Endothelial microsomal prostaglandin E synthase-1 exacerbates neuronal loss induced by kainate.
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).
Takemiya
Takako
T
Medical Research Institute, Tokyo Women's Medical University, Shinjuku, Tokyo, Japan. takakot@lab.twmu.ac.jp
Matsumura
Kiyoshi
K
Sugiura
Hiroko
H
Maehara
Michiyo
M
Yasuda
Shin
S
Uematsu
Satoshi
S
Akira
Shizuo
S
Yamagata
Kanato
K
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D056654:CA3 Region, Hippocampal / Q000201:enzymology / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D015232:Dinoprostone / Q000378:metabolism; D004730:Endothelium, Vascular / Q000201:enzymology / Q000378:metabolism*; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D007608:Kainic Acid / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology / Q000502:physiology*; D000071876:Prostaglandin-E Synthases; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D058308:Receptors, Prostaglandin E, EP3 Subtype; D014680:Veins / Q000201:enzymology / Q000378:metabolism
C545648:Ptger3 protein, mouse; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone; D007608:Kainic Acid