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

Abstract

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.

Hydrogen peroxide mediated the neurotoxicity of an antibody against plasmalemmal neuronspecific enolase in primary cortical neurons

“…We confirmed that N-acetyl cystein and glutathione attenuated the 15d-PGJ 2 -induced cell death (Liu et al, 2013). In addition, vitamin E also suppressed neurotoxicities of amyloid b (Ueda et al, 1997) and secretory phospholipase A 2 (Yagami et al, 2003a(Yagami et al, , 2013.…”

Effects of MicroRNA-592-5p on Hippocampal Neuron Injury Following Hypoxic-Ischemic Brain Damage in Neonatal Mice - Involvement of PGD2/DP and PTGDR

“…PGD2 is synthesized in many organs and may function as a signaling molecule in the modulation of multiple biological processes, such as broncho-constriction, platelet aggregation, seizures, sleep and wakefulness, and hypoxia [40] As the most abundant prostaglandin in the brain, PGD2 exerts its functions primarily through PTGDR, which is also referred to as DP [13]. PGD2 may regulate neuronal cell death by activating DP receptors or their metabolism, inducing cell apoptosis independently of prostaglandin receptors [41]. Studies have revealed that PGD2 induces apoptosis in human leukemia cells [42] and in human osteoclasts by activating the CRTH2 receptor (PTGDR) [43].…”

PACAP27 prevents Parkinson-like neuronal loss and motor deficits but not microglia activation induced by prostaglandin J2

“…These levels represent average brain concentrations, but it is predicted that local cellular and intracellular concentrations of PGJ2 could be much higher [52]. Importantly, stroke and TBI increase the long-term risk for PD [8,35,73,86].…”