Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Mail Code: UHN-2, Portland, OR 97239, USA.
Neuroscience. 2011 Dec 29;199:368-74. doi: 10.1016/j.neuroscience.2011.09.053. Epub 2011 Oct 4.
The volatile anesthetic, isoflurane, can protect the brain if administered before an insult such as an ischemic stroke. However, this protective "preconditioning" response to isoflurane is specific to males, with females showing an increase in brain damage following isoflurane preconditioning and subsequent focal cerebral ischemia. Innate cell sex is emerging as an important player in neuronal cell death, but its role in the sexually dimorphic response to isoflurane preconditioning has not been investigated. We used an in vitro model of isoflurane preconditioning and ischemia (oxygen and glucose deprivation, OGD) to test the hypotheses that innate cell sex dictates the response to isoflurane preconditioning and that 17β-estradiol attenuates any protective effect from isoflurane preconditioning in neurons via nuclear estrogen receptors. Sex-segregated neuron cultures derived from postnatal day 0-1 mice were exposed to either 0% or 3% isoflurane preconditioning for 1 h. In separate experiments, 17β-estradiol and the non-selective estrogen receptor antagonist ICI 182,780 were added 24 h before preconditioning and then removed at the end of the preconditioning period. Twenty-three hours after preconditioning, all cultures underwent 2 h of OGD. Twenty-four hours following OGD, cell viability was quantified using calcein-AM fluorescence. We observed that isoflurane preconditioning increased cell survival following subsequent OGD regardless of innate cell sex, but that the presence of 17β-estradiol before and during isoflurane preconditioning attenuated this protection only in female neurons independent of nuclear estrogen receptors. We also found that independent of preconditioning treatment, female neurons were less sensitive to OGD compared with male neurons and that transient treatment with 17β-estradiol protected both male and female neurons from subsequent OGD. More studies are needed to determine how cell type, cell sex, and sex steroids like 17β-estradiol may impact on anesthetic preconditioning and subsequent ischemic outcomes in the brain.
挥发性麻醉剂异氟醚，如果在缺血性中风等损伤前给予，可以保护大脑。然而，这种对异氟醚的保护性“预处理”反应是特异于雄性的，而雌性在异氟醚预处理和随后的局灶性脑缺血后表现出脑损伤增加。先天细胞性别正在成为神经元细胞死亡的一个重要参与者，但它在异氟醚预处理的性别二态反应中的作用尚未被研究。我们使用异氟醚预处理和缺血（氧和葡萄糖剥夺，OGD）的体外模型来检验以下假设：先天细胞性别决定对异氟醚预处理的反应，17β-雌二醇通过核雌激素受体减弱异氟醚预处理的任何保护作用。从出生后 0-1 天的小鼠中分离出性别分离的神经元培养物，分别暴露于 0%或 3%的异氟醚预处理 1 小时。在单独的实验中，17β-雌二醇和非选择性雌激素受体拮抗剂 ICI 182,780 在预处理前 24 小时添加，并在预处理结束时去除。预处理 23 小时后，所有培养物都经历了 2 小时的 OGD。OGD 后 24 小时，使用 calcein-AM 荧光定量细胞活力。我们观察到，无论先天细胞性别如何，异氟醚预处理都会增加随后 OGD 后的细胞存活，但在存在 17β-雌二醇的情况下，在异氟醚预处理前后，这种保护作用仅在雌性神经元中减弱，而与核雌激素受体无关。我们还发现，无论预处理治疗如何，雌性神经元对 OGD 的敏感性都低于雄性神经元，而短暂的 17β-雌二醇处理可以保护雄性和雌性神经元免受随后的 OGD。需要更多的研究来确定细胞类型、细胞性别和 17β-雌二醇等性激素如何影响大脑中的麻醉预处理和随后的缺血结局。
