Regulation of heme oxygenase expression by cyclopentenone prostaglandins

Hean Zhuang, Sokhon Pin, Xiaoling Li, Sylvain Doré

Research output: Contribution to journalArticle

Abstract

Prostaglandins (PGs) originate from the degradation of membranar arachidonic acid by cyclooxygenases (COX-1 and COX-2). The prostaglandin actions in the nervous system are multiple and have been suggested to play a significant role in neurodegenerative disorders. Some PGs have been reported to be toxic and, interestingly, the cyclopentenone PGs have been reported to be cytoprotective at low concentration and could play a significant role in neuronal plasticity. They have been shown to be protective against oxidative stress injury; however, the cellular mechanisms of protection afforded by these PGs are still unclear. It is postulated that the cascade leading to neuronal cell death in acute and chronic neurodegenerative conditions, such as cerebral ischemia and Alzheimer's disease, would be mediated by free radical damage. We tested the hypothesis that the neuroprotective action of cyclopentanone could be caused partially by an induction of heme oxygenase 1 (HO-1). We and others have previously reported that modulation of HO total activity may well have direct physiological implications in stroke and in Alzheimer's disease. HO acts as an antioxidant enzyme by degrading heme into iron, carbon monoxide, and biliverdin that is rapidly converted into bilirubin. Using mouse primary neuronal cultures, we demonstrated that PGs of the J series induce HO-1 in a dose-dependent manner (0, 0.5, 5, 10, 20, and 50 μg/ml) and that PGJ 2 and dPGJ2 were more potent than PGA2, dPGA2, PGD2, and PGE2. No significant effects were observed for HO-2 and actin expression. In regard to HO-3 expression found in rat, with its protein deducted sequence highly homologous to HO-2, no detection was observed in HO-2-/- mice, suggesting that HO-3 protein would not be present in mouse brain. We are proposing that several of the protective effects of PGJ2 could be mediated through beneficial actions of heme degradation and its metabolites. The design of new mimetics based on the cyclopentenone structure could be very useful as neuroprotective agents and be tested in animal models of stroke and Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)499-505
Number of pages7
JournalExperimental Biology and Medicine
Volume228
Issue number5
DOIs
StatePublished - May 2003

Keywords

  • Alzheimer's disease
  • Antioxidant
  • Cerebral ischemia
  • Free radical
  • Iron
  • Neurodegeneration
  • Oxidative stress
  • Prostaglandin
  • Stroke

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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