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Thyroxin treatment protects against white matter injury in the immature brain via brain-derived neurotrophic factor
Pi-Lien Hung1, Chao-Ching Huang, Hsiu-Mei Huang
1Department of Pediatrics and Graduate Institute of Clinical Medicine Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Insights
Thyroxin (T4) treatment protects immature rat brains from white matter injury following hypoxic-ischemia. This protection is mediated by brain-derived neurotrophic factor (BDNF) signaling, improving both tissue damage and motor function.
Area of Science:
- Neuroscience
- Developmental Biology
- Endocrinology
Background:
- Low thyroid hormone levels are a risk factor for white matter (WM) injury in preterm infants.
- Thyroxin (T4) influences brain development and neurotrophic factor expression.
Purpose of the Study:
- To investigate if thyroxin protects against white matter injury in the immature brain.
- To determine if this protection is mediated by brain-derived neurotrophic factor (BDNF).
Main Methods:
- Hypoxic-ischemic (HI) injury was induced in P7 rat pups.
- Pups received thyroxin (T4) or saline injections.
- White matter damage, preoligodendrocyte apoptosis, and BDNF expression were assessed.
- Neuromotor functions were evaluated.
- TrkB-Fc and 7,8-dihydroxyflavone were used to probe signaling pathways.
Main Results:
- HI induced white matter damage and reduced T4 levels.
- T4 treatment attenuated axonal injury, astrogliosis, and microgliosis, promoting preoligodendrocyte survival.
- T4 upregulated BDNF expression, increased myelination, and improved neuromotor deficits.
- The protective effects of T4 were dependent on BDNF-TrkB signaling.
Conclusions:
- Thyroxin protects against white matter injury in the immature brain at pathological and functional levels.
- This neuroprotection is achieved through the upregulation of BDNF-TrkB signaling.
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.
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