Hypothetical molecular mechanisms mediating sleep loss effect on blood-brain barrier permeability. During sleep loss the increase of soluble inflammatory mediators such as TNF-α, IL-1β, IL-17A, CRP, and VEGF activates several membrane receptors that converge in cellular pathways hallmark of inflammation, for example, the NFκB pathway. The final outcome involves the phosphorylation of tight junction proteins and the generation of actin fiber stress. But also other pathways are potentially activated, such as the NADPH oxidase pathway, leading to ROS generation and the subsequent lipoxidation and protein oxidation. The activation of transcription factors (eg., NFκB) and their translocation to the nuclei may promote the transcription of inflammatory-related genes (e.g., ICAM-1, prostaglandins, and matrix metalloproteinases (MMP)) as well as death-related genes (e.g., caspase 3) and the repression of genes involved in the maintenance of the barrier properties (e.g., claudin-5). Conjointly, all those pathways could lead to increased blood-brain barrier permeability during chronic sleep loss. Cldn5: claudin-5, COX: cyclooxygenase, CRP: C-reactive protein, Fcγ receptor: fragment crystallizable region, ICAM-1: intracellular adhesion molecule-1, IL: interleukin, NADPHox: nicotinamide adenine dinucleotide phosphate oxidase, NFκB: nuclear factor kappa-light-chain-enhancer, MMP: matrix metalloproteinase, MLC: myosin light chain, MLCK: myosin light chain kinase, PGE: prostaglandin, PKC: protein kinase C, sICAM: soluble ICAM, sTNFaR: soluble TNF-α receptor, VEGF: vascular endothelial growth factor, TNF: tumor necrosis factor, and ZO: zonula occludens.