Table 3 MicroRNAs (miRNAs) and their target genes involved in the main elements of pathogenesis non-traumatic intracerebral hemorrhage (ICH). Note: in vitro and in vivo studies, expression level shown during application anti-miRNA or miRNA mimics

MiR-126

Up

Apoptosis

C57BL/6 mice and BMECs

VEGF-A

Inhibits of ECs apoptosis after ICH

[37]

MiR-126

Up

Apoptosis

SD rats and rats brain tissue

VEGF-A and caspase-3

May significantly improve behavioral performance in ICH. Decrease the damage to the brain and cell apoptosis

[38]

MiR-126

Up

Apoptosis and neuroinflammation

SD rats and rats brain tissue

ZEB1, GFAP, TNF-α, IL-1β, and IL-6

Anti-inflammatory effect and inhibits of neuronal apoptosis in hematoma area

[39]

MiR-126-3p

Up

BBB permeability, cerebral edema, apoptosis, and neuroinflammation

SD rats and BMECs

PIK3R2/Akt axis

Reduces brain edema and BBB permeability. Inhibits neutrophil

infiltration, microglial activation,

and neuronal apoptosis

[40]

MiR-130a

Down

BBB permeability, and cerebral edema

SD rats and rats BMECs

Cav-1/MMP-2/MMP-9 signaling pathway

Attenuates brain edema, preserves BBB integrity

and improves neurological behavioral functions score

[41]

MiR-132

Up

BBB permeability, cerebral edema, apoptosis, and neuroinflammation

C57BL/6J mice and mouse brain tissue

AChE, IL-6, IL‐1β and TNF-a

Protective effect on BBB permeability, anti-inflammatory effect and inhibits of neuronal apoptosis in hematoma area

[42]

MiR-27a-3p

Up

BBB permeability, cerebral edema, apoptosis, and neuroinflammation

SD rats and rats BMECs

AQP-11

Reduces neuronal apoptosis, brain edema, BBB permeability and microglia activation in the perihematomal area

[43]

MiR-126-3p

Up

BBB permeability

SD rats and rats BMECs

VCAM-1

Reduces BBB permeability

[44]

MiR‐21‐5p

Down

BBB permeability, neuroinflammation and apoptosis

Sprague-Dawley rats and HEK293T cells

HO‐1, DUSP8, IL‐1β, IL‐6 and TNF‐α

Reduces the neurological defects and BBB permeability, repairs cognitive impairment, permeability, anti-inflammatory effect and inhibits neuronal apoptosis in the perihematomal area

[45]

MiR-126-3p

Up

BBB permeability and apoptosis

SD rats and rats brain tissue

ZO-1, claudin-5, RAR-1, and MMP-9

Reduces BBB permeability and inhibits neuronal apoptosis in the perihematomal area

[46]

MiR-18a

Up

BBB permeability and apoptosis

SD rats, rats BMECs, and rats astrocytes

RUNX1-Occludin/ZO-1 axis, MMP-2, MMP-9 and TIMP-1

Reduces BBB permeability and inhibits neuronal apoptosis in the perihematomal area.

[47]

MiR-137

Up

Oxidative stress and apoptosis

SH-SY5Y cells and human EPCs

COX2/PGE2 pathway

Neuroprotective effect

[48]

MiR-29a

Up

Oxidative stress and apoptosis

SD and culture neurons

PTEN/PI3K/Akt/mTOR signaling pathway

Promotes regenerative outgrowth of injured axons and improves neurobehavioral and

cognitive impairments. Alleviates neuronal damage and mitochondrial dysfunctions, and facilitates neurite outgrowth

[49]

MiR-146a-5p

Up

BBB permeability, oxidative stress, apoptosis, and neuroinflammation

SD rats and rats brain tissue

iNOS, COX-2, MCP-1, IRAK-1, and NFAT-5

Reduces neuronal apoptosis and inflammation (inhibition of microglial M1 polarization)

[50]

MiR-183-5p

Up

Oxidative stress, apoptosis and neuroinflammation

C57BL/6 mice, and BV2 microglial cell line

HO-1 and Nrf2.

Reduces BBB permeability, inflammation, ROS production and inhibits neuronal apoptosis in the perihematomal area

[51]

MiR-331-3p

Down

Neuroinflammation

C57BL/6 mice, and BV2 microglial cell line

NLRP6, TNF-α and IL-6.

Alleviates the inflammatory response and promotes the neurological function recovery

[52]

MiR-378a-5p

Down

BBB permeability, oxidative stress, apoptosis, and neuroinflammation

C57BL/6J mice and mouse brain tissue

Hspa5, IL-1β, IL-6, and TNF-α

Reduces BBB permeability, Alleviates the inflammatory response and promotes the neurological function recovery

[53]

MiR-34a-5p

Up

Apoptosis and neuroinflammation

SD rats and rats brain tissue

KLF-4

Inhibits microglia M2 polarization while accelerating M1 polarization and anti-apoptotic effects in the perihemorrhagic penumbra

[54]

MiR-383-3p

Up

Neuroinflammation

SD rats and BV2 microglial cell line

ATF4

Activates microglia and promotes neuronal necroptosis

[55]

MiR-150-3p

Up

Gut microbiota, metabolism, apoptosis, and neuroinflammation

C57BL/6J mice and mouse brain tissue

TRAF6/NF-κB axis

Reduces apoptosis and levels of inflammatory factors

[56]

MiR‑93‑5p

Down

Apoptosis and neuroinflammation

Thrombin‑treated human microglial HMO6 cells

TGF‑β1 and Nrf2

Reduces neuronal apoptosis and inflammation

[57]

MiR-124-3p

Up

Apoptosis and neuroinflammation

HMC3 cells

TRAF6

Reduces the inflammatory factors and apoptosis rate

[58]

MiR-23a-3p

Up

Apoptosis

hCMEC/D3 cells

ZO-1

Decreases vascular endothelial cells proliferation and increases their apoptosis

[59]

MiR-146a

Up

Oxidative stress, apoptosis and neuroinflammation

SD rats and hCMEC/D3

TRAF6/NF-κB signaling pathway, MDA, SOD, GSH-Px, TNF-α and IL-1β

Reduces BBB permeability, pro-inflammatory cytokine production, oxidative stress inhibits and neuronal apoptosis

[60]

MiR‑155

Down

Neuroinflammation

SD rats and astrocytes

SOCS‑1, IFN‑β, TNF‑α and IL‑6

Anti-inflammatory effect

[61]

MiR-27b

Down

Oxidative stress, apoptosis and neuroinflammation

SD rats and PC12 cells

Nrf2/ARE signaling pathway

Reduces the lipid peroxidation, neuroinflammation, cell death and neurological deficits

[62]

MiR-25-3p

Up

Oxidative stress, apoptosis and neuroinflammation

Human blood (plasma) and C57BL/6 mice

P53/SLC7A11/GPX4 signaling pathway

Neuroprotective role against ferroptosis. Promotes locomotion recovery of ICH mice.

[63]

MiR-133b

Up

Apoptosis

C57BL/6 mice and mouse brain tissue

FOXO4/Bcl-2 axis

Inhibits of hippocampal neuronal apoptosis

[64]

MiR-23b

Up

Oxidative stress, apoptosis and neuroinflammation

Wistar rat BMSCs, HT22 cells and Wistar rats

PTEN/Nrf2 signaling pathway

Improves behavioral functions and reduces brain injuries. Inhibits the amount of microglia/macrophages and cell apoptosis. Reduces oxidative stress

[65]

MiR-185-5p

Down

Apoptosis

C57BL/6J mice, 293T cell line and HT22 cell line

4933404O12Rik/Sh2b3/ERK1/2 signaling pathway

Anti-apoptotic effect

[66]

MiR-488

Up

Oxidative stress and apoptosis

C57BL/6J mice and mouse brain tissue

CLSTN3

Increases cell viability and reduced markers of oxidative stress and lipid peroxidation

[67]

MiR-29a-3p

Up

Apoptosis

C57BL/6J mice and HT22 cell line

SOX10/ACSL4 axis

Contributes to ferroptosis of hippocampal neurons after ICH and inhibits the iron death of hippocampal neuronal cells

[68]

MiR-124-3p

Down

Apoptosis

Human blood (plasma) and HMC3 cell

MTF1

Inhibits cell viability and enhances cell apoptosis

[69]

MiR-124

Up

BBB permeability, oxidative stress, apoptosis, and neuroinflammation

C57BL/6J mice and BV2 microglia

ZO-1, claudin-5, MMP-9, IL-1β, IL-6, and TNF-α

Attenuates BBB damage, reduces cell death and inhibits brain inflammation after ICH. Attenuates neurological deficits and brain edema. Reduces immune cell infiltration

[70]

MiR-106a-5p

Down

BBB permeability, oxidative stress, and apoptosis

C57BL/6J mice and mouse brain tissue

Nrf2/ARE signaling pathway and PHLPP2

Neuroprotective role.

[71]

MiR-122-5p

Down

BBB permeability, apoptosis, and neuroinflammation

C57BL/6J mice and BV2 microglia

MLLT1/PI3K/Akt signaling pathway

Decreases neurological deficits, BBB permeability, and inflammation

[72]

MiR-204-5p

Down

Neurological regeneration

SD rats and rats brain tissue

CLCN3

Inhibits neuronal injury, improves neurological function, and then alleviates ICH

[73]