17β-Estradiol Activates Adenosine A2a Receptor After Subarachnoid Hemorrhage

BackgroundOur previous study showed that 17β-estradiol (E2) and an adenosine A2A receptor (AR-A2A) 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-A2A and extracellular signal-regulated kinase 1 and 2 (ERK1/2), and by altering antiapoptotic and proapoptotic protein expression (Bcl-2 and Bax, respectively).Materials and MethodsThe 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-A2A, and ERK1/2 in the cerebral cortex, hippocampus, and dentate gyrus were investigated.ResultsE2 significantly attenuated vasospasm. Seven days after the first SAH, TUNEL scores were significantly increased, and protein levels of AR-A2A, 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.ConclusionsThe down-regulated AR-A2A 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-A2A and ERK via ER-dependent mechanisms. These data may support further investigation of E2 in the treatment of SAH in humans.