17Beta-estradiol activates adenosine A(2a) receptor after subarachnoid hemorrhage.
BACKGROUND
Our previous study showed that 17beta-estradiol (E2) and an adenosine A(2A) receptor (AR-A(2A)) agonist could attenuate subarachnoid hemorrhage (SAH)-induced cerebral vasospasm via preventing the augmentation of iNOS expression and preserving the normal eNOS expression. This study tests the hypothesis that E2 attenuates SAH-induced vasospasm and apoptosis by activating adenosine AR-A(2A) and extracellular signal-regulated kinase 1 and 2 (ERK1/2), and by altering antiapoptotic and proapoptotic protein expression (Bcl-2 and Bax, respectively).


METHODS
The two-hemorrhage SAH model in rat was used. Animals were treated with E2 with or without a nonselective estrogen receptor (ER) antagonist (ICI182,780). The cross sectional areas of the basilar artery and terminal dUTP nick-end labeling (TUNEL) were used to determine the degree of vasospasm and apoptosis, respectively. The expressions of Bcl-2, Bax, AR-A(2A), and ERK1/2 in the cerebral cortex, hippocampus, and dentate gyrus were investigated.


RESULTS
E2 significantly attenuated vasospasm. Seven days after the first SAH, TUNEL scores were significantly increased, and protein levels of AR-A(2A), ERK1/2, and Bcl-2 were significantly decreased in the dentate gyrus only but not in the cortex and hippocampus. These changes were reversed by E2 while ICI182,780 abrogated the antiapoptotic and anti-spastic effects of E2. The expression of Bax did not change in the dentate gyrus after SAH with or without treatment.


CONCLUSIONS
The down-regulated AR-A(2A) and ERK may play a role in vasospasm and apoptosis after SAH. The beneficial effect of E2 in the attenuating SAH-induced vasospasm and apoptosis may be due to an increased expression of AR-A(2A) and ERK via ER-dependent mechanisms. These data may support further investigation of E2 in the treatment of SAH in humans.
Lin
Chih-Lung
CL
Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. chihlung1@yahoo.com
Dumont
Aaron S
AS
Tsai
Yee-Jean
YJ
Huang
Jih-Hui
JH
Chang
Kao-Ping
KP
Kwan
Aij-Lie
AL
Hong
Yi-Ren
YR
Howng
Shen-Long
SL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018891:Dentate Gyrus / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D004967:Estrogens / Q000494:pharmacology*; D000077267:Fulvestrant; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D023421:Models, Animal; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000378:metabolism*; D020301:Vasospasm, Intracranial / Q000188:drug therapy / Q000209:etiology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D004967:Estrogens; D019253:Proto-Oncogene Proteins c-bcl-2; D043705:Receptor, Adenosine A2A; D011960:Receptors, Estrogen; D051028:bcl-2-Associated X Protein; D000077267:Fulvestrant; D004958:Estradiol; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3