{'fraction_non_alphanumeric': 0.02912621359223301, 'fraction_numerical': 0.013592233009708738, 'mean_word_length': 5.691558441558442, 'pattern_counts': {'":': 0, '<': 1, '<?xml version=': 0, '>': 1, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Size-selective opening of the blood–brain barrier by targeting endothelial sphingosine 1–phosphate receptor 1

Significance The blood–brain barrier (BBB) poses a major obstacle for drug delivery to the central nervous system (CNS). This study revealed that genetic or pharmacological targeting of sphingosine 1–phosphate receptor-1 (S1P1) facilitates a small-molecule-selective BBB opening, without major signs of CNS inflammation or injury. This size-selective BBB opening could be attributed to changes in the cytoskeletal association of tight junction proteins. Importantly, BBB opening by pharmacological blockage of S1P1 was reversible, suggesting that targeting S1P1 may be a promising strategy for the safe delivery of therapeutic agents into the CNS to treat neurodegenerative and neuroinflammatory diseases and neurological cancers. The vasculature of the central nervous system (CNS) forms a selective barrier termed the blood–brain barrier (BBB). Disruption of the BBB may contribute to various CNS diseases. Conversely, the intact BBB restricts efficient penetration of CNS-targeted drugs. Here, we report the BBB-regulatory role of endothelial sphingosine 1–phosphate (S1P) receptor-1, a G protein-coupled receptor known to promote the barrier function in peripheral vessels. Endothelial-specific S1pr1 knockout mice (S1pr1iECKO) showed BBB breach for small-molecular-mass fluorescence tracers (<3 kDa), but not larger tracers (>10 kDa). Chronic BBB leakiness was associated with cognitive impairment, as assessed by the novel object recognition test, but not signs of brain inflammation. Brain microvessels of S1pr1iECKO mice showed altered subcellular distribution of tight junctional proteins. Pharmacological inhibition of S1P1 function led to transient BBB breach. These data suggest that brain endothelial S1P1 maintain the BBB by regulating the proper localization of tight junction proteins and raise the possibility that endothelial S1P1 inhibition may be a strategy for transient BBB opening and delivery of small molecules into the CNS.