Divergent effects of prostaglandin receptor signaling on neuronal survival

doi:10.1016/j.neulet.2007.05.055

Neuroscience Letters

Volume 421, Issue 3, 29 June 2007, Pages 253-258

https://doi.org/10.1016/j.neulet.2007.05.055 Get rights and content

Abstract

Induction of cyclooxygenase-2 (COX-2) with production of prostaglandins occurs in a wide spectrum of acute and chronic neurodegenerative diseases and is associated with neuronal death. Inhibition of the COX-2 pathway and downstream production of prostaglandins protect neurons in rodent models of cerebral ischemia and neurodegeneration. Recent studies investigating the functions of selected prostaglandin receptor pathways in mediating COX-2 neurotoxicity have demonstrated both toxic and paradoxically neuroprotective effects of several receptors in models of excitotoxicity. In this study, we investigate the functions of additional prostaglandin receptors not previously characterized in organotypic models of glutamate excitotoxicity. We find that PGD₂, PGI₂, and PGF_2α receptors protect motor neurons in an organotypic spinal cord model of amyotrophic lateral sclerosis (ALS). In addition, PGI₂ and TXA₂ receptors rescue CA1 neurons in an organotypic hippocampal model of N-methyl-d-aspartate excitotoxicity. However, in a model of inflammation induced by lipopolysaccharide, prostaglandin receptors previously found to be protective in excitotoxicity now cause CA1 neuronal death. Taken together, these studies identify novel eicosanoid receptor signaling pathways that mediate neuronal protection in excitotoxic paradigms; these data also support the emerging hypothesis that the toxic/protective effects of eicosanoid signaling on neuronal viability diverge significantly depending on whether excitotoxicity or inflammation predominates as the underlying toxic stimulus.

Section snippets

Acknowledgements

This work was supported by NINDS (K.A.), DOD (K.A.), the MDA and Packard Foundation (K.A.), and the American Federation for Aging Research (K.A.).

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TP receptor consists of two isoforms, TPα and TPβ, which are produced via alternative mRNA splicing, and TPα mRNA expression is dominant in the brain and vascular endothelial cells (Miggin and Kinsella, 1998). Although TP receptor is expressed on neurons in the central nervous system (CNS) (Gao et al., 1997), identified roles of TXA2 in neurons has been limited to cell protection against neurotoxicity (Cazevieille et al., 1994; Wu et al., 2007). Here, we report a novel role for TXA2 in promoting neurite outgrowth in cortical neurons based on mitogen activated protein kinase (MAPK) activation.
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PGD2 is the most abundant prostaglandin in brain and has been shown to be involved in the regulation of body temperature, the sleep–wake cycle, blood flow, neurotransmission and pain responses (Abdel-Halim et al., 1980; Chiu and Richardson, 1985). PGD2 has been shown to have both protective and toxic effects in various models of CNS and neuronal injury, thus its role in modulating neuronal injury in disease states remains controversial (Li et al., 2008; Liang et al., 2005; Taniguchi et al., 2007; Wu et al., 2007; Xiang et al., 2007). PGD2 may protect neurons from glutamate toxicity or ischemia–reperfusion injury through the activation of DP1 receptors in neuronal cells (Liang et al., 2005).
Prostaglandin D₂ (PGD₂) is the most abundant prostaglandin in brain but its effect on neuronal cell death is complex and not completely understood. PGD₂ may modulate neuronal cell death via activation of DP receptors or its metabolism to the cyclopentenone prostaglandins (CyPGs) PGJ₂, Δ¹²-PGJ₂ and 15-deoxy-Δ^12,14-PGJ₂, inducing cell death independently of prostaglandin receptors. This study aims to elucidate the effect of PGD₂ on neuronal cell death and its underlying mechanisms. PGD₂ dose-dependently induced cell death in rat primary neuron-enriched cultures in concentrations of ≥10 μM, and this effect was not reversed by treatment with either DP1 or DP2 receptor antagonists. Antioxidants N-acetylcysteine (NAC) and glutathione which contain sulfhydryl groups that can bind to CyPGs, but not ascorbate or tocopherol, attenuated PGD₂-induced cell death. Conversion of PGD₂ to CyPGs was detected in neuronal culture medium; treatment with these CyPG metabolites alone exhibited effects similar to those of PGD₂, including apoptotic neuronal cell death and accumulation of ubiquitinated proteins. Disruption of lipocalin-type prostaglandin D synthase (L-PGDS) protected neurons against hypoxia. These results support the hypothesis that PGD₂ elicits its cytotoxic effects through its bioactive CyPG metabolites rather than DP receptor activation in primary neuronal culture.
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EP2 expression is substantially induced during systemic inflammation in models of innate immunity produced by lipopolysaccharide (LPS), IL-1β, or turpentine [80]. EP2 upregulation by LPS contributes to cerebral oxidative damage and secondary neurotoxicity, usually accompanied by induction of NOS and COX activities [81–83]. As the resident macrophages in the brain, microglia are the major executors of innate immunity in the CNS and their activities are highly regulated by PGE2–EP2 signaling [52,84–86].
Modulation of a specific prostanoid synthase or receptor provides therapeutic alternatives to nonsteroidal anti-inflammatory drugs (NSAIDs) for treating pathological conditions governed by cyclooxygenase-2 (COX-2 or PTGS2). Among the COX-2 downstream signaling pathways, the prostaglandin E₂ (PGE₂) receptor EP2 subtype (PTGER2) is emerging as a crucial mediator of many physiological and pathological events. Genetic ablation strategies and recent advances in chemical biology provide tools for a better understanding of EP2 signaling. In the brain, the EP2 receptor modulates some beneficial effects, including neuroprotection, in acute models of excitotoxicity, neuroplasticity, and spatial learning via cAMP–PKA signaling. Conversely, EP2 activation accentuates chronic inflammation mainly through the cAMP–Epac pathway, likely contributing to delayed neurotoxicity. EP2 receptor activation also engages β-arrestin in a G-protein-independent pathway that promotes tumor cell growth and migration. Understanding the conditions under which multiple EP2 signaling pathways are engaged might suggest novel therapeutic strategies to target this key inflammatory prostaglandin receptor.
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Alzheimer's disease (AD) neuropathology is characterized by innate immune activation primarily through prostaglandin E2 (PGE₂) signaling. Dedicator of cytokinesis 2 (DOCK2) is a guanyl nucleotide exchange factor expressed exclusively in microglia in the brain and is regulated by PGE₂ receptor EP2. DOCK2 modulates microglia cytokine secretion, phagocytosis, and paracrine neurotoxicity. EP2 ablation in experimental AD results in reduced oxidative damage and amyloid beta (Aβ) burden. This discovery led us to hypothesize that genetic ablation of DOCK2 would replicate the anti-Aβ effects of loss of EP2 in experimental AD. To test this hypothesis, we crossed mice that lacked DOCK2 (DOCK2 −/−), were hemizygous for DOCK2 (DOCK2 +/−), or that expressed two DOCK2 genes (DOCK2 +/+) with APPswe-PS1Δe9 mice (a model of AD). While we found no DOCK2-dependent differences in cortex or in hippocampal microglia density or morphology in APPswe-PS1Δe9 mice, cerebral cortical and hippocampal Aβ plaque area and size were significantly reduced in 10-month-old APPswe-PS1Δe9/DOCK2 −/− mice compared with APPswe-PS1Δe9/DOCK2 +/+ controls. DOCK2 hemizygous APPswe-PS1Δe9 mice had intermediate Aβ plaque levels. Interestingly, soluble Aβ₄₂ was not significantly different among the three genotypes, suggesting the effects were mediated specifically in fibrillar Aβ. In combination with earlier cell culture results, our in vivo results presented here suggest DOCK2 contributes to Aβ plaque burden via regulation of microglial innate immune function and may represent a novel therapeutic target for AD.
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This chapter surveys the neurochemistry of lipid messengers, as well as the mechanisms by which bioactive lipids accumulate upon stimulation in response to injury, cerebral ischemia, seizures, neurotrauma or neurodegenerative diseases, and their significance in pathophysiology. The understanding of excitable membrane organization has evolved from the lipid bilayer with embedded proteins to a dynamic, heterogeneous patchwork of microdomains that contain ion channels, receptors, transporters, and other proteins. Cellular membranes in the nervous system were divided in the past into relatively more fluid membranes (e.g., those of cells of gray matter) and relatively more rigid membranes (e.g., oligodendrocyte plasma membrane that spirals around the axon to form the myelin), according to the higher or lower content of polyunsaturated fatty acids (PUFA) in phospholipids. Several phospholipid pools in neurons, glia and endothelial cells of the cerebrovasculature are now recognized as reservoirs of lipid messengers. In addition, there are lipid rafts that are cholesterol- and sphingolipid-rich microdomains in specific cellular compartments of the nervous system, including dendrites where they are associated with specific postsynaptic proteins.

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Divergent effects of prostaglandin receptor signaling on neuronal survival

Abstract

Section snippets

Acknowledgements

Pharmacol. Ther.

Neuron

Increased expression of the pro-inflammatory enzyme cyclooxygenase-2 in amyotrophic lateral sclerosis

Ann. Neurol.

Age-dependent cognitive deficits and neuronal apoptosis in cyclooxygenase-2 transgenic mice

J. Neurosci.

PGE2 receptors rescue motor neurons in a model of amyotrophic lateral sclerosis

Ann. Neurol.

Arachidonic acid metabolism in brain physiology and pathology: lessons from genetically altered mouse models

J. Neurochem.

Prostanoid receptors: subtypes and signaling

Annu. Rev. Pharmacol. Toxicol.

Cyclooxygenase-2 regulates prostaglandin E2 signaling in hippocampal long-term synaptic plasticity

J. Neurophysiol.

Cyclooxygenase 2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS

Ann. Neurol.

Inhibition of cyclooxygenase-2 protects motor neurons in an organotypic model of amyotrophic lateral sclerosis

Ann. Neurol.

The role of COX-1 and COX-2 in Alzheimer's disease pathology and the therapeutic potentials of non-steroidal anti-inflammatory drugs

Curr. Drug Targets

Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity

Nat. Med.