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Extracellular HMGB1 released by NMDA treatment confers neuronal apoptosis via RAGE-p38 MAPK/ERK signaling pathway.
- Source :
-
Neurotoxicity research [Neurotox Res] 2011 Aug; Vol. 20 (2), pp. 159-69. Date of Electronic Publication: 2010 Nov 30. - Publication Year :
- 2011
-
Abstract
- High mobility group box 1 (HMGB1) was originally identified as ubiquitously expressed nonhistone DNA-binding protein, but recently, it was found to act as an endogenous danger molecule, which signals danger and traumatic cell death. Previously, the authors showed that HMGB1 is massively released immediately after an ischemic insult and that it subsequently activates microglia and induces inflammation in the postischemic brain. Here, we showed the endogenous danger molecule-like function of HMGB1 in primary cortical cultures. HMGB1 was found to be accumulated in NMDA-treated primary cortical culture media, and media collected from these cultures were able to induce neuronal cell death when added to fresh primary cortical cultures. However, HMGB1-depleted NMDA-conditioned media produced by HMGB1 siRNA transfection or by preincubation with anti-HMGB1 antibody or with HMGB1 A box failed to induce neuronal cell death. Furthermore, siRNA-mediated HMGB1 knockdown substantially suppressed NMDA- or Zn(2+)-induced cell death. It was interesting to find that extracellular HMGB1-induced neuronal apoptosis, as evidenced by TUNEL staining and caspase 3 assay in combination with double immunofluorescence staining. A series of RAGE and HMGB1 co-immunoprecipitation experiments in the presence of SB203580 and PD98059 (p38 MAPK and ERK inhibitors, respectively) demonstrated that RAGE-p38 MAPK and RAGE-ERK pathway might underlie extracellular HMGB1-mediated neuronal apoptosis. These results together with our previous reports regarding microglial activation by extracellular HMGB1 indicate that HMGB1 functions as a novel danger signal, which aggravates brain damage via autocrine and paracrine manners.
- Subjects :
- Analysis of Variance
Animals
Caspase 3 metabolism
Cell Survival drug effects
Cerebral Cortex cytology
Culture Media, Conditioned pharmacology
Dose-Response Relationship, Drug
Drug Interactions
Embryo, Mammalian
Enzyme Inhibitors pharmacology
Enzyme-Linked Immunosorbent Assay
Excitatory Amino Acid Agonists
Extracellular Signal-Regulated MAP Kinases metabolism
Gene Expression Regulation drug effects
Glial Fibrillary Acidic Protein metabolism
HMGB1 Protein pharmacology
Immunoprecipitation
In Situ Nick-End Labeling methods
Mice
Neuroglia drug effects
Neuroglia physiology
Neurons metabolism
Phosphopyruvate Hydratase metabolism
RNA, Small Interfering genetics
RNA, Small Interfering metabolism
Receptor for Advanced Glycation End Products
Receptors, Immunologic genetics
Time Factors
Transfection
Zinc pharmacology
p38 Mitogen-Activated Protein Kinases metabolism
Apoptosis drug effects
Extracellular Fluid drug effects
HMGB1 Protein metabolism
N-Methylaspartate pharmacology
Neurons drug effects
Receptors, Immunologic metabolism
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1476-3524
- Volume :
- 20
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Neurotoxicity research
- Publication Type :
- Academic Journal
- Accession number :
- 21116767
- Full Text :
- https://doi.org/10.1007/s12640-010-9231-x