Microsphere embolism-induced endothelial nitric oxide synthase expression mediates disruption of the blood–brain barrier in rat brain
Article first published online: 24 JUL 2006
Journal of Neurochemistry
Volume 99, Issue 1, pages 97–106, October 2006
How to Cite
Han, F., Shirasaki, Y. and Fukunaga, K. (2006), Microsphere embolism-induced endothelial nitric oxide synthase expression mediates disruption of the blood–brain barrier in rat brain. Journal of Neurochemistry, 99: 97–106. doi: 10.1111/j.1471-4159.2006.04048.x
- Issue published online: 24 JUL 2006
- Article first published online: 24 JUL 2006
- Received December 28, 2005; revised manuscript received April 1, 2006; accepted May 22, 2006.
- blood–brain barrier;
- cerebral ischemia;
- endothelial cells;
- nitric oxide synthase;
- tyrosine nitration
Microsphere embolism (ME)-induced up-regulation of endothelial nitric oxide synthase (eNOS) in endothelial cells of brain microvessels was observed 2–48 h after ischemia. eNOS induction preceded disruption of the blood–brain barrier (BBB) observed 6–72 h after ischemia. In vascular endothelial cells, ME-induced eNOS expression was closely associated with protein tyrosine nitration, which is a marker of generation of peroxynitrite. Leakage of rabbit IgG from microvessels was also evident around protein tyrosine nitration-immunoreactive microvessels. To determine whether eNOS expression and protein tyrosine nitration in vascular endothelial cells mediates BBB disruption in the ME brain, we tested the effect of a novel calmodulin-dependent NOS inhibitor, 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (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 (EB) 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, ME-induced eNOS expression in vascular endothelial cells likely mediates BBB disruption and, in turn, brain edema.