Dehydroepiandrosterone sulfate is neuroprotective in a reversible spinal cord ischemia model -: Possible involvement of GABAA receptors

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 tin 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 28.8+/-2.0 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 (P<0.05) prolonged the P-50 of the group to 36.8+/-3.9 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 26.1+/-2.2 minutes, whereas the P-50 for the DHEAS-treated group was 38.6+/-5.9 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.