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Abstract

Azulenyl nitrones are novel chain-breaking antioxidants with low oxidation potentials and high lipophilicity—properties favoring their efficacy as neuroprotectants. We tested the second-generation azulenyl nitrone, stilbazunenlyl nitrone (STAZN), in focal ischemic stroke. Physiologically monitored rats received 2 hours of middle cerebral artery occlusion by intraluminal suture, resulting in substantial cortical and striatal infarcation. Neurobehavior was quantified on a standard battery, and brains were perfusion-fixed for quantitative histopathology at 3 days. In 3 independent series, rats were treated at either 2h + 4h, or 2h + 4h + 24h + 48h, after onset of ischemia; vehicle-treated rats received dimethylsulfoxide or saline. All animals (n = 52) developed high-grade neurological deficits (score 11 of 12) during ischemia, which improved, in STAZN-treated rats, within 1–1.5 h of the initial dose and fell to a median score of 3 at 72 h, compared to 8 in vehicle rats. STAZN treatment reduced mean cortical infarct volume by 64–97%, and total infarct volume by 42–72%. In over one-half of STAZN-treated animals, cortical infarction was virtually abolished. Regression analysis predicted that STAZN would confer ∼50% cortical neuroprotection even in the most severely affected cases. The potency of STAZN was orders-of-magnitude greater than other nitrones such as NXY-059. These results suggest that STAZN has great promise for ischemic stroke. Ann Neurol 2003