DHEA-neuroprotection and -neurotoxicity after transient cerebral ischemia in rats.
Dehydroepiandrosterone (DHEA) has been implicated not only to prevent N-methyl-D-aspartate (NMDA)-induced neurotoxicity but also to enhance Ca(2+) influx through NMDA receptor (NMDAr). However, these DHEA effects, which would produce inconsistent outcomes about neuronal damages, are not well studied in ischemia-induced cerebral damages. Herein, we report that a single administration of DHEA (20 mg/kg) during 3 to 48 h after transient global cerebral ischemia in rats exerted neuroprotective effects such as reduction of ischemia-induced neuronal death in the hippocampal CA1 and improvement of ischemia-induced deficits in spatial learning. By contrast, at 1 h before or after ischemia, the administration of DHEA exacerbated the ischemia-induced neuronal death and learning impairment. This DHEA neurotoxicity appeared to be caused by DHEA itself, but not through its metabolite testosterone, and was inhibited by a pretreatment with the NMDAr blocker MK801 or the sigma-1 (sigma(1)) receptor antagonist NE100. However, the DHEA neuroprotection was blocked by NE100. These results show that DHEA not only provides robust ischemic neuroprotection with a long therapeutic opportunity but also exerts neurotoxicity when administered during ischemia and early reperfusion, which points to the importance of administration timing of DHEA in the clinical treatment of brain damages by the transient brain ischemia including stroke.
Li
Zhen
Z
Laboratory of Reproductive Medicine, Nanjing Medical University, Jiangsu, China.
Cui
Shengzhong
S
Zhang
Zhuo
Z
Zhou
Rong
R
Ge
Yingbin
Y
Sokabe
Masahiro
M
Chen
Ling
L
D000818:Animals; D016923:Cell Death; D003687:Dehydroepiandrosterone / Q000627:therapeutic use* / Q000633:toxicity*; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy; D018696:Neuroprotective Agents / Q000627:therapeutic use* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D003687:Dehydroepiandrosterone