Gender-specific response to isoflurane preconditioning in focal cerebral ischemia
Gender-specific response to isoflurane preconditioning in focal cerebral ischemia
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DOI：
10.1038/sj.jcbfm.9600444
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发表时间：
2007-07-01
影响因子：
6.3
通讯作者：
Murphy, Stephanie J.
中科院分区：
文献类型：
--
作者：
Kitano, Hideto;Young, Jennifer M.;Murphy, Stephanie J.
吸入麻醉剂是实验性脑缺血的有效化学预处理剂。然而，之前的工作仅在雄性动物中进行。我们确定异氟烷预处理 (IsoPC) 后缺血结果是否存在性别差异，以及这种性别特异性反应是否与 Akt 磷酸化或神经元诱导细胞死亡推定激酶 (NIPK)（Akt 激活的负调节剂）表达的差异有关。年轻和中年雄性和雌性小鼠用空气（假PC）或1.0％IsoPC预处理4小时并恢复24小时。从预处理的年轻雄性和雌性小鼠的皮质中进行细分，以测量 Akt 磷酸化（蛋白质印迹）和 NIPK mRNA（定量聚合酶链反应）。其他队列接受了 2 小时的可逆性大脑中动脉闭塞。最后，对雄性和雌性 Akt1(+/+) 和 Akt1(-/-) 小鼠进行了研究，以确定 IsoPC 后缺血结果的性别差异是否依赖于 Akt1。再灌注22小时时测定梗塞体积（2,3,5-三苯基氯化四唑）。正如预期的那样，与假 PC 相比，IsoPC 减少了年轻和中年雄性小鼠的缺血性损伤。相比之下，IsoPC 显着增加年轻雌性小鼠的梗塞发生率，而对中年雌性小鼠则没有影响。仅在雄性小鼠中，与假 PC 相比，IsoPC 增加了皮质磷酸化 Akt。在 IsoPC 雌性小鼠中没有观察到增加。无论预处理状态如何，雌性小鼠的 NIPK mRNA 均高于雄性小鼠。 Aktl 缺陷的雄性小鼠失去了雄性 IsoPC 的神经保护作用。我们得出的结论是，IsoPC 仅对缺血性男性大脑有益，并且 IsoPC 的性别差异是通过 Akt 激活和基础 NIPK 表达介导的。
Inhalation anesthetics are effective chemical preconditioning agents in experimental cerebral ischemia. However, previous work has been performed exclusively in male animals. We determined if there is a gender difference in ischemic outcome after isoflurane preconditioning (IsoPC), and if this sex-specific response is linked to differences in Akt phosphorylation or expression of neuronal inducible cell-death putative kinase (NIPK), a negative modulator of Akt activation. Young and middle-aged male and female mice were preconditioned for 4 h with air (sham PC) or 1.0% IsoPC and recovered for 24 h. Cortices were subdissected from preconditioned young male and female mice for measurement of Akt phosphorylation (Western blot) and NIPK mRNA (quantitative polymerase chain reaction). Additional cohorts underwent 2h of reversible middle cerebral artery occlusion. Lastly, male and female Akt1(+/+) and Akt1(-/-) mice were studied to determine if gender differences in ischemic outcome after IsoPC is Akt1-dependent. Infarction volume was determined at 22h reperfusion (2,3,5-triphenyltetrazolium chloride). As expected, IsoPC decreased ischemic damage as compared with sham PC in young and middle-aged male mice. In contrast, IsoPC markedly increased infarction in young female mice and had no effect in middle-aged female mice. Cortical phospho-Akt was increased by IsoPC versus sham PC only in male mice. No increase was observed in IsoPC female mice. NIPK mRNA was higher in female mice than in male mice regardless of preconditioning status. Male IsoPC neuroprotection was lost in Aktl-deficient male mice. We conclude that IsoPC is beneficial only in ischemic male brain and that sex differences in IsoPC are mediated through Akt activation and basal NIPK expression.