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Vol. 284, Issue 1, 215-221, 1998
Eukarion, Inc., Bedford, Massachusetts
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.
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