Department of Biology, Program in Behavior, Cognition and Neuroscience, and the Center for Behavioral Neuroscience, American University, 4400 Massachusetts Avenue NW, Washington, DC, 20016, USA.
J Neuroinflammation. 2017 Dec 29;14(1):262. doi: 10.1186/s12974-017-1040-1.
Astrocytic aromatization and consequent increases in estradiol are neuroprotective in the injured brain. In zebra finches, cyclooxygenase-activity is necessary for injury-induced aromatase expression, and increased central estradiol lowers neuroinflammation. The mechanisms underlying these influences are unknown. Here, we document injury-induced, cyclooxygenase-dependent increases in glial aromatase expression and replicate previous work in our lab showing increases in central prostaglandin E2 and estradiol following brain damage. Further, we describe injury-dependent changes in E-prostanoid and estrogen receptor expression and reveal the necessity of E-prostanoid and estrogen receptors in the injury-dependent, reciprocal interactions of neuroinflammatory and neurosteroidogenic pathways.
Adult male and female birds were shams or received bilateral injections of the appropriate drug or vehicle into contralateral telencephalic lobes.
Injuries sustained in the presence of indomethacin (a cyclooxygenase inhibitor) had fewer aromatase-expressing reactive astrocytes relative to injuries injected with vehicle suggesting that cyclooxygenase activity is necessary for the induction of glial aromatase around the site of damage. Injured hemispheres had higher prostaglandin E2 and estradiol content relative to shams. Importantly, injured hemispheres injected with E-prostanoid- or estrogen receptor-antagonists showed elevated prostaglandin E2 and estradiol, respectively, but lower prostaglandin E2 or estradiol-dependent downstream activity (protein kinase A or phosphoinositide-3-kinase mRNA) suggesting that receptor antagonism did not affect injury-induced prostaglandin E2 or estradiol, but inhibited the effects of these ligands. Antagonism of E-prostanoid receptors 3 or 4 prevented injury-induced increases in neural estradiol in males and females, respectively, albeit this apparent sex-difference needs to be tested more stringently. Further, estrogen receptor-α, but not estrogen receptor-β antagonism, exaggerated neural prostaglandin E2 levels relative to the contralateral lobe in both sexes.
These data suggest injury-induced, sex-specific prostaglandin E2-dependent estradiol synthesis, and estrogen receptor-α dependent decreases in neuroinflammation in the vertebrate brain.
星形胶质细胞的芳香化作用和随之而来的雌二醇增加对受损大脑具有神经保护作用。在斑马雀中，环氧化酶活性对于损伤诱导的芳香酶表达是必要的，而中央雌二醇的增加则降低了神经炎症。这些影响的机制尚不清楚。在这里，我们记录了损伤诱导的、环氧化酶依赖性的神经胶质芳香酶表达增加，并复制了我们实验室之前的工作，表明脑损伤后中央前列腺素 E2 和雌二醇增加。此外，我们描述了损伤依赖性的 E-前列腺素和雌激素受体表达变化，并揭示了 E-前列腺素和雌激素受体在神经炎症和神经甾体生成途径的损伤依赖性相互作用中的必要性。
成年雄性和雌性鸟类接受假手术或双侧向对侧端脑叶注射适当的药物或载体。
与用载体注射的损伤相比，在吲哚美辛（环氧化酶抑制剂）存在下发生的损伤中，表达芳香酶的反应性星形胶质细胞较少，这表明环氧化酶活性对于损伤部位周围神经胶质芳香酶的诱导是必要的。受伤的半球相对于假手术组有更高的前列腺素 E2 和雌二醇含量。重要的是，用 E-前列腺素或雌激素受体拮抗剂注射的受伤半球分别显示出更高的前列腺素 E2 和雌二醇，但更低的前列腺素 E2 或雌二醇依赖性下游活性（蛋白激酶 A 或磷酸肌醇 3-激酶 mRNA），这表明受体拮抗剂没有影响损伤诱导的前列腺素 E2 或雌二醇，但抑制了这些配体的作用。E-前列腺素受体 3 或 4 的拮抗作用分别阻止了雄性和雌性动物中损伤诱导的神经雌二醇增加，尽管这种明显的性别差异需要更严格地测试。此外，雌激素受体-α，但不是雌激素受体-β，拮抗作用相对于两性的对侧叶增加了神经前列腺素 E2 水平。
这些数据表明，在脊椎动物大脑中，损伤诱导的、性别特异性的前列腺素 E2 依赖性雌二醇合成，以及雌激素受体-α 依赖性降低神经炎症。
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