Selective inhibition of plasma kallikrein protects brain from reperfusion injury.
We have studied the effect of DX-88, a selective recombinant inhibitor of human plasma kallikrein, in transient or permanent focal brain ischemia (with or without reperfusion, respectively) induced in C57BL/6 mice. Twenty-four hours after transient ischemia, DX-88 administered at the beginning of ischemia (pre) induced a dose-dependent reduction of ischemic volume that, at the dose of 30 microg/mouse, reached 49% of the volume of saline-treated mice. At the same dose, DX-88 was also able to reduce brain swelling to 32%. Mice treated with DX-88 pre had significantly lower general and focal deficit score. Fluoro-Jade staining, a marker for neuronal degeneration, showed that DX-88-treated mice had a reduction in the number of degenerating cells, compared with saline-treated mice. Seven days after transient ischemia, the DX-88 protective effect was still present. When the inhibitor was injected at the end of ischemia (post), it was still able to reduce ischemic volume, brain swelling, and neurological deficits. DX-88 efficacy was lost when the inhibitor was given 30 min after the beginning of reperfusion (1 h post) or when reperfusion was not present (permanent occlusion model). This study shows that DX-88 has a strong neuroprotective effect in the early phases of brain ischemia preventing reperfusion injury and indicates that inhibition of plasma kallikrein may be a useful tool in the strategy aimed at reducing the detrimental effects linked to reperfusion.
Storini
Claudio
C
Department of Neuroscience, Mario Negri Institute, Milan, Italy.
Bergamaschini
Luigi
L
Gesuete
Raffaella
R
Rossi
Emanuela
E
Maiocchi
Diana
D
De Simoni
Maria Grazia
MG
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000473:pathology; D001929:Brain Edema / Q000473:pathology / Q000517:prevention & control; D002452:Cell Count; D002561:Cerebrovascular Disorders / Q000517:prevention & control*; D005452:Fluoresceins; D005456:Fluorescent Dyes; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000473:pathology; D009474:Neurons / Q000473:pathology; D009930:Organic Chemicals; D020842:Plasma Kallikrein / Q000037:antagonists & inhibitors*; D015427:Reperfusion Injury / Q000517:prevention & control*
D005452:Fluoresceins; D005456:Fluorescent Dyes; D009930:Organic Chemicals; C435731:fluoro jade; D020842:Plasma Kallikrein