Endothelial microsomal prostaglandin E synthase‐1 exacerbates neuronal loss induced by kainate

Abstract

Prostaglandin E(2) (PGE(2)) is increased in the brain after kainic acid (KA) treatment. We previously demonstrated that KA also induces PG synthase cyclooxygenase-2 (COX-2) expression rapidly in neurons of the brain and slowly in astrocytes and endothelia. Prevention of KA-induced neuronal damage by nonneuronal COX-2 inhibition suggests a novel modulatory mechanism for neuronal injury by nonneuronal PGs. It remains unclear, however, which PG synthase is responsible for this modulation following COX-2 synthesis after neuronal insult. In addition, the PG receptor subtype that is involved in neuronal loss remains controversial. Here we demonstrate that microinjection of KA induces microsomal prostaglandin E synthase-1 (mPGES-1) in venous endothelial cells but not in neurons or astrocytes. We found that mPGES-1 plays a central role in delayed production of PGE(2) and that mPGES-1-deficient mice exhibit significantly less neuronal loss induced by KA. Furthermore, KA injection caused an increase in the immunoreactivity for the EP3 receptor in the astrocytic endfeet that surround vascular endothelia. Neurons form intimate interactions with astrocytes via glutamate, and astrocytes contact vascular endothelia through endfeet. These findings suggest that endothelial cells may control neuronal excitotoxicity, most likely by regulating astrocytes via inducible PGE(2).

Role of Inflammatory Mediators in the Pathogenesis of Epilepsy

“…Three PGE 2 synthase (PGES) genes have been identified, including membrane-bound PGES (mPGES)-1, mPGES-2, and cytosolic PGES (cPGES). mPGES-1 is induced in the venous endothelia of the brain following an injection of KA [64], and its expression is upregulated in conditions of inflammation, pain, and fever [16, 65, 66]. mPGES-2 and cPGES show constitutive levels of expression, and their physiological functions remain unknown.…”

“…mPGES-1-KO mice show little postictal production of PGE 2 , and the lack of increased PGE 2 production resulted in the promotion of neuronal survival following KA injection [64, 68]. Furthermore, the intraventricular injection of PGE 2 decreased the latency to methylmalonate- (MMA-) induced seizures and increased the amplitude of spikes measured by an electroencephalogram (EEG) in rats [69].…”

Endothelial prostaglandin E2 regulates neuronal injury after seizure via activation of astrocytes

“…Unilateral KA microinjection induces COX-2 in bilateral neurons in the hippocampi, but in ipsilateral blood vessels both at 8 h and 24 h after KA injection 6 . Moreover, mPGES-1 is also localized in the blood vessels at 8 h, lasting until 24 h after KA microinjection 12 . Double immunostaining for both mPGES-1 and von Willebrand factor (an endothelial cell marker) shows that mPGES-1 is induced with COX-2 in the ECs for 48 h after the microinjection 12 .…”

“…Moreover, mPGES-1 is also localized in the blood vessels at 8 h, lasting until 24 h after KA microinjection 12 . Double immunostaining for both mPGES-1 and von Willebrand factor (an endothelial cell marker) shows that mPGES-1 is induced with COX-2 in the ECs for 48 h after the microinjection 12 . Finally, neuronal loss is caused in the KA microinjection side 6 , therefore we judge that PGE 2 synthesized by endothelial COX-2 and mPGES-1 facilitates neuronal injury in the hippocampus.…”

“…Moreover, we find that mPGES-1 is induced in the hippocampus after epileptic seizures caused by kainic acid (KA) microinjection 12 . KA is an analogue of the excitatory amino acid glutamate, and it is used in research to investigate the mechanisms of hippocampal neuronal loss after seizures because it induces generalized convulsion and causes neuronal loss in the hippocampus after seizures 13 .…”