The neuroactive steroid 3-α-ol-5-β-pregnan-20-one hemisuccinate, a selective NMDA receptor antagonist improves behavioral performance following spinal cord ischemia

The initial response to an ischemic event is the rapid release of excitatory amino acid's followed by the activation of the "ischemic cascade". It has been suggested that neurosteroids, which act as negative modulators of excitatory amino acid receptors, may improve behavioral functions and promote neuronal survival following ischemia. The present study evaluated the pharmacological effects of 3-alpha-ol-5-beta-pregnan-20-one hemisuccinate (ABHS), a neurosteroid that inhibits excitatory amino acid receptor function, in a rabbit reversible spinal cord ischemia model (RSCIM). ABHS was administered (25 mg/kg) intravenously (i.v.) 5 or 30 min following the start of occlusion to groups of rabbits exposed to ischemia induced by temporary occlusion of the infrarenal aorta. The group P-50 represents the duration of ischemia (min) associated with a 50% probability of resultant permanent paraplegia. Quantal analysis indicated that the P-50 of the control group was 23.44+/-4.32 min. Using the RSCIM, neuroprotection is observed if a drug significantly prolongs the P-50 compared to the control group. Treatment with ABHS (25 mg/kg) 5 min post-occlusion significantly (p < 0.05) prolonged the P-50 of the group to 49.18+/-10.44 min, an increase of 110%. The effect of ABHS was not durable following a single injection since a significant difference between the control and ABHS-treated groups was not measurable at 48 h. However, if ABHS was injected 5 min following the start of ischemia and again 24 h after ischemia, there was a persistent effect of the drug at 48 h. Moreover, ABHS also increased the tolerance to ischemia if administered 30 min following the start of occlusion. Our results suggest that neuroactive steroids such as ABHS, which are selective NMDA receptor antagonists, may have substantial therapeutic benefit for the treatment of ischemic injuries including spinal cord neurodegeneration and stroke. (C) 2003 Elsevier B.V. All rights reserved.