Stilbazulenyl nitrone, a novel antioxidant, is highly neuroprotective in focal ischemia

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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