Stroke is a severe and prevalent syndrome for which there is a great need for treatment, including agents to block the cascade of
brain injury that occurs in the hours after the onset of
ischemia.
Reactive oxygen species (ROS) have been implicated in this destructive process, but
antioxidant enzymes such as
superoxide dismutase (SOD) have been unsatisfactory in experimental
stroke models. This study is an evaluation of the effectiveness of
salen-
manganese complexes, a class of synthetic SOD/
catalase mimetics, in a rat focal
ischemia model involving
middle cerebral artery occlusion. We focus on
EUK-134, a newly reported
salen-manganese complex demonstrated here to have greater
catalase and cytoprotective activities and equivalent SOD activity compared with the previously described prototype
EUK-8. The administration of
EUK-134 at 3 hr after
middle cerebral artery occlusion significantly reduced
brain infarct size, with the highest dose apparently preventing further
infarct growth.
EUK-8 was also protective but substantially less effective. These findings support a key role for ROS in the cascade of
brain injury after
stroke, even well after the onset of
ischemia. The enhanced activity of
EUK-134 suggests that, in particular,
hydrogen peroxide contributes significantly to this injury. Overall, this study suggests that synthetic SOD/
catalase mimetics might serve as novel, multifunctional therapeutic agents for
stroke.