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Neurotoxicology. 2013 Dec;39:35-44. doi: 10.1016/j.neuro.2013.08.001. Epub 2013 Aug 22.

Prostaglandin D2 toxicity in primary neurons is mediated through its bioactive cyclopentenone metabolites.

Author information

1
Geriatric Research Education and Clinical Center, V.A. Pittsburgh Healthcare System, 7180 Highland Drive, Pittsburgh, PA 15206, USA; Department of Neurology, University of Pittsburgh School of Medicine, 811 Kaufmann Medical Building, 3471 Fifth Avenue, Pittsburgh, PA 15213, USA.

Abstract

Prostaglandin D2 (PGD2) is the most abundant prostaglandin in brain but its effect on neuronal cell death is complex and not completely understood. PGD2 may modulate neuronal cell death via activation of DP receptors or its metabolism to the cyclopentenone prostaglandins (CyPGs) PGJ2, Δ(12)-PGJ2 and 15-deoxy-Δ(12,14)-PGJ2, inducing cell death independently of prostaglandin receptors. This study aims to elucidate the effect of PGD2 on neuronal cell death and its underlying mechanisms. PGD2 dose-dependently induced cell death in rat primary neuron-enriched cultures in concentrations of ≥10μM, and this effect was not reversed by treatment with either DP1 or DP2 receptor antagonists. Antioxidants N-acetylcysteine (NAC) and glutathione which contain sulfhydryl groups that can bind to CyPGs, but not ascorbate or tocopherol, attenuated PGD2-induced cell death. Conversion of PGD2 to CyPGs was detected in neuronal culture medium; treatment with these CyPG metabolites alone exhibited effects similar to those of PGD2, including apoptotic neuronal cell death and accumulation of ubiquitinated proteins. Disruption of lipocalin-type prostaglandin D synthase (L-PGDS) protected neurons against hypoxia. These results support the hypothesis that PGD2 elicits its cytotoxic effects through its bioactive CyPG metabolites rather than DP receptor activation in primary neuronal culture.

KEYWORDS:

Cell death; Cyclopentenone prostaglandins; DP receptors; Primary neuron; Prostaglandin D(2); Ubiquitinated protein

PMID:
23973622
PMCID:
PMC3904641
DOI:
10.1016/j.neuro.2013.08.001
[Indexed for MEDLINE]
Free PMC Article
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