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]