Table 2.

LncRNAs 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	2017	Malat1	Up	BMECs	Malat1 upregulation promotes autophagy in BMECs to promote survival	Malat1/miR-26b/ULK2 regulatory axis promotes autophagy and survival in BMECs	[95]
	2017	Malat1	Up	Mice, mBMECs	Silencing of Malat1 increases apoptotic factor Bim and proinflammatory cytokines MCP-1, IL-6, and E-selectin. Malat1 KO increases brain infarct size, worsens neurological scores, and reduces sensorimotor functions	Malat1 binds to Bim and E-selectin to play anti-apoptotic and anti-inflammatory roles	[96]
	2018	LOC102640519	Up	Mice, mBMECs	Administration of VEGF upregulates LOC102640519 and aggravates BBB permeability	LOC102640519 positively regulates the expression of HOXC13, thus negatively regulates the expression of ZO-1, occludin, and claudin-5	[98]
	2019	MEG3	Up	Rats	MEG3 inhibition ameliorates neurological impairments, reduces infarct area, water content, BBB permeability, neuronal apoptosis and necrosis, and enhances neurogenesis	MEG3 affects neurological injury by regulating Wnt/β-catenin signaling pathway	[99]
	2020	Malat1	Up	Mice, astrocytes	Knockdown of MALAT1 increases cell viability and reduces cell apoptosis in astrocyte cells	MALAT1 acts as competing endogenous RNA (ceRNA) for miR-145 to positively regulate AQP4 expression	[97]
	2021	Snhg8	Down	Mice, BMECs	Snhg8 upregulation increases ZO‐1 and occludin, promotes angiogenesis, inhibits microglial activation after MCAO, and reduces inflammatory factor IL‐1β, IL‐6, and TNF‐α	Snhg8 serves as a ceRNA by sponging miR‐425‐5p to regulate sirtuin1-mediated NF-κB pathway	[100]
	2021	XIST	Down in the early stages	Mice, BMECs	Silencing of lncRNA XIST impairs angiogenesis, reduces the expressions of KLF4 and TJPs (claudin-5 and ZO-1), but increases E-selectin, VCAM-1, ICAM-1, and p-NF-kB	lncRNA XIST upregulates the expression of proangiogenic factor-integrin a5 (Itga5) and anti-inflammation factor KLF4 by targeting miR-92a	[61]
Hemorrhagic stroke	2019	Snhg3	Up	Mice, BMVECs	Snhg3 inhibition improves cell proliferation and migration and reduces cell apoptosis and monolayer permeability in vitro, and improves behavioral scores, BBB integrity, brain water content and cell apoptosis in vivo	Snhg3 regulates cerebral microvascular cell injury through Snhg3/TWEAK/Fn14/STAT3/MMP-2/-9 pathways	[112]
	2021	Blnc1	Up	Mice, BMVECs	Blnc1 overexpression suppresses cell viability and migration but increases permeability, apoptosis, and inflammation in vitro, and its suppression ameliorates nerve injury, brain edema, BBB permeability, and the levels of inflammatory cytokines in vivo	Blnc1 exacerbates nerve injury and inflammatory response through PPAR-γ/SIRT6/FoxO3 pathway	[113]
TBI	2021	KCNQ1OT1	Up	Mice, BV2 microglia	KCNQ1OT1 knockdown relieves neurological deficits, neuron loss, microglial activation and inflammation, and BBB permeability	KCNQ1OT1 inhibition is neuroprotective against TBI in mice by regulating the miR-873-5p/TRAF6/P38/NF-κB axis	[120]
SCI	2021	TUG1	Up	Rats	Knockdown of TUG1 alleviates BSCB leakage and improves hind-limb motor function	TUG1 targets miR-29b-1-5p to regulate inflammatory damage mediated by MTDH/NF-κB/IL-1b pathway	[133]
Glioma/Brain metastasis	2015	TUG1	Up	Patient glioma tissues, GECs	Knockdown of TUG1 increases BTB permeability, and downregulates the expression of the TJ proteins ZO-1, occludin, and claudin-5	TUG1 influences BTB permeability via miR-144/Heat shock transcription factor 2/TJ proteins pathway	[153]
	2016	MALAT1	Up	Patient glioma tissues, GECs	Knockdown of MALAT1 increases BTB permeability of BTB and decreases the expression of ZO-1, occludin, and claudin-5	MALAT1 reciprocally represses miR-140, and that MALAT1 regulates BTB permeability via miR-140/nuclear factor YA/TJ proteins axis	[155]
	2017	Lnc-BM	Up	Mouse	Lnc-BM elevation induces BCBM, while depletion of Lnc-BM inhibits BCBM	LNC-BM increases the cell migration through BBB, and enhances BCBM via Lnc-BM/STAT3/ICMA-1 and CCL2 axis	[62]
	2017	TUG1	Up	Patient glioma tissues, GECs	Knockdown of TUG1 suppresses tumor-induced EC proliferation, migration, and tube formation, and reduces spheroid-based angiogenesis	TUG1 influences tumor angiogenesis via TUG1/miR-299/VEGFA axis	[154]
	2017	XIST	Up	GECs	XIST knockdown increases BTB permeability and inhibits glioma angiogenesis	XIST knockdown increases BTB permeability and inhibits glioma angiogenesis by inhibiting Forkhead Box C1 and ZO-2 expression via increasing miR-137	[157]
	2017	NEAT1	Up	GECs	NEAT1 knockdown increases the BTB permeability, accompanied by downregulated TJ proteins ZO-1, occludin and claudin-5	NEAT1 influences BTB permeability via miR-181d-5p/SOX5/ZO-1, occludin and claudin-5 axis	[158]
	2017	HOTAIR	Up	GECs	Knockdown of HOTAIR increases BTB permeability and downregulates ZO-1, occludin, claudin-5	HOTAIR regulates BTB permeability probably via HOTAIR/miR-148b-3p/USF1 axis	[159]
	2019	linc00174	Up	GECs	Knockdown of linc00174 increases BTB permeability and reduces the expression of TJ-related proteins ZO-1, occludin, and claudin-5	linc00174 regulates BTB permeability via miR-138-5p and miR-150-5p/FOSL2 (FOS Like 2)/ZO-1, occludin, claudin-5 axis	[160]
	2020	GS1-600G8.5	Up	BMECs	lncRNA GS1-600G8.5 highly expressed exosomes increases BBB permeability, and promotes invasion of the breast cancer cells in the BBB model	lncRNA GS1-600G8.5 transferred from exosomes of brain metastatic breast cancer cells might destroy the BBB system by decreasing TJ proteins	[163]
	2020	MIAT	Up	GECs	MIAT promotes the endothelial leakage of BTB	MIAT increases BTB permeability via miR-140-3p/ZAK/NF-κB-p65/TJ associated proteins axis	[164]
	2020	Lnc00462717	Up	GECs	Knockdown of Lnc00462717 significantly increases the BTB permeability	Lnc00462717 reduces the permeability of the BTB through interaction with PTBP1 to inhibit the miR-186-5p/occludin signaling pathway	[161]
	2021	CCRR	Up	Patient tissue, CSF	The expression of lncRNA-CCRR was positively correlated with the up-regulated expression of CX43	lncRNA-CCRR can upregulate the expression of CX43, and promote gap junction formation in brain metastasis of breast cancer	[162]
MS	2021	Gm13568	Up	mice, astrocytes	Inhibiting Gm13568 in astrocytes ameliorates inflammation and demyelination in EAE mice	Knockdown of lncRNA Gm13568 inhibits the Notch1 expression, astrocytosis, and the phosphorylation of STAT3 (p-STAT3), and the production of inflammatory cytokines and chemokines in astrocytes	[174]
AD	2020	LINC00662	Up	BMECs	Knockdown of TRA2A or LINC00662 decreases BBB permeability	TRA2A increases the stability of LINC00662, and LINC00662 decreases ELK4 expression through SMD pathway to downregulate the expression of ZO-1, occludin, and claudin-5	[183]
Bacterial meningitis	2021	NEAT1	Up	Mouse, hCMEC/D3, glioma cells	Downregulation of NEAT1 alleviates BBB damage	NEAT regulates the permeability of BBB via NEAT/miR-135a/HIF1α/ZO-1, occludin, and claudin-5 axis	[189]
	2021	LncRSPH9-4	Up	hBMECs	lncRSPH9-4 overexpression in hBMECs mediates the BBB disruption	Infection induced lncRSPH9-4 upregulates the BBB permeability via miR-17-5p/MMP3/ZO-1, occludin and claudin-5 axis	[190]