Premarin stimulates estrogen receptor-alpha to protect against traumatic brain injury in male rats.
OBJECTIVE
To establish mechanisms of neuroprotective actions induced by Premarin (an estrogen sulfate) during traumatic brain injury.


METHODS
Chi Mei Medical Center research laboratory.


METHODS
Male Sprague-Dawley rats 244 to 268 g.


METHODS
Anesthetized rats, immediately after the onset of fluid percussion injury, were divided into three major groups and given the vehicle solution (1 mL/kg of body weight), Premarin (1 mg/kg of body weight), or Premarin (1 mg/kg of body weight) plus the nonselective estrogen receptor-alpha antagonist ICI 182, 780 (0.25 mg/kg of body weight) intravenously and immediately after fluid percussion injury.


RESULTS
Premarin, in addition to inducing pharmacologic levels of estradiol, causes attenuation of fluid percussion injury-induced cerebral infarction and motor and cognitive function deficits. Fluid percussion injury-induced apoptosis (e.g., increased numbers of both terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive and caspase-3-positive cells) as well as activated inflammation (e.g., increased levels of tumor necrosis factor-alpha) was also significantly Premarin-reduced. In peri-ischemic areas of hippocampus, both angiogenesis (e.g., increased numbers of both 5-bromodeoxyuridine-positive endothelial and vascular endothelial growth factor-positive cells) and neurogenesis (e.g., increased numbers of both 5-bromodeoxyuridine/neuronal-specific nuclear protein double-positive and glial cell line-derived neurotrophic factor-positive cells) were Premarin therapy-promoted. In estrogen receptor-alpha blockade rats, Premarin therapy had less or no effect on fluid percussion injury-induced behavioral deficits, cerebral infarction and apoptosis, and activated inflammation. Furthermore, Premarin-induced angiogenesis and neurogenesis were estrogen receptor-alpha blockade-reduced.


CONCLUSIONS
Our results indicate that pharmacologic levels of Premarin therapy-induced estradiol protect against cortical and hippocampal programmed cell death after fluid percussion injury through mechanisms stimulating estrogen receptor-alpha in the male rats.
Department of Obstetrics and Gynecology, Chi Mei Medical Center, Tainan, Taiwan.
Sheng-Hsien
SH
Chen
Chia-Yu
CY
Chang
Hsiu-Kang
HK
Chang
Wei-Chun
WC
Chen
Mao-Tsun
MT
Lin
Jhi-Joung
JJ
Wang
Jeffrey Cheng-Yu
JC
Chen
Fong-Ming
FM
Chang
D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy*; D047628:Estrogen Receptor alpha / Q000187:drug effects*; D004967:Estrogens / Q000494:pharmacology* / Q000627:therapeutic use*; D004966:Estrogens, Conjugated (USP) / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D047628:Estrogen Receptor alpha; D004967:Estrogens; D004966:Estrogens, Conjugated (USP)