Stilbazulenyl nitrone, a novel azulenyl nitrone antioxidant, improved neurological deficit and reduced contusion size after traumatic brain injury in rats

Abstract

Object. Stilbazulenyl nitrone (STAZN) is a second-generation azulenyl nitrone that has markedly enhanced antioxidant properties compared with those of conventional alpha-phenyl nitrones. In this study, the authors assessed the potential efficacy of STAZN in a rodent model of fluid-percussion brain injury, which results in a consistent cortical contusion. Methods. After anesthesia had been induced in normothermic Sprague—Dawley rats (brain temperature 36–36.5°C) by halothane—nitrous oxide, the animals were subjected to a right parietooccipital parasagittal fluid-percussion injury (1.5–2 atm). The agent (STAZN, 30 mg/kg; eight animals) or vehicle (dimethyl sulfoxide; eight animals) was administered intraperitoneally at 5 minutes and 4 hours after trauma. The neurological status of each rat was evaluated on Days 1, 2, and 7 postinjury (normal score 0, maximum injury 12). Seven days after trauma, the rat brains were perfusion fixed, coronal sections at various levels were digitized, and areas of contusion were measured. Treatment with STAZN significantly improved neurological scores on Days 2 and 7 postinjury compared with vehicle-treated rats. Administration of STAZN also significantly reduced the total contusion area by 63% (1.8 ± 0.5 mm2 in STAZN-treated animals compared with 4.8 ± 2.1 mm2 in vehicle-treated animals; p = 0.04) and the deep cortical contusion area by 60% (1.2 ± 0.2 mm2 in STAZN-treated animals compared with 2.9 ± 1.2 mm2 in vehicle-treated animals; p = 0.03). By contrast, hippocampal cell loss in the CA3 sector was unaffected by STAZN treatment. Conclusions. Therapy with STAZN, a novel potent antioxidant, administered following traumatic brain injury, markedly improves neurological and histological outcomes. Azulenyl nitrones appear to represent a promising class of neuroprotective agents for combating this devastating condition.