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Br J Pharmacol. 2014 Jul;171(13):3234-45. doi: 10.1111/bph.12672.

JAK2/STAT5/Bcl-xL signalling is essential for erythropoietin-mediated protection against apoptosis induced in PC12 cells by the amyloid β-peptide Aβ25-35.

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1
Department of Pharmacology, Tongji Medical College of Huazhong University of Science & Technology, Wuhan, China.

Abstract

BACKGROUND AND PURPOSE:

Erythropoietin (EPO) exerts neuroprotective actions in the CNS, including protection against apoptosis induced by the amyloid β-peptide Aβ25-35 . However, it remains unclear which signalling pathway activated by EPO is involved in this neuroprotection. Here, we have investigated whether JAK2/STAT5/Bcl-xL and ERK1/2 signalling pathways are essential for EPO-mediated protection against apoptosis induced by Aβ25-35 .

EXPERIMENTAL APPROACH:

EPO was added to cultures of PC12 cells, 1 h before Aβ25-35 . For kinase inhibitor studies, AG490 and PD98059 were added to PC12 cells, 0.5 h before the addition of EPO. Transfection with siRNA was used to knockdown STAT5. Activation of JAK2/STAT5/Bcl-xL and ERK1/2 signalling pathways were investigated by Western blotting. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl-tetrazolium bromide assay and apoptosis was detected by TUNEL and acridine orange-ethidium bromide double staining.

KEY RESULTS:

EPO increased phosphorylation of JAK2 and STAT5 in PC12 cells treated with Aβ25-35 . Furthermore, EPO modulated the nuclear translocation of phospho-STAT5, which increased expression of Bcl-xL and decreased levels of caspase-3. These beneficial effects were blocked by the JAK2 inhibitor, AG490 or STAT5 knockdown. However, the ERK1/2 pathway did not play a crucial role in our model.

CONCLUSIONS AND IMPLICATIONS:

EPO protected PC12 cells against Aβ25-35 -induced neurotoxicity. Activation of JAK2/STAT5/Bcl-xL pathway was important in EPO-mediated neuroprotection. EPO may serve as a novel protective agent against Aβ25-35 -induced cytotoxicity in, for instance, Alzheimer's disease.

KEYWORDS:

Aβ; ERK1/2; JAK2/STAT5; apoptosis; erythropoietin; kinase inhibitor

PMID:
24597613
PMCID:
PMC4080977
DOI:
10.1111/bph.12672
[Indexed for MEDLINE]
Free PMC Article
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