Endothelial microsomal prostaglandin E synthase-1 facilitates neurotoxicity by elevating astrocytic Ca2+ levels

Recurrent seizures may cause neuronal damage in the hippocampus. As neurons form intimate interactions with astrocytes via glutamate, this neuron–glia circuit may play a pivotal role in neuronal excitotoxicity following such seizures. On the other hand, astrocytes contact vascular endothelia with their endfeet. Recently, we found kainic acid (KA) administration induced microsomal prostaglandin E synthase-1 (mPGES-1) and prostaglandin E2 (PGE2) receptor EP3 in venous endothelia and on astrocytes, respectively. In addition, mice deficient in mPGES-1 exhibited an improvement in KA-induced neuronal loss, suggesting that endothelial PGE2 might modulate neuronal damage via astrocytes. In this study, we therefore investigated whether the functional associations between endothelia and astrocytes via endothelial mPGES-1 lead to neuronal injury using primary cultures of hippocampal slices. We first confirmed the delayed induction of endothelial mPGES-1 in the wild-type (WT) slices after KA-treatment. Next, we examined the effects of endothelial mPGES-1 on Ca2+ levels in astrocytes, subsequent glutamate release and neuronal injury using cultured slices prepared from WT and mPGES-1 knockout mice. Moreover, we investigated which EP receptor on astrocytes was activated by PGE2. We found that endothelial mPGES-1 produced PGE2 that enhanced astrocytic Ca2+ levels via EP3 receptors and increased Ca2+-dependent glutamate release, aggravating neuronal injury. This novel endothelium–astrocyte–neuron signaling pathway may be crucial for neuronal damage after repetitive seizures, and hence could be a new target for drug development.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideResearch highlights► mPGES-1 is late induced by kainate in endothelium to produce prostaglandin E2. ► PG E2 produced by mPGES-1 raises astrocytic Ca2+ levels via EP3 receptors. ► Endothelial mPGES-1 increases Ca2+-dependent glutamate release. ► Endothelial mPGES-1 facilitates neurotoxicity in the hippocampus. ► Endothelial cells regulate hippocampal neurotoxicity via astrocytes.