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] |