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 micro g/ml) and that PGJ(2) and dPGJ(2) were more potent than
PGA(2), dPGA(2),
PGD(2), and
PGE(2). 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 PGJ(2) 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.