Department of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, University Rd, Tainan, 701, Taiwan.
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.
Mol Neurobiol. 2017 Nov;54(9):7083-7095. doi: 10.1007/s12035-016-0241-4. Epub 2016 Oct 28.
Dexamethasone, a synthetic glucocorticoid, has been widely used to prevent or ameliorate morbidity of chronic lung disease in preterm infants with respiratory distress syndrome. Despite its beneficial effect on neonatal lung function, growing concern has arisen about adverse effects of this clinical practice on fetal brain development. We demonstrated previously that neonatal dexamethasone (DEX) treatment may render the newborn brain to be more vulnerable to hypoxia/ischemia (HI)-induced gray matter injury. Here, we examined whether neonatal DEX treatment may also affect the extent of HI-induced subcortical white matter (WM) injury in the developing rat brain. Using a HI model of premature brain injury, we demonstrated that a 3-day tapering course (0.5, 0.3, and 0.1 mg/kg) of DEX treatment in rat pups on postnatal days 1-3 (P1-3) significantly reduced the number of all stages of the oligodendroglial lineage cells on P7 and exacerbated HI-induced WM injury. Neonatal DEX treatment also enhanced HI-induced oligodendroglial apoptosis and astrocyte activation in the developing WM on P14. Likewise, HI-induced reductions in myelin thickness, axon caliber, and function during WM development were exacerbated by neonatal DEX treatment. Furthermore, neonatal DEX treatment further aggravated HI-induced motor deficits as assessed in the rotarod test. We also found that the administration of β-lactam antibiotic ceftriaxone increased glutamate transporter-1 protein expression and significantly reduced HI-induced WM injury in neonatal DEX-treated rats. These results suggest that neonatal DEX treatment may lead the developing brain to be more vulnerable to subsequent HI-induced WM injury, which can be ameliorated by ceftriaxone administration.
地塞米松是一种合成的糖皮质激素，已被广泛用于预防或改善患有呼吸窘迫综合征的早产儿的慢性肺部疾病的发病率。尽管它对新生儿肺功能有有益的影响，但人们越来越关注这种临床实践对胎儿大脑发育的不良影响。我们之前已经证明，新生儿地塞米松（DEX）治疗可能使新生儿大脑更容易受到缺氧/缺血（HI）引起的灰质损伤。在这里，我们研究了新生儿 DEX 治疗是否也会影响发育中大鼠大脑中 HI 诱导的皮质下白质（WM）损伤的程度。使用早产脑损伤的 HI 模型，我们证明在 P1-3 期间对新生大鼠进行为期 3 天的逐渐减少剂量（0.5、0.3 和 0.1mg/kg）的 DEX 治疗可显著减少 P7 时所有阶段的少突胶质细胞谱系细胞数量，并加剧 HI 诱导的 WM 损伤。新生 DEX 治疗还增强了 HI 诱导的 WM 中发育中的少突胶质细胞凋亡和星形胶质细胞活化在 P14。同样，HI 诱导的 WM 发育过程中的少突胶质细胞髓鞘厚度、轴突直径和功能的减少也被新生 DEX 治疗加剧。此外，新生 DEX 治疗进一步加重了 HI 诱导的运动缺陷，如在旋转棒测试中评估的那样。我们还发现，β-内酰胺类抗生素头孢曲松的给药增加了谷氨酸转运蛋白-1 蛋白表达，并显著减轻了新生 DEX 治疗大鼠的 HI 诱导的 WM 损伤。这些结果表明，新生 DEX 治疗可能使发育中的大脑更容易受到随后的 HI 诱导的 WM 损伤，而头孢曲松的给药可以改善这种损伤。
