Oxygen glucose deprivation/re-oxygenation-induced neuronal cell death is associated with Lnc-D63785 m6A methylation and miR-422a accumulation

Abstract Oxygen glucose deprivation/re-oxygenation (OGD/R) induces neuronal injury via mechanisms that are believed to mimic the pathways associated with brain ischemia. In SH-SY5Y cells and primary murine neurons, we report that OGD/R induces the accumulation of the microRNA miR-422a, leading to downregulation of miR-422a targets myocyte enhancer factor-2D (MEF2D) and mitogen-activated protein kinase kinase 6 (MAPKK6). Ectopic miR-422a inhibition attenuated OGD/R-induced cell death and apoptosis, whereas overexpression of miR-422a induced significant neuronal cell apoptosis. In addition, OGD/R decreased the expression of the long non-coding RNA D63785 (Lnc-D63785) to regulate miR-422a accumulation. Lnc-D63785 directly associated with miR-422a and overexpression of Lnc-D63785 reversed OGD/R-induced miR-422a accumulation and neuronal cell death. OGD/R downregulated Lnc-D63785 expression through increased methyltransferase-like protein 3 (METTL3)-dependent Lnc-D63785 m6A methylation. Conversely METTL3 shRNA reversed OGD/R-induced Lnc-D63785 m6A methylation to decrease miR-422a accumulation. Together, Lnc-D63785 m6A methylation by OGD/R causes miR-422a accumulation and neuronal cell apoptosis.

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BID mediates neuronal cell death after oxygen/ glucose deprivation and focal cerebral ischemia

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.261323298 ◽

2001 ◽

Vol 98 (26) ◽

pp. 15318-15323 ◽

Cited By ~ 171

Author(s):

N. Plesnila ◽

S. Zinkel ◽

D. A. Le ◽

S. Amin-Hanjani ◽

Y. Wu ◽

...

Keyword(s):

Cell Death ◽

Cerebral Ischemia ◽

Focal Cerebral Ischemia ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Glucose Deprivation ◽

Oxygen Glucose Deprivation

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1-O-Hexyl-2,3,5-Trimethylhydroquinone Ameliorates l-DOPA-Induced Cytotoxicity in PC12 Cells

Molecules ◽

10.3390/molecules24050867 ◽

2019 ◽

Vol 24 (5) ◽

pp. 867 ◽

Cited By ~ 2

Author(s):

Hyun Park ◽

Jong Kang ◽

Myung Lee

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Pc12 Cells ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Mitogen Activated Protein Kinase ◽

Protective Effects ◽

Extracellular Signal ◽

Dopaminergic Neuronal Cell ◽

Mitogen Activated Protein

1-O-Hexyl-2,3,5-trimethylhydroquinone (HTHQ) has previously been found to have effective anti-oxidant and anti-lipid-peroxidative activity. We aimed to elucidate whether HTHQ can prevent dopaminergic neuronal cell death by investigating the effect on l-DOPA-induced cytotoxicity in PC12 cells. HTHQ protected from both l-DOPA-induced cell death and superoxide dismutase activity reduction. When assessing the effect of HTHQ on oxidative stress-related signaling pathways, HTHQ inhibited l-DOPA-induced phosphorylation of sustained extracellular signal-regulated kinases (ERK1/2), p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK1/2). HTHQ also normalized l-DOPA-reduced Bcl-2-associated death protein (Bad) phosphorylation and Bcl-2-associated X protein (Bax) expression, promoting cell survival. Taken together, HTHQ exhibits protective effects against l-DOPA-induced cell death through modulation of the ERK1/2-p38MAPK-JNK1/2-Bad-Bax signaling pathway in PC12 cells. These results suggest that HTHQ may show ameliorative effects against oxidative stress-induced dopaminergic neuronal cell death, although further studies in animal models of Parkinson’s disease are required to confirm this.

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