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Fig. 2 | Journal of Neuroinflammation

Fig. 2

From: Blood-brain barrier permeability and physical exercise

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

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