Glucocorticoid receptor stimulation and the regulation of neonatal cerebellar neural progenitor cell apoptosis.
Glucocorticoid receptor stimulation and the regulation of neonatal cerebellar neural progenitor cell apoptosis.
复制标题
DOI：
10.1016/j.nbd.2011.04.004
复制
发表时间：
2011-08
影响因子：
6.1
通讯作者：
Farber, Nuri B.
中科院分区：
文献类型：
--
作者：
Noguchi, Kevin K.;Lau, Karen;Smith, Derek J.;Swiney, Brant S.;Farber, Nuri B.
关键词：
糖皮质激素被用于治疗与早产相关的呼吸功能障碍，但已被证明在治疗时会导致神经发育障碍。最近，我们建立了临床相关剂量的急性糖皮质激素暴露导致发育中的小鼠小脑外颗粒层的神经前体细胞凋亡和小脑神经元数量的永久性减少。随着小脑的自然成熟和不再需要神经发生，外部颗粒层减少了增殖，并在生命的第二周永久消失。与此同时，皮质酮(啮齿动物内源性糖皮质激素)的释放增加，保护外部颗粒层免受糖皮质激素受体刺激的糖皮质激素代谢酶(11B-羟基类固醇脱氢酶-2型；HSD2)自然消失。在这里，我们表明，抑制HSD2或将皮质酮提高到成年生理水平都可以独立地增加新生小鼠神经前体细胞的凋亡。相反，糖皮质激素受体拮抗剂减少了同一祖细胞群体中的自然生理性凋亡，提示内源性糖皮质激素刺激可能调节外部颗粒层的凋亡。我们还发现，糖皮质激素HSD2能有效代谢，产生较少的外颗粒层细胞凋亡，而糖皮质激素这种酶不能有效地分解。这一发现可能解释了为什么这种酶可以代谢的糖皮质激素在临床上对治疗呼吸功能障碍有效，但似乎不会产生神经发育缺陷。最后，我们证明，急性和慢性糖皮质激素暴露都会导致外颗粒层细胞凋亡，但如果没有适当的对照组，这种影响就会被掩盖。讨论了这些结果对糖皮质激素治疗和围产期神经发育的影响。
Glucocorticoids are used to treat respiratory dysfunction associated with premature birth but have been shown to cause neurodevelopmental deficits when used therapeutically. Recently, we established that acute glucocorticoid exposure at clinically relevant doses produces neural progenitor cell apoptosis in the external granule layer of the developing mouse cerebellum and permanent decreases in the number of cerebellar neurons. As the cerebellum naturally matures and neurogenesis is no longer needed, the external granule layer decreases proliferation and permanently disappears during the second week of life. At this same time, corticosterone (the endogenous rodent glucocorticoid) release increases and a glucocorticoid-metabolizing enzyme that protects the external granule layer against glucocorticoid receptor stimulation (11B-Hydroxysteroid-Dehydrogenase-Type 2; HSD2) naturally disappears. Here we show that HSD2 inhibition or raising corticosterone to adult physiological levels can both independently increase neural progenitor cell apoptosis in the neonatal mouse. Conversely, glucocorticoid receptor antagonism decreased natural physiological apoptosis in this same progenitor cell population suggesting endogenous glucocorticoid stimulation may regulate apoptosis in the external granule layer. We also found that glucocorticoids HSD2 can effectively metabolize generate less external granule layer apoptosis then glucocorticoids this enzyme is ineffective at breaking down. This finding may explain why glucocorticoids this enzyme can metabolize are clinically effective at treating respiratory dysfunction yet seem to produce no neurodevelopmental deficits. Finally, we demonstrate that both acute and chronic glucocorticoid exposure produces external granule layer apoptosis but without appropriate control groups this effect becomes masked. These results are discussed in terms of their implications for glucocortiocid therapy and neurodevelopment during the perinatal period.
登录
查看更多内容
影响因子：
15.9
作者：
Heine, Vivi M.;Rowitch, David H.
通讯作者：
Rowitch, David H.
影响因子：
2.9
作者：
BOHN, MC;LAUDER, JM
通讯作者：
LAUDER, JM
影响因子：
3.7
作者：
JUNGTESTAS, I;BAULIEU, EE
通讯作者：
BAULIEU, EE
影响因子：
8
作者：
Lodygensky, GA;Rademaker, K;Huppi, PS
通讯作者：
Huppi, PS
影响因子：
3.6
作者：
Benders MJ;Groenendaal F;van Bel F;Ha Vinh R;Dubois J;Lazeyras F;Warfield SK;Hüppi PS;de Vries LS
通讯作者：
de Vries LS