Dehydroepiandrosterone sulfate is neuroprotective in a reversible spinal cord ischemia model: possible involvement of GABA(A) receptors.
OBJECTIVE
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 28.8+/-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.
University of California San Diego, Department of Neuroscience, La Jolla, CA 92093-0624, USA. plapchak@ucsd.edu
P A
PA
Lapchak
D F
DF
Chapman
S Y
SY
Nunez
J A
JA
Zivin
D000818:Animals; D001522:Behavior, Animal; D001640:Bicuculline / Q000494:pharmacology; D019314:Dehydroepiandrosterone Sulfate / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018756:GABA Antagonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D007275:Injections, Intravenous; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010264:Paraplegia / Q000188:drug therapy / Q000209:etiology; D011817:Rabbits; D011963:Receptors, GABA-A / Q000378:metabolism; D020127:Recovery of Function / Q000502:physiology*; D020760:Spinal Cord Ischemia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism
D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D018696:Neuroprotective Agents; D011963:Receptors, GABA-A; D019314:Dehydroepiandrosterone Sulfate; D001640:Bicuculline