Microsphere embolism-induced endothelial nitric oxide synthase expression mediates disruption of the blood-brain barrier in rat brain.

Abstract

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.

• Authors: Feng Han, Yasufumi Shirasaki, Kohji Fukunaga
• Journal: Journal of neurochemistry (J Neurochem) Vol. 99 Issue 1 Pg. 97-106 (Oct 2006) ISSN: 0022-3042 [Print] England
• PMID: 16987238 (Publication Type: Journal Article)

Chemical References

• 3-(2-(4-(3-chloro-2-methylphenyl)1-piperazinyl)ethyl)5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazol dihydrochloride 3.5 hydrate
• Calmodulin
• Indazoles
• Nitric Oxide Synthase Type III

Topics

• Animals
• Blood-Brain Barrier (physiology)
• Brain (enzymology)
• Brain Ischemia (enzymology, physiopathology)
• Calmodulin (antagonists & inhibitors)
• Cerebrovascular Circulation
• Embolism (etiology, physiopathology)
• Endothelium, Vascular (enzymology)
• Enzyme Induction
• Immunohistochemistry
• Indazoles (pharmacology)
• Microspheres
• Nitric Oxide Synthase Type III (biosynthesis)
• Rats