[Brain embolism-induced injury of vascular endothelial cells and a novel vasoprotective drug].
Microsphere embolism-induced up-regulation of endothelial nitric oxide synthase (eNOS) in endothelial cells of brain microvessels was found after brain ischemia. The eNOS induction preceded disruption of the blood-brain barrier following ischemia. In vascular endothelial cells, microsphere embolism-induced eNOS expression was associated with protein tyrosine nitration, which is a marker of generation of peroxynitrite. To determine whether eNOS expression and protein tyrosine nitration in vascular endothelial cells mediates the blood-brain barrier disruption in the microsphere embolism brain, we tested the effect of a novel calmodulin-dependent NOS inhibitor, DY-9760e, which inhibits eNOS activity and in turn protein tyrosine nitration. Concomitant with inhibition of protein tyrosine nitration in vascular endothelial cells, DY-9760e significantly inhibited BBB disruption as assessed by Evans blue excretion. DY-9760e also inhibited cleavage of poly(ADP-ribose) polymerase as a marker of the apoptotic pathway in vascular endothelial cells. Taken together with previous evidence in which DY-9760e inhibited brain edema, microsphere embolism-induced eNOS expression in vascular endothelial cells likely mediates BBB disruption and in turn brain edema.
Han
Feng
F
Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. hanfeng@mail2.pharm.tohoku.ac.jp
Fukunaga
Kohji
K
D000818:Animals; D001812:Blood-Brain Barrier; D001929:Brain Edema / Q000188:drug therapy / Q000209:etiology; D002147:Calmodulin / Q000037:antagonists & inhibitors; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use*; D020766:Intracranial Embolism / Q000188:drug therapy* / Q000209:etiology*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
C109602:3-(2-(4-(3-chloro-2-methylphenyl)1-piperazinyl)ethyl)5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazol dihydrochloride 3.5 hydrate; D002147:Calmodulin; D007191:Indazoles; D014443:Tyrosine; D052250:Nitric Oxide Synthase Type III