Table 3 CircRNAs in the regulation of BBB functions in different CNS disorders
CNS disorders | Year | LncRNAs | Levels in disease | Study materials | Main regulatory effects on BBB | Main mechanisms | Refs. |
|---|---|---|---|---|---|---|---|
Ischemic stroke | 2018 | circDLGAP4 | Down | Mouse, bEnd.3 | Upregulation of circDLGAP4 expression significantly attenuates neurological deficits and decreases infarct areas and BBB damage, and downregulates the EndoMT | circDLGAP4 ameliorates ischemic stroke outcomes by targeting miR-143 to downregulate EndoMT and increase TJ proteins claudin-5, occludin, and ZO-1 | [63] |
2020 | circCCDC9 | Down | Mice | circCCDC9 overexpression protects the BBB barrier with decreased permeability and brain water content and restores NO production and eNOS expression | circCCDC9 overexpression inhibits apoptosis and the expression of Notch1, NICD (Notch intracellular domain), and Hes1 to suppress the Notch pathway | [102] | |
Subarachnoid hemorrhage | 2021 | circARF3 | Down | Rats | circARF3 overexpression improves BBB integrity and neurological scores, decreases neuronal apoptosis and microglial activation | circARF3 attenuates BBB destruction in SAH by regulating the miR-31-5p-activated MyD88-NF-κB pathway | [114] |
TBI | 2021 | circLphn3 | Down | Mice | circLphn3 overexpression attenuates the hemin-induced BBB permeability | circLphn3 binds to miR-185-5p and regulates the expression of tight junction proteins after TBI | [121] |
SCI | 2021 | circRNAAbca1 | Up | mice | miR-135b-5p was the most downregulated miRNA after SCI, circRNAAbca1 and KLF4 were predicted to be its target circRNA and mRNA, respectively | circAbca1 plays a neuroinhibitory role by targeting the miR-135b-5P/KLF4 axis | [134] |
Glioma | 2019 | circ‐USP1 | Up | GECs | Knockdown of circ‐USP1 disrupts the barrier integrity, increases its permeability, and reduces claudin‐5, occludin, and ZO‐1 expressions | circ‐USP1 regulates barrier permeability via miR‐194‐5p/FLI1/claudin‐5, occludin, and ZO‐1 axis | [165] |
2019 | CircRNA_001160 | Up | GECs | Polypyrimidine tract binding protein 1 (PTBP1) promotes the function of circRNA_001160, and double silencing of PTBP1 and circRNA_001160 increases BTB permeability | circRNA_001160 regulates BTB permeability via miR-195-5p/ETV1/claudin-5, ZO-1, and occludin axis | [166] | |
2019 | cDENND4C | Up | GECs | Knockdown of cDENND4C increases BTB permeability via downregulating the expressions of tight junction-related proteins | cDENND4C regulates BTB permeability via miR-577/ZO-1, occludin, and claudin-1 axis | [167] | |
MS, EndoMT | 2018 | circular RNA HECW2 | Up | hBMECs | Knockdown of circHECW2 expression inhibits the EndoMT, which may contribute to BBB damage | circHECW2 acts as a sponge for miR-30D to regulate the EndoMT, and increases expression of ATG5 (Autophagy Related 5) and the NOTCH pathway | [175] |
2020 | circ_HECW2 | Up | hBMECs | circ_HECW2 silencing promotes cell proliferation, suppresses cell apoptosis and EndoMT | circ_HECW2 directly binding to miR-30e-5p to regulate NEGR1 and LPS-induced EndoMT | [176] | |
Meningitis | 2020 | circ_2858 | Up | hBMECs | Overexpression of circ_2858 decreases the level of TJ proteins and increase BBB permeability | circ_2858 regulated BBB permeability by competitively binding miR-93-5p, thereby inducing the upregulation of VEGFA and downregulation TJ proteins such as ZO-1, occludin, and claudin-5 | [191] |