miR-455 inhibits neuronal cell death by targeting TRAF3 in cerebral ischemic stroke

Background/Aims: LncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) was reported to be highly expressed in an in vitro mimic of ischemic stroke conditions. However, the exact biological role of MALAT1 and its underlying mechanism in ischemic stroke remain to be elucidated. Methods: The roles of MALAT1 and miR-30a on cell death and infarct volume and autophagy were evaluated in experimental ischemic stroke. The relationships between miR-30a and MALAT1, Beclin1 were confirmed by luciferase reporter assay. The autophagy inhibitor 3-methyadenine (3-MA) was used to examine the impact of autophagy on ischemic injury. Results: We found that MALAT1, along with the levels of conversion from autophagy-related protein microtubule-associated protein light chain 3-I (LC3-I) to LC3-phosphatidylethanolamine conjugate (LC3-II), as well as Beclin1 were up-regulated and miR-30a was down-regulated in cerebral cortex neurons after oxygen-glucose deprivation (OGD) and mouse brain cortex after middle cerebral artery occlusion-reperfusion (MCAO). Down-regulation of MALAT1 suppressed ischemic injury and autophagy in vitro and in vivo. Furthermore, MALAT1 may serve as a molecular sponge for miR-30a and negatively regulate its expression. In addition, MALAT1 overturned the inhibitory effect of miR-30a on ischemic injury and autophagy in vitro and in vivo, which might be involved in the derepression of Beclin1, a direct target of miR-30a. Mechanistic analyses further revealed that autophagy inhibitor 3-methyadenine (3-MA) markedly suppressed OGD-induced neuronal cell death and MCAO-induced ischemic brain infarction. Conclusion: Taken together, our study first revealed that down-regulation of MALAT1 attenuated neuronal cell death through suppressing Beclin1-dependent autophagy by regulating miR-30a expression in cerebral ischemic stroke. Besides, our study demonstrated a novel lncRNA-miRNA-mRNA regulatory network that is MALAT1-miR-30a-Beclin1 in ischemic stroke, contributing to a better understanding the pathogenesis and progression of ischemic stroke.

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Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications

Medicinal Research Reviews ◽

10.1002/med.21817 ◽

2021 ◽

Author(s):

Qing‐zhang Tuo ◽

Shu‐ting Zhang ◽

Peng Lei

Keyword(s):

Cell Death ◽

Ischemic Stroke ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Therapeutic Implications

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Evidence that γ-Secretase-Mediated Notch Signaling Induces Neuronal Cell Death via the Nuclear Factor-κB-Bcl-2-Interacting Mediator of Cell Death Pathway in Ischemic Stroke

Molecular Pharmacology ◽

10.1124/mol.111.071076 ◽

2011 ◽

Vol 80 (1) ◽

pp. 23-31 ◽

Cited By ~ 60

Author(s):

Thiruma V. Arumugam ◽

Yi-Lin Cheng ◽

Yuri Choi ◽

Yun-Hyung Choi ◽

Sunghee Yang ◽

...

Keyword(s):

Cell Death ◽

Ischemic Stroke ◽

Notch Signaling ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Cell Death Pathway

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Abstract W P210: Plasma Kallikrein Induces Ischemic Brain Damage Through Cleavage-Dependent Activation of NMDA Receptors

Stroke ◽

10.1161/str.45.suppl_1.wp210 ◽

2014 ◽

Vol 45 (suppl_1) ◽

Author(s):

Gongxiong wu ◽

Long-Jun Wu ◽

David E. Clapham ◽

Edward P. Feener

Keyword(s):

Cell Culture ◽

Cell Death ◽

Ischemic Stroke ◽

Nmda Receptor ◽

Brain Damage ◽

Infarct Volume ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Plasma Kallikrein ◽

Ischemic Brain

Background and Purpose: Ischemic stroke ultimately leads to brain dysfunction and neurological deficits. However, the mechanisms that contribute to neuronal injury and dysfunction in ischemic stroke are not fully understood. Recent studies have shown that pharmacological inhibition of the serine protease plasma kallikrein (PK) reduced neuron death and neurological impairment in ischemic brain in mice. In this study, we examine the effects of PK on the neuronal cell death and brain damage in mice and investigate the molecular mechanism of PK-induced neuronal cell death in ischemic stroke. Methods: Ischemia was produced in wild-type (WT) and PK knockout mice by permanent middle cerebral artery occlusion (pMCAO). Infarct volume was quantified by TTC staining and brain function was evaluated by neurological scoring. The effect of PK on neuron cell death in cell culture was determined by lactate dehydrogenase (LDH) release. NMDA receptor function was measured by patch clamp and Ca2+ imaging. NR1 cleavage was detected by western blot. The effect of systemic PK inhibition on pMCAO-induced infarct volume was evaluated in mice treated with the PK inhibitor (BPCCB) or vehicle alone delivered using subcutaneously implanted osmotic pumps. Results: We show that PK deficiency in mice decreased MCAO-induced infarct volume by 39.8% (P<0.01) and improved neurological function compared responses in WT mice. Addition of PK to cell culture media enhanced NMDA-induced cell death of cortical neurons. We further show that PK induced cleavage of NR1 and identify the cleavage site in the extracellular N-terminal domain of NR1. The truncated form of NR1 displayed enhanced NMDA-stimulated current and calcium influx. Treatment of mice with a PK inhibitor reduced MCAO-induced brain damage and neuronal injury. Conclusions: PK enhances NMDA receptor-mediated excitotoxicity and ischemic neuronal death. These findings suggest that PK may serve as a potential therapeutic target for treatment of ischemic stroke.

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