title: PGE(2) receptor EP1 renders dopaminergic neurons selectively vulnerable to low-level oxidative stress and direct PGE(2) neurotoxicity.
abstract: 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 17-phenyl 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 muM 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.
authors.affiliation: Department of Neurology, Albert Einstein College of Medicine, The Bronx, New York, USA.
authors.forename: Emilce
authors.initials: E
authors.lastname: Carrasco
authors.forename: Diana
authors.initials: D
authors.lastname: Casper
authors.forename: Peter
authors.initials: P
authors.lastname: Werner
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D015232:Dinoprostone / Q000633:toxicity*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D016627:Oxidopamine / Q000633:toxicity; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D011465:Prostaglandins, Synthetic / Q000494:pharmacology; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013378:Substantia Nigra / Q000166:cytology; D013565:Sympatholytics / Q000633:toxicity; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D011448:Prostaglandin Antagonists; D011465:Prostaglandins, Synthetic; C545637:Ptger1 protein, rat; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013565:Sympatholytics; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D015232:Dinoprostone; D004298:Dopamine