Therapeutic effects of tetramethylpyrazine nitrone in rat ischemic stroke models

Free radical‐mediated neuronal cell damage is an important pathological process in ischemic stroke. We have previously reported a novel dual‐functional agent, 2‐[[(1,1‐dimethylethyl)oxidoimino]‐methyl]‐3,5,6‐trimethylpyrazine (TBN), a derivative of tetramethylpyrazine armed with anitrone moiety. In this report, we further evaluate TBN'stherapeutic parameters in a rat middle cerebral artery occlusion (MCAO) model. Its abilities to cross the blood–brain barrier, scavenge free radicals, and inhibitCa 2+ influx were also investigated. TBN showed significant activity in both the transient MCAO (t‐MCAO) and permanent MCAO (p‐MCAO) stroke models in the rat. The therapeutic time window is 8 hr in the t‐MCAO model. TBN readily crossed the blood–brain barrier and in vitro had strong activity in neutralizing ·OH, O − 2 ·, and ONOO − and significantly decreased intracellular Ca 2+ concentration. TBN is a promising new treatment forischemic stroke, with multiple mechanisms of action. It blocks Ca 2+ overload and neutralizes ·OH, O − 2 ·, and ONOO − . © 2012 Wiley Periodicals, Inc.