Received for publication January 12, 2005.
Revised February 10, 2005.
Accepted for publication February 10, 2005.

STILBAZULENYL NITRONE, A SECOND-GENERATION AZULENYL NITRONE ANTIOXIDANT, CONFERS ENDURING NEUROPROTECTION IN EXPERIMENTAL FOCAL CEREBRAL ISCHEMIA IN THE RAT: NEUROBEHAVIOR, HISTOPATHOLOGY, AND PHARMACOKINETICS

Abstract

Stibazulenyl nitrone (STAZN) is a potent lipophilic second-generation azulenyl nitrone antioxidant, which is highly neuroprotective in rodent models of cerebral ischemia and trauma. This study was conducted to establish whether the neuroprotection induced by STAZN persists with chronic survival; and to characterize STAZN's pharmacokinetics. Physiologically regulated rats received 2-hour middle cerebral artery occlusion by intraluminal suture and were treated with either STAZN (four 0.6 mg/kg doses i.p. administered at 2 h (i.e., onset of recirculation), 4 h, 24 h, and 48 h; N=16) or dimethylsulfoxide vehicle (N=11). They received sequential neurobehavioral examinations followed by quantitative neuropathology at 30 days. STAZN improved neurological deficits compared to vehicle-controls, beginning within < 2 hours of the first dose and persisting throughout 30-day survival. Large cystic-necrotic infarcts were common in vehicle-treated rats but infrequent in STAZN-treated rats, and non-infarcted forebrain tissue was increased on average by 15%. In normal rats administered 5 mg/kg STAZN i.v. in Solutol HS 15 / ethanol / saline vehicle, STAZN blood levels exhibited a biexponential decline, with an initial half-life of 28 min and a subsequent slow decay with half-life of ~7 hours. STAZN tissue levels at 2-3 hours were, on average, 2.5% of blood levels in forebrain, 56% in myocardium, and 41% in kidney. STAZN was concentrated in liver with initial concentrations averaging 5.2-fold above blood levels and a subsequent linear decline of 40% between 24 and 72 hours. These results establish that STAZN confers enduring ischemic neuroprotection, has a long circulating half-life, and penetrates well into brain and other organs - characteristics favoring its potential therapeutic utility.

Key words: antioxidant, cerebral ischemia, middle cerebral artery occlusion, neuroprotection, nitrone, rat

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