Prostaglandins compromise basal forebrain cholinergic neuron differentiation and survival: action at EP1/3 receptors results in AIF-induced death.

Federated Department of Biological Sciences, New Jersey Institute of Technology, Newark, NJ 07102, USA. Jonakait@andromeda.rutgers.edu

Brain research 2009 Aug 18

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Activated microglia produce a factor or cocktail of factors that promotes cholinergic neuronal differentiation of undifferentiated precursors in the embryonic basal forebrain (BF) in vitro. To determine whether microglial prostaglandins mediate this action, microglia were stimulated in the presence of the cyclooxygenase inhibitor ibuprofen, and microglial conditioned medium (CM) was used to culture rat BF precursors at embryonic day 15. Choline acetyltransferase (ChAT) activity served as a measure of cholinergic differentiation. While inhibition of prostaglandin biosynthesis did not affect the ability of microglial CM to promote ChAT activity, treatment of microglia with prostaglandin E2 (PGE2) inhibited it. Agonists of E prostanoid receptors EP2 (butaprost) and EP1/3 (sulprostone) mimicked PGE2, while misoprostol (E1-4) actually enhanced the action of CM. PGE2 added directly to BF cultures together with microglial CM also inhibited ChAT activity. While BF cultures expressed all four prostanoid receptors, direct addition of sulprostone but not butaprost mimicked PGE2, suggesting that PGE2 engaged EP1/3 receptors in the BF. Neither PKA inhibition by H89 nor cAMP induction by forskolin or dibutyrl-cAMP altered the action of sulprostone. Sulprostone severely compromised ChAT activity, dendrite number, axonal length and axonal branching, but caspase inhibition did not restore these. However, sulprostone resulted in increased staining intensity and nuclear translocation of apoptosis-inducing factor (AIF) suggesting caspase-independent cell death. We have found that PGE2 action at microglial EP2 receptors inhibits the microglial production of the cholinergic differentiating cocktail, while action at neuronal EP3 receptors has a deleterious effect on cholinergic neurons causing neurite retraction and cell death.

Citation

G Miller Jonakait, Li Ni. Prostaglandins compromise basal forebrain cholinergic neuron differentiation and survival: action at EP1/3 receptors results in AIF-induced death. Brain research. 2009 Aug 18;1285:30-41