Background and Purpose-Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) may function as neurotrophic or neuroprotective factors to protect central nervous system (CNS) neurons against a variety of insults, including excitotoxicity. The present study evaluated the pharmacological effects of DHEAS in a reversible spinal cord ischemia model. Methods-DHEAS was administered (50 mg/kg IV) 5 or 30 minutes after the start of occlusion to groups of rabbits exposed to ischemia induced by temporary (15 to 60 minutes) occlusion of the infrarenal aorta. The group P 50 represents the duration of ischemia (in minutes) associated with 50% probability of resultant permanent paraplegia. Results-The P 50 of the vehicle-treated control group, when behavioral analysis was assessed 18 hours after aortal occlusion, was 28.8Ϯ2.0 minutes. Neuroprotection was demonstrated if a drug significantly prolonged the P 50 compared with the vehicle-treated control group. Treatment with DHEAS at 5 minutes significantly (PϽ0.05) prolonged the P 50 of the group to 36.8Ϯ3.9 minutes. In addition, the DHEAS effect appeared durable, because a significant difference between the control and DHEAS-treated groups was still measurable at the 4-day time point. At 4 days, the P 50 of the control group was 26.1Ϯ2.2 minutes, whereas the P 50 for the DHEAS-treated group was 38.6Ϯ5.9 minutes. DHEAS was not neuroprotective if administered 30 minutes after occlusion. In addition, the GABA A antagonist bicuculline abolished the neuroprotective effect of DHEAS. Conclusions-The present study suggests that neurosteroids may have substantial therapeutic benefit for the treatment of ischemic stroke.

Background and Purpose-Tissue plasminogen activator (tPA) is an effective treatment for stroke, but its utility is limited by fear of cerebral hemorrhage. Tenecteplase (TNK), a genetically modified form of wild-type tPA, exhibits a longer biological half-life and greater fibrin specificity, features that could lead to fewer cerebral hemorrhages than wild-type tPA in stroke patients. Methods-We injected radiolabeled blood clots into the cerebral circulation of New Zealand White rabbits. One hour later, we administered tPA (nϭ57), 0.6 mg/kg TNK (nϭ43), 1.5 mg/kg TNK (nϭ27), or vehicle control (nϭ37). A blinded observer examined the brains for macroscopic hemorrhage using a semiquantitative score. We estimated thrombolysis by assessing the amount of radiolabel remaining in the cerebral vessels postmortem. Results-Both wild-type tPA and TNK caused thrombolysis in most subjects. Hemorrhage was detected in 26% (6/23) of the control group, 66% (27/41) of the wild-type tPA group, 55% (16/29) in the 0.6-mg/kg TNK group, and 53% (9/17) in the 1.5-mg/kg TNK group (PϽ0.05, 2 test). The tPA group was statistically significantly different from the control group, but the TNK and tPA groups did not differ from each other. Neither TNK nor tPA affected the size of the hemorrhages. Conclusions-TNK shows comparable rates of recanalization compared with wild-type tPA in a model of embolic stroke.While tPA increases hemorrhage rate, the hemorrhage associated with TNK treatment is not statistically different compared with controls or the tPA group. These findings suggest that TNK shows promise as an alternative thrombolytic treatment for stroke, but we could not demonstrate improved safety compared with wild-type tPA.

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We sought to extend the therapeutic window for acute stroke therapy using the combination of a glutamate antagonist and a GABA agonist, which in prior studies was effective if given 5 min after stroke. We used a quantal bioassay to measure neuroprotective potency after injection of several thousand microspheres into the cerebral circulation of rats. The GABA-A agonist muscimol, but not MK-801, was effective if given 30, 45, or 60 min after embolization (potency ratio compared with saline of 3.0, 2.3, 1.8, respectively). If muscimol was combined with MK-801 at lower doses of each drug, the combination was neuroprotective (potency ratio of 4.2). Agonists of GABA-A, but not GABA-B, receptors blocked the toxic vacuolization seen in the cingulate and retrosplenial cortex after MK-801 treatment. Combination chemotherapy appears to extend the time window for acute stroke therapy in rats to 1 h and to result in fewer side effects.