Prostanoid EP1 receptor antagonist reduces blood-brain barrier leakage after cerebral ischemia.
Disruption of the blood-brain barrier (BBB) after cerebral ischemia is considered to be the initial step in the development of brain injuries, and an increase in the tyrosine phosphorylation of the tight junctional protein occludin has been shown to cause an increase in BBB permeability. Prostaglandin E2 (PGE2) appears to be associated with both toxic and protective effects on neuronal survival in vitro. However, it remains to be determined whether the prostanoid EP1 receptor is involved in the disruption of the BBB after cerebral ischemia. So we examined the effect of a prostanoid EP1 receptor antagonist, SC51089, on BBB leakage and tyrosine phosphorylation of occludin after cerebral ischemia. We demonstrated that SC51089 attenuated the increase in the tyrosine phosphorylation of occludin in isolated brain capillaries, which was coincident with a decrease in BBB leakage. These results suggest that the prostanoid EP1 receptor is involved in the tyrosine phosphorylation of occludin at tight junction, which may lead to disruption of the BBB and be linked to the development of cerebral infarctions.
Fukumoto
Ken-ichi
K
Department of Molecular and Cellular Pharmacology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Takagi
Norio
N
Yamamoto
Ritsuko
R
Moriyama
Yoshiyuki
Y
Takeo
Satoshi
S
Tanonaka
Kouichi
K
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism* / Q000503:physiopathology; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000378:metabolism; D006834:Hydrazines / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D062793:Occludin; D010077:Oxazepines / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D012709:Serum Albumin / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
C518288:FITC-albumin; D006834:Hydrazines; D008565:Membrane Proteins; D062793:Occludin; C568987:Ocln protein, rat; D010077:Oxazepines; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D012709:Serum Albumin; C086836:SC 51089; D014443:Tyrosine; D016392:Proto-Oncogene Proteins pp60(c-src); D016650:Fluorescein-5-isothiocyanate