Testosterone increases neurotoxicity of glutamate in vitro and ischemia-reperfusion injury in an animal model.
Increasing evidence has demonstrated striking sex differences in the outcome of neurological injury. Whereas estrogens contribute to these differences by attenuating neurotoxicity and ischemia-reperfusion injury, the effects of testosterone are unclear. The present study was undertaken to determine the effects of testosterone on neuronal injury in both a cell-culture model and a rodent ischemia-reperfusion model. Glutamate-induced HT-22 cell-death model was used to evaluate the effects of testosterone on cell survival. Testosterone was shown to significantly increase the toxicity of glutamate at a 10 microM concentration, whereas 17beta-estradiol significantly attenuated the toxicity at the same concentration. In a rodent stroke model, ischemia-reperfusion injury was induced by temporal middle cerebral artery occlusion (MCAO) for 1 h and reperfusion for 24 h. To avoid the stress-related testosterone reduction, male rats were castrated and testosterone was replaced by testosterone pellet implantation. Testosterone pellets were removed at 1, 2, 4, or 6 h before MCAO to determine the duration of acute testosterone depletion effects on infarct volume. Ischemic lesion volume was significantly decreased from 239.6 +/- 25.9 mm(3) in control to 122.5 +/- 28.6 mm(3) when testosterone pellets were removed at 6 h before MCAO. Reduction of lesion volume was associated with amelioration of the hyperemia during reperfusion. Our in vitro and in vivo studies suggest that sex differences in response to brain injury are partly due to the consequence of damaging effects of testosterone.
Yang
Shao-Hua
SH
Department of Pharmacology and Neuroscience, Health Science Center at Fort Worth, University of North Texas, Fort Worth, Texas 76107, USA.
Perez
Evelyn
E
Cutright
Jason
J
Liu
Ran
R
He
Zhen
Z
Day
Arthur L
AL
Simpkins
James W
JW
D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D004343:Drug Implants; D004958:Estradiol / Q000494:pharmacology; D005971:Glutamates / Q000633:toxicity*; D008297:Male; D020768:Middle Cerebral Artery / Q000502:physiology; D009474:Neurons / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000473:pathology*; D009919:Orchiectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology*; D013739:Testosterone / Q000008:administration & dosage / Q000494:pharmacology*
D004343:Drug Implants; D005971:Glutamates; D013739:Testosterone; D004958:Estradiol