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 P50 represents the duration of
ischemia (min) associated with a 50% probability of resultant permanent
paraplegia. Quantal analysis indicated that the P50 of the control group was 23.44 +/- 4.32 min. Using the RSCIM, neuroprotection is observed if a
drug significantly prolongs the P50 compared to the control group. Treatment with ABHS (25 mg/kg) 5 min post-occlusion significantly (p < 0.05) prolonged the P50 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.