PGE2 receptor EP1 renders dopaminergic neurons selectively vulnerable to low-level oxidative stress and direct PGE2 neurotoxicity
✍ Scribed by Emilce Carrasco; Diana Casper; Peter Werner
- Publisher
- John Wiley and Sons
- Year
- 2007
- Tongue
- English
- Weight
- 273 KB
- Volume
- 85
- Category
- Article
- ISSN
- 0360-4012
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✦ Synopsis
Oxidative stress and increased cyclooxygenase-2 (COX-2) activity are both implicated in the loss of dopaminergic neurons from the substantia nigra (SN) in idiopathic Parkinson's disease (PD). Prostaglandin E 2 (PGE 2 ) is one of the key products of COX-2 activity and PGE 2 production is increased in PD. However, little is known about its role in the selective death of dopaminergic neurons. Previously, we showed that oxidative stress evoked by low concentrations of 6-hydroxydopamine (6-OHDA) was selective for dopaminergic neurons in culture and fully dependent on COX-2 activity. We postulated that this loss was mediated by PGE 2 acting through its receptors, EP1, EP2, EP3, and EP4. Using double-label immunohistochemistry for specific EP receptors and tyrosine hydroxylase (TH), we identified EP1 and EP2 receptors on dopaminergic neurons in rat SN. EP2 receptors were also found in non-dopaminergic neurons of this nucleus, as were EP3 receptors, whereas the EP4 receptor was absent. PGE 2 , 16-phenyl tetranor PGE 2 (a stable synthetic analogue), and 17phenyl trinor PGE 2 (an EP1 receptor-selective agonist) were significantly toxic to dopaminergic cells at nanomolar concentrations; EP2-and EP3-selective agonists were not. We challenged dopaminergic neurons in embryonic rat mesencephalic primary neuronal cultures and tested whether these receptors mediate selective 6-OHDA toxicity. The nonselective EP1-3 receptor antagonist AH-6809 and two selective EP1 antagonists, SC-19220 and SC-51089, completely prevented the 40%-50% loss of dopaminergic neurons caused by exposure to 5 lM 6-OHDA. Together, these results strongly implicate PGE 2 activation of EP1 receptors as a mediator of selective toxicity in this model of dopaminergic cell loss. V