potential role of conditioning as well as the effect of exercise on BBB tight junctions is outlined. There is a body of evidence that regular physical exercise diminishes BBB permeability as it reinforces antioxidative capacity, reduces oxidative stress and has anti-inflammatory effects. It improves endothelial function and might increase the density of brain capillaries. Thus, physical training can be emphasised as a component of prevention programs developed for patients to minimise the risk of the onset of neuroinflammatory diseases as well as an augmentation of existing treatment. Unfortunately, despite a sound theoretical background, it remains unclear as to whether exercise training is effective in modulating BBB permeability in several specific diseases. Further research is needed as the impact of exercise is yet to be fully elucidated.

Keywords: Blood-brain barrier permeability; Brain renin-angiotensin system; Central autonomic function; Inflammation; Kynurenine pathway; Physical exercise.

Fig. 1

A low-grade systemic inflammation observed in metabolic syndrome, insulin resistance, type 2 diabetes, arterial hypertension, dyslipidaemia and obesity contributes to BBB damage via pro-inflammatory cytokines inducing kynurenine pathway leading to neurotoxic process on BBB and its permeability. In inflammatory states, ROS are also produced and may impair TJs structure and function causing the direct damage of BBB. RAA system activation due to the systemic inflammation increases the destruction of TJs and production of ROS leading to further damage of TJs and BBB. Physical exercise counteracts obesity and diminishes the low-grade systemic inflammation, production of ROS and changes kynurenine pathway metabolism course into neuroprotective agents as well as downregulates brain RAA system, which all leads to BBB protection. BBB blood-brain barrier, ROS reactive oxygen species, TJs tight junctions, RAA renin-angiotensin-aldosterone

Fig. 2

In systemic low-grade inflammatory states, cytokines can stimulate ROS production destroying tight junctions and increasing BBB permeability. Cytokines can also activate IDO catalyzing degradation of tryptophan into KYN. KYN can be transformed into neuroprotective KYNA by KATs enzyme or into neurotoxic products, mainly QUIN, which stimulates NMDA receptors and leads to glutamatergic overproduction increasing Ca²⁺ influx and BBB breakage. Low-grade inflammation in insulin resistance causes lipid dysregulation and increased ceramide production and its pass through the BBB, intensifying brain inflammation and promoting Aβ production. In leaky states of BBB, TJs lose their function and pro-inflammatory factors can easily pass through BBB leading to its further damage. The presence of inflammation and increased oxidative stress in brain impair significantly mitochondrial and neuronal functions causing cell death. During BBB disruption, facilitated Ang II access can initiate inflammation by promotion of vascular permeability via AT₁ receptors, rising the recruitment of inflammatory cells, ROS production, microglial activation and inflammation in autonomic areas such as the PVN and the RVLM, which potentiate glutamatergic toxicity. Physical activity enhances KAT gene expression and the conversion of toxic KYN to neuroprotective KYNA, which protects BBB. During physical activity, the muscles release of anti-inflammatory cytokines IL-1ra and IL-10, which can itself reduce the concentration of pro-inflammatory cytokines (TNF-α, IL-1, IL-6, IL-17) as well as by upregulation of skeletal muscle peroxisome proliferator activated receptor 1α. NE released during physical activity acts via microglia and astrocytes β2-receptors and lymphocytes β2-receptors reducing the neuroinflammation. Physical training also diminishes the tissue Ang II content and can suppress microglial activation in the PVN and the RVLM. Physical exercise reinforces antioxidative capacity by upregulating endogenous anti-oxidative molecules, reduces oxidative stress and ceramide levels with a suppressive effect on the TJs and BBB damage cycle. Ang II angiotensin II, AT₁ angiotensin II type 1, BBB blood-brain barrier, IDO indoleamine 2,3-dioxygenase, KYN kynurenine, KYNA kynurenic acid, KATs kynurenine aminotransferases, NE norepinephrine, NMDA N-methyl-d-aspartate, PVN paraventricular nucleus, QUIN quinolinic acid, RVLM rostral ventrolateral medulla, ROS reactive oxygen species, TJs tight junctions, TRP tryptophan