Prostaglandin D₂Protects Neonatal Mouse Brain from Hypoxic Ischemic Injury

Abstract

Prostaglandin D 2 (PGD) is synthesized by hematopoietic PGD synthase (HPGDS) or lipocalin-type PGDS (L-PGDS), depending on the organ in which it is produced, and binds specifically to either DP 1 or DP 2 receptors. We investigated the role of PGD 2 in the pathogenesis of hypoxic-ischemic encephalopathy (HIE) in neonatal mice at postnatal day 7. In wild-type mice, hypoxia-ischemia increased PGD 2 production in the brain up to 90-fold compared with the level in sham-operated brains at 10 min after cessation of hypoxia. Whereas the size of the infarct was not changed in L-PGDS or DP 2 knock-out mouse brains compared with that in the wild-type HIE brains, it was significantly increased in HPGDS-L-PGDS double knock-out or DP 1 knock-out mice. The PGD 2 level in L-PGDS, HPGDS, and HPGDS-L-PGDS knock-out mice at 10 min of reoxygenation was 46, 7, and 1%, respectively, of that in the wild-type ones, indicating the infarct size to be in inverse relation to the amount of PGD 2 production. DP 1 receptors were exclusively expressed in endothelial cells after 1 h of reoxygenation, and cerebral blood flow decreased more rapidly after the onset of hypoxia and did not return to the baseline level after reoxygenation in HPGDS-L-PGDS knock-out mice. Endothelial cells were severely damaged in HPGDS-L-PGDS and DP 1 knock-out mice after 1 h of reoxygenation. In the human neonatal HIE brain, HPGDS-positive microglia were increased in number. In conclusion, it is probable that PGD 2 protected the neonatal brain from hypoxic-ischemic injury mainly via DP 1 receptors by preventing endothelial cell degeneration.

The New Ketone Alphabet Soup: BHB, HCA, and HDAC

“…PGD was shown previously to have neuroprotective effects in a neonatal hypoxia-ischemia model (16). Consistent with the hypothesis that the protective effect of HCA 2 receptor-mediated neuroprotection is mediated via PGD 2 , Rahman and colleagues found that PGD 2 levels are elevated in both plasma and brain after nicotinic acid treatment.…”

The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

“…Previous work has shown that PGD 2 helps to resolve inflammation 42 . In addition, it has neuroprotective effects 22,43 . PGD 2 has a short half-life in tissue and is spontaneously converted into the cyclopentenone 15-deoxy-D 12,14 -prostaglandin J 2 (15d-PGJ 2 ), which inhibits the IkB kinase (IKK), the main activator of the transcription factor NF-kB and a key player in ischemic brain damage 44,45 .…”

“…In the skin, PGD 2 is responsible for the flushing response induced by nicotinic acid. In the brain, however, PGD 2 exerts neuroprotective effects 22 . Therefore, we investigated whether PGD 2 production mediates the neuroprotective effect of HCA 2 activation.…”

Divergent effects of prostaglandin receptor signaling on neuronal survival

“…Taken together, these data demonstrate novel and paradoxical protective effects of additional prostaglandin receptors in organotypic models of glutamate toxicity. The effects of prostaglandin receptors in organotypic models of excitotoxicity so far predicts their roles in vivo in models of cerebral ischemia where glutamate toxicity is an early and acute event [15,16,21].…”

“…In vivo, the EP2 receptor mediates a significant protective function in models of focal ischemia [15,16]. PGD 2 , signaling via its DP1 receptor similarly rescues CA1 and CA3 neurons in organotypic hippocampal slices treated with NMDA [14] and in vivo in a model of postnatal hypoxia-ischemia [21]. Mechanistically, EP2 and DP1 neuroprotection are dependent on intact cAMP signaling, whereas EP3 neuroprotection is associated with increased AKT phosphorylation [3,16].…”