Thyroxin Treatment Protects Against White Matter Injury in The Immature Brain via Brain-Derived Neurotrophic Factor

被引:50
|
作者
Hung, Pi-Lien [1 ,2 ]
Huang, Chao-Ching [4 ,5 ]
Huang, Hsiu-Mei [3 ]
Tu, Dom-Gene [6 ]
Chang, Ying-Chao [1 ,2 ]
机构
[1] Kaohsiung Chang Gung Mem Hosp, Dept Pediat, Kaohsiung, Taiwan
[2] Kaohsiung Chang Gung Mem Hosp, Grad Inst Clin Med Sci, Kaohsiung, Taiwan
[3] Kaohsiung Chang Gung Mem Hosp, Kaohsiung, Taiwan
[4] Natl Cheng Kung Univ, Coll Med, Inst Clin Med, Tainan 70101, Taiwan
[5] Natl Cheng Kung Univ, Coll Med, Dept Pediat, Tainan 70101, Taiwan
[6] Chia Yi Christian Hosp, Dept Nucl Med, Chiayi, Taiwan
关键词
brain-derived neurotrophic factor; hypoxic ischemia; immature brain; thyroxin; white matter injury; THYROID-HORMONE; OLIGODENDROCYTE DEVELOPMENT; PRETERM INFANTS; MESSENGER-RNA; HYPOTHYROXINEMIA; PREMATURITY; EXPRESSION; DAMAGE; RATS;
D O I
10.1161/STROKEAHA.113.001552
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Background and Purpose Low level of thyroid hormone is a strong independent risk factor for white matter (WM) injury, a major cause of cerebral palsy, in preterm infants. Thyroxin upregulates brain-derived neurotrophic factor during development. We hypothesized that thyroxin protected against preoligodendrocyte apoptosis and WM injury in the immature brain via upregulation of brain-derived neurotrophic factor. Methods Postpartum (P) day-7 male rat pups were exposed to hypoxic ischemia (HI) and intraperitoneally injected with thyroxin (T4; 0.2 mg/kg or 1 mg/kg) or normal saline immediately after HI at P9 and P11. WM damage was analyzed for myelin formation, axonal injury, astrogliosis, and preoligodendrocyte apoptosis. Neurotrophic factor expression was assessed by real-time polymerase chain reaction and immunohistochemistry. Neuromotor functions were measured using open-field locomotion (P11 and P21), inclined plane climbing (P11), and beam walking (P21). Intracerebroventricular injection of TrkB-Fc or systemic administration of 7,8-dihydroxyflavone was performed. Results On P11, the HI group had significantly lower blood T4 levels than the controls. The HI group showed ventriculomegaly and marked reduction of myelin basic protein immunoreactivities in the WM. T4 (1 mg/kg) treatment after HI markedly attenuated axonal injury, astrocytosis, and microgliosis, and increased preoligodendrocyte survival. In addition, T4 treatment significantly increased myelination and selectively upregulated brain-derived neurotrophic factor expression in the WM, and improved neuromotor deficits after HI. The protective effect of T4 on WM myelination and neuromotor performance after HI was significantly attenuated by TrkB-Fc. Systemic 7,8-dihydroxyflavone treatment ameliorated hypomyelination after HI injury. Conclusions T4 protects against WM injury at both pathological and functional levels via upregulation of brain-derived neurotrophic factor-TrkB signaling in the immature brain.
引用
收藏
页码:2275 / 2283
页数:9
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