15d-Prostaglandin J2 Enhancement of Nerve Growth Factor–Induced Neurite Outgrowth Is Blocked by the Chemoattractant Receptor– Homologous Molecule Expressed on T-Helper Type 2 Cells (CRTH2) Antagonist CAY10471 in PC12 Cells

Hatanaka, Michiyoshi; Shibata, Norihiro; Shintani, Norihito; Haba, Ryota; Hayata, Atsuko; Hashimoto, Hitoshi; Baba, Akemichi

doi:10.1254/jphs.10001sc

Cited by 16 publications

(11 citation statements)

References 14 publications

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“…To investigate the role of DP receptors, the DP1 receptor antagonist BW A868C (0.1 and 1 μM) (Hatanaka et al, 2010) and the DP2 receptor antagonist BAY-u3405 (1 and 10 μM) (Zhu et al, 2010) were incubated with primary neurons in combination with 10 and 20 μM PGD 2 . Neuronal cell death was measured 48 h after treatment.…”

Section: Resultsmentioning

confidence: 99%

Prostaglandin D2 toxicity in primary neurons is mediated through its bioactive cyclopentenone metabolites

Líu

Rose

et al. 2013

NeuroToxicology

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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-Δ12,14-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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Section: Resultsmentioning

confidence: 99%

Prostaglandin D2 toxicity in primary neurons is mediated through its bioactive cyclopentenone metabolites

Líu

Rose

et al. 2013

NeuroToxicology

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“…The norepinephrine transporter is phosphorylated and activated by p38-MAP kinase, leading to the rapid clearing of synaptic NE [49]. We recently found that a selective CRTH2 agonist stimulates p38-MAP kinase and enhances NGF-induced neurite outgrowth in PC12 cells [50], suggesting that the CRTH2-mediated pathway may directly regulate NE content through the phosphorylation of the norepinephrine transporter in the hippocampus. In addition, corticotropinreleasing hormone mediates PGD 2 -mediated regulation of NE content [51].…”

Section: Discussionmentioning

confidence: 99%

CRTH2, a prostaglandin D2 receptor, mediates depression-related behavior in mice

Onaka

Shintani

Nakazawa

et al. 2015

Behavioural Brain Research

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“…DP1 has been primarily reported to regulate dendritic cell function [44] while DP2 was suggested to promote inflammatory pathways [45]. 13,14-Dihydro-15-keto PGD 2 is a selective DP2 agonist [46], while little information is available about the ability of 15d-PGJ 2 to stimulate DP1 [24] and/or DP2 receptors [47].…”

Section: Discussionmentioning

confidence: 99%

15-deoxy-Δ12,14-PGJ2 promotes inflammation and apoptosis in cardiomyocytes via the DP2/MAPK/TNFα axis

Koyani

Windischhofer

Rossmann

et al. 2014

International Journal of Cardiology

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BackgroundProstaglandins (PGs), lipid autacoids derived from arachidonic acid, play a pivotal role during inflammation. PGD2 synthase is abundantly expressed in heart tissue and PGD2 has recently been found to induce cardiomyocyte apoptosis. PGD2 is an unstable prostanoid metabolite; therefore the objective of the present study was to elucidate whether its final dehydration product, 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2, present at high levels in ischemic myocardium) might cause cardiomyocyte damage.Methods and resultsUsing specific (ant)agonists we show that 15d-PGJ2 induced formation of intracellular reactive oxygen species (ROS) and phosphorylation of p38 and p42/44 MAPKs via the PGD2 receptor DP2 (but not DP1 or PPARγ) in the murine atrial cardiomyocyte HL-1 cell line. Activation of the DP2-ROS-MAPK axis by 15d-PGJ2 enhanced transcription and translation of TNFα and induced apoptosis in HL-1 cardiomyocytes. Silencing of TNFα significantly attenuated the extrinsic (caspase-8) and intrinsic apoptotic pathways (bax and caspase-9), caspase-3 activation and downstream PARP cleavage and γH2AX activation. The apoptotic machinery was unaffected by intracellular calcium, transcription factor NF-κB and its downstream target p53. Of note, 9,10-dihydro-15d-PGJ2 (lacking the electrophilic carbon atom in the cyclopentenone ring) did not activate cellular responses. Selected experiments performed in primary murine cardiomyocytes confirmed data obtained in HL-1 cells namely that the intrinsic and extrinsic apoptotic cascades are activated via DP2/MAPK/TNFα signaling.ConclusionsWe conclude that the reactive α,β-unsaturated carbonyl group of 15d-PGJ2 is responsible for the pronounced upregulation of TNFα promoting cardiomyocyte apoptosis. We propose that inhibition of DP2 receptors could provide a possibility to modulate 15d-PGJ2-induced myocardial injury.

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15d-Prostaglandin J2 Enhancement of Nerve Growth Factor–Induced Neurite Outgrowth Is Blocked by the Chemoattractant Receptor– Homologous Molecule Expressed on T-Helper Type 2 Cells (CRTH2) Antagonist CAY10471 in PC12 Cells

Cited by 16 publications

References 14 publications

Prostaglandin D2 toxicity in primary neurons is mediated through its bioactive cyclopentenone metabolites

Prostaglandin D2 toxicity in primary neurons is mediated through its bioactive cyclopentenone metabolites

CRTH2, a prostaglandin D2 receptor, mediates depression-related behavior in mice

15-deoxy-Δ12,14-PGJ2 promotes inflammation and apoptosis in cardiomyocytes via the DP2/MAPK/TNFα axis

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