Effects And Mechanisms Of Neurosteroid DHEA And DHEAS On Ischemia-induced Brain Injury

Dehydroepiandrosterone (DHEA) and its sulfate form (DHEAS)are the most abundant neurosteroids synthesized de novo in thenervous system. The age-dependent withdrawal of DHEA andDHEAS levels is very likely to be involved in the onset ofage-related neuronal diseases, including stroke which is the thirdcause of death after heart disease and cancer and is the leadingcause of chronic disability in the developed countries. Both in vivoand in vitro studies have shown that DHEA functions as aneurotrophic or neuroprotective factor to prevent glutamate-inducedneurotoxicity, giving rise to a possibility that compensating thedecline of DHEA and DHEAS may have clinical benefits forpreventing and treating stroke. However, human clinical trialsinvestigating its efficacy in conditions such as Alzheimer disease,advancing age, stroke and cardiovascular disease have provided inconsistent results. Thus, it is important to determine whichadministration condition produces neuroprotection or neurotoxicityof DHEA.We have reported that dehydroepiandrosterone sulfate (DHEAS)reduces the threshold for long-term potentiation (LTP) in Shaffercollateral-CA1 synapses through the amplification of Src-dependentNMDA receptor signaling. The present study is a follow-up of theabove reports, aiming at evaluating the effects of DHEAS on theimpaired LTP in reversible forebrain ischemic rats. Transient(20min) incomplete forebrain ischemia led to an impaired LTP inthe hippocampal CA1 region without damages to the basal synaptictransmission between the Shaffer collaterals and pyramidal neurons.Repetitive administrations of DHEAS (20mg/kg for 3 days) fromthe first 3h of reperfusion, but not acute DHEAS application(50μM),prevented the ischemic LTP impairment. Co-administrationof the specificσ1 receptor antagonist NE-100 with DHEAScompletely prevented the protective effect of DHEAS. In contrast,progesterone (PROG) not only had no protective effect against theischemic LTP impairment, but also attenuated the protective effectof DHEAS on the impaired LTP. Tyrosine phosphorylation ofNMDA receptor subunit 2B (NR2B) significantly decreased afterischemia, whereas that of NR1 had no obvious change. Furthermore,the repetitive administration of DHEAS improved the reduction intyrosine phosphorylation of NR2B, which was blocked by NE-100, a selective inhibitor forσ1 receptor. These findings suggest that therepetitive activation ofσ1 receptor induced by DHEAS mightprevent the ischemic LTP impairment through regulating thetyrosine phosphorylation of NR2B.Neurosteroid dehydroepiandrosterone (DHEA) is capable ofprotecting neurons from the cell death caused by various insultssuch as ischemia. However, little is known about the propermedication of this drug. Using an animal model of transient cerebralischemia, we sought in this study a proper administration timing ofDHEA through morphological, electrophysiological and behavioraltests. Male Sprague-Dawley rats were subjected to permanentvertebral arteries and 10 min bilateral common carotid arteriesocclusions (4VO). 4VO-rats were treated with a single admini-stration of DHEA (40mg/kg) at different time points before or afterischemia/reperfusion. Surprisingly, the administration of DHEA at 1hr before or after ischemia significantly increased the neuronaldeath in the hippocampal CA1 as compared to 4VO-rats treated withvehicle (DMSO) alone. In contrast, within 3-48 hrs after reperfusionthe administration of DHEA attenuated remarkably the neuronal loss.The same protocol of DHEA administration largely improved theischemic deficit in LTP induction and the retardation in "Morris"water maze test. These findings determine that in the hippocampalCA1 subjected to ischemia/reperfusion DHEA exerts a neurotoxiceffect during the ischemia and the early phase of reperfusion, and a delayed neuroprotection with wide efficacious time-window. Boththe DHEA-neurotoxicity and the neuroprotection were prevented bythe selectiveσ1 receptor antagonist NE-100. The delayed neuro-protective effects of DHEA with a wide administration time-windowindicate that DHEA, as a safe, clinically applicable agent, wouldgive great therapeutic benefits in treating stroke.These results may have important implications for the effectiveuse of hormone replacement therapy in treating stroke.