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Increased Generation of Cyclopentenone Prostaglandins after Brain Ischemia and Their Role in Aggregation of Ubiquitinated Proteins in Neurons

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Abstract

The cyclopentenone prostaglandin (CyPG) J2 series, including prostaglandin J2 (PGJ2), Δ12-PGJ2, and 15-deoxy-∆12,14-prostaglandin J2 (15d-PGJ2), are active metabolites of PGD2, exerting multiple effects on neuronal function. However, the physiologic relevance of these effects remains uncertain as brain concentrations of CyPGs have not been precisely determined. In this study, we found that free PGD2 and the J2 series CyPGs (PGJ2, Δ12-PGJ2, and 15d-PGJ2) were increased in post-ischemic rat brain as detected by UPLC-MS/MS with 15d-PGJ2 being the most abundant CyPG. These increases were attenuated by pre-treating with the cyclooxygenase (COX) inhibitor piroxicam. Next, effects of chronic exposure to 15d-PGJ2 were examined by treating primary neurons with 15d-PGJ2, CAY10410 (a 15d-PGJ2 analog lacking the cyclopentenone ring structure), or vehicle for 24 to 96 h. Because we found that the concentration of free 15d-PGJ2 decreased rapidly in cell culture medium, freshly prepared medium containing 15d-PGJ2, CAY10410, or vehicle was changed twice daily to maintain steady extracellular concentrations. Incubation with 2.5 μM 15d-PGJ2, but not CAY10410, increased the neuronal cell death without the induction of caspase-3 or PARP cleavage, consistent with a primarily necrotic mechanism for 15d-PGJ2-induced cell death which was further supported by TUNEL assay results. Ubiquitinated protein accumulation and aggregation was observed after 96 h 15d-PGJ2 incubation, accompanied by compromised 20S proteasome activity. Unlike another proteasome inhibitor, MG132, 15d-PGJ2 treatment did not activate autophagy or induce aggresome formation. Therefore, the cumulative cytotoxic effects of increased generation of CyPGs after stroke may contribute to delayed post-ischemic neuronal injury.

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Acknowledgments

This work was supported by the National Institutes of Health/National Institute of Neurological Disorders and Stroke R01NS37459. The authors thank Pat Strickler for secretarial support.

Conflict of Interest

The authors declare no conflict of interest. The contents do not represent the views of the Department of Veterans Affairs or the United States Government.

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Correspondence to Steven H. Graham.

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Hao Liu, Wenjin Li, and Muzamil Ahmad have contributed equally to this work.

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Liu, H., Li, W., Ahmad, M. et al. Increased Generation of Cyclopentenone Prostaglandins after Brain Ischemia and Their Role in Aggregation of Ubiquitinated Proteins in Neurons. Neurotox Res 24, 191–204 (2013). https://doi.org/10.1007/s12640-013-9377-4

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  • DOI: https://doi.org/10.1007/s12640-013-9377-4

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