Table 2.

MiRNAs modulate BBB function in non-stroke CNS diseases

Diseases	miRNAs	Study subject	Proposed contribution to BBB	Target gene/Mechanism	Refs
TBI	Negative
	miR-21–3p	Mouse	MiR-21–3p aggravates BBB damage	Regulating TJ protein expression by binding to MAT2B	(Ge et al., 2019)
	Positive
	miR-21	Rat	MiR-21 alleviates brain edema and BBB leakage	Reducing the loss of TJ proteins by promoting the expression of Ang-1/Tie-2 axis in BMECs	(Ge et al., 2015; Navi et al., 2014)
	miR-212/132	Mouse	MiR212/132 maintains the BBB integrity	Directly targeting claudin-1, JAM3, and Tjap1	(Burek et al., 2019)
	miR-21–5p	Rat BMVECs	MiR-21–5p alleviates BBB leakage in vitro	Suppressing inflammation and apoptosis	(Ge et al., 2016)
Spinal cord injury	Positive
	miR-320a	Rat	mir-320a protects BSCB integrity	Binding to AQP1	(Li et al., 2016)
	miR-129–5p	Mouse	miR-129–5p prevents BSCB leakage	Targeting HMGB1	(Li et al., 2017)
AD	Negative
	miR-33	Mouse	MiR-33 impairs cellular cholesterol efflux and increases the accumulation of Aβ in neural cells	Regulating Aβ metabolism by directly targeting ABCA1, promoting Aβ secretion and impairing Aβ clearance	(Kim et al., 2015)
	Positive
	miR-107	hCMEC/D3	MiR-107 prevents Aβ-induced BBB disruption	Targeting endophilin-1	(Liu et al., 2016)
	miR-224–5p(miR497–5p)	hCMEC/D3	MiR-224–5p decreases the BBB permeability	Increasing the expression of ZO-1, occludin, and claudin-5 by binding to endophilin-1	(Zhu et al., 2019)
VD	Positive
	miR-501–3p	Mouse	MiR-501–3p decreases the BBB permeability	Directly binding to ZO-1	(Toyama et al., 2018)
Brain tumor	Negative
	miR-181c	Mouse	Breast cancer cell-derived EVs contained miR-181 triggers the BBB disruption	Controlling the reorganization of actin filament by suppressing PDPK-1	(Tominaga et al., 2015)
	miR-181a	hCMEC/D3	MiR-181a impairs BTB integrity	Regulating the expression of ZO-1, occludin, and claudin-5 by binding to KLF6	(Ma et al., 2014)
	miR-18a	hCMEC/D3	MiR-18a increases the permeability of BTB	Down-regulating the expressions of ZO-1, claudin-5, and occludin by binding to MEF2D	(Zhao et al., 2015c)
	miR-34c	hBMEC/D3	MiR-34c impairs BTB integrity	Regulating the BBB integrity by directly binding to MAZ gene	(Zhao et al., 2015a)
	miR-34a	Glioma ECs	MiR-34a impairs BTB integrity	Reducing the expression of TJ-related proteins by directly binding to PKCε gene	(Zhao et al., 2015b)
	miR-144	hCMEC/D3	MiR-144 increases BTB permeability	Regulating the expression of ZO-1, occludin, and claudin-5 by binding to HSF2	(Cai et al., 2015)
	miR-140	hCMEC/D3	MiR-140 increases BTB permeability	Regulating the expression of ZO-1, occludin, and claudin-5 by targeting NFYA	(Ma et al., 2016)
	miR-181d-5d	hCMEC/D3	MiR-181d-5d increases the BTB permeability	Regulating the expression of ZO-1, occludin, and claudin-5 by binding to SOX5	(Guo et al., 2017)
	miR-137	hCMEC/D3	MiR-137 increases BTB permeability	Regulating the expression of ZO-1, occludin, and claudin-5 by binding to USF1	(Yu et al., 2017)
	miR-148b-3p	hCMEC/D3	MiR-148b-3p increases BTB permeability	Regulating the expression of ZO-1, occludin, and CXCR7 by binding to ZO-2 and FOXC1	(Sa et al., 2017)
	piR-DQ590027/miR-17HG	hCMEC/D3	piR-DQ590027/miR-17HG increases the BBB permeability	Decreasing the expression of ZO-1, occludin, and claudin-5 by binding to miR-153 (miR-377) which binds to FOXR2	(Leng et al., 2018)
	miR-429	hCMEC/D3	MiR-429 increases the BTB permeability	Regulating the expression of tight junction proteins by binding to ZO-1 and occludin genes	(Dai et al., 2018)
	Positive
	miR-509	Mouse	MiR-509 decreases the BBB permeability	Promoting the secretion of TNF-α and inhibiting the expression of MMP-9 by binding to RhoC	(Xing et al., 2015)
	miR-497	Mouse	MiR-497 reduces the permeability of blood vessels	Targeting CHEK1, AKT3, and VEGF-A	(Soriano et al., 2016)
	miR-200b	hCMEC/D3	MiR-200b restores the BTB integrity	Regulating the expression of occludin and claudin-5 by binding to RhoA and ROCKII genes	(Ma and Xue, 2016)
	miR-330–3p	hCMEC/D3	MiR-330–3p decreases the BTB permeability	Increasing the expression of TJs such as ZO-1, occludin, and claudin-5 by binding to PKCα	(Liu et al., 2017)
MS	Negative
	miR-155	Mouse	MiR-155 impairs BBB integrity	Reorganizing the structures of vinculin and ZO-1 by binding to DOCK-1, syntenin-1, claudin-1, and annexin-2 genes	Lopez-Ramirez et al. 2014
	miR-125a-5p	hCMEC/D3	MiR-125a-5p increases brain endothelial cell barrier function and the expression level of 107 miRNAs	Regulating claudin-5 and ZO-1	Reijerkerk et al. 2013
	miR-126/miR-126*	hCMEC/D3	MiR-126/miR-126* reduces leukocyte adhesion to endothelial cells	Reducing monocytic and T cell shear-resistant adhesion by binding to VCAM1, CCL2, E selection, and CCL7	Cerutti et al. 2017
	Positive
	miR-98 and let-7g*	Mouse	MiR-98 and let-7g* diminish BBB permeability	Reducing pro-inflammation by directly binding to CCL5 gene	Rom et al. 2015
Brain infection	Negative
	miR-101	hBMVECs	MiR-101 impairs BBB integrity and permeability	Inhibiting claudin-5 expression by directly binding to VE-cadherin	Mishra et al. 2013
	miR-155	Mouse	MiR-155 impairs BBB integrity	Targeting Ang/Tie2 axis	Barker et al. 2017
	miR-1303	Human umbilical vein ECs	MiR-1303 increases the BBB permeability	Degrading junction proteins claudin-4, claudin-5, VE-cadherin, and ZO-1 by binding to MMP-9	Song et al. 2018
Others	Negative
	miR-29b	Mouse	MiR-29a mediates the opening of the BBB	Directly binding to DNMT3β and subsequently regulating MMP-9	Kalani et al. 2014
	miR-143	Mouse	MiR-137 increases BBB permeability	Inducing the activation of NF-κB and p53 transcription factors by binding to PUMA, consequently regulating the expression of TJ-related proteins	Bai et al. 2016
	Positive
	miR-203	Z310 cells (immortalized murine choroidal epithelial cells)	MiR-203 preserves the lead-induced BCB integrity	Directly binding to tricellulin	Su et al. 2015