Dexamethasone (DEX) 是一種人工合成的醣皮質類固醇，被廣泛用於促進早產兒肺泡內的表面張力素之生成以及肺部發育之成熟，進而降低早產兒慢性肺疾病發生率及死亡率。通常給予 DEX 治療的時間為新生兒腦部發育的重要時期，愈來愈多的研究顯示新生給予 DEX 作治療會影響新生兒腦部的生長與發育且會影響其往後的神經發展，並可能增加罹患腦性麻痺 (cerebral palsy, CP) 的風險，因此對於類固醇用於早產兒治療對這些早產兒的安全性以及長期發展的影響也有愈來愈多人關注。儘管新生早期給予 DEX 對於治療與預防慢性肺疾病有很大的幫助，早產兒還是可能因為多重器官發育不全而面臨到缺血-缺氧的情況而使得腦部遭受嚴重傷害，尤其是大腦白質病變 (white matter injury, WMI)。具大腦白質病變的早產兒有 10–15% 在往後會發展成為腦性麻痺，而有 50% 可能會有認知及行為的缺損。然而，關於新生暴露 DEX 對往後因遭遇缺血-缺氧而引起的白質腦傷有何影響目前仍不清楚。因此，這個研究的主要目的是去探討新生暴露 DEX 是否會影響往後因缺血-缺氧而引起之白質腦傷並探討 DEX 影響因缺血-缺氧而引起之白質腦傷可能的因素。我們利用在大鼠P1-P3間給予遞減劑量的 DEX 來模擬臨床上早產兒的類固醇治療，並在P7進行缺血-缺氧的處理。我們發現新生暴露 DEX 會延遲大腦白質區域的發育、降低寡突細胞族群 (oligodendrocyte population) 數量以及加重往後因缺血-缺氧所造成的大腦白質區域 (包含 cingulum 和 external capsule) 髓鞘蛋白 MBP、 MAG、 MOG、 PLP 的缺損。我們還發現新生暴露 DEX 會加重往後因缺血-缺氧所造成的大腦白質區域 GFAP 表現量上升與微小膠細胞 (microglia) 的活化。除此之外，我們還發現新生暴露 DEX 會加重往後因缺血-缺氧而引起的腦性麻痺相關運動功能失調至少到3週且會破壞至少到5週 corpus callosum 正常的神經傳導。綜合以上結果顯示，早期使用 DEX 治療的方式可能會因為延遲 oligodendrocytes 的生長與發育而加重往後遭遇缺血-缺氧所引起之白質腦傷。

The synthetic glucocorticoid dexamethasone (DEX) has been widely used to prevent or lessen the morbidity of chronic lung disease (CLD) by facilitating surfactant synthesis in pulmonary alveolus in preterm infants. Typically, DEX were administered during a period of life that is critical for the development of the infant brain. There is growing evidence that postnatal DEX therapy will adversely affect the growth and development of the immature brain and is often associated with neurodevelopmental impairment and an increased risk of cerebral palsy. Therefore, growing concern has arisen for the long-term safety of this therapy on the brain development of the child. Although DEX treatment is a powerful way for the prevention and improvement of CLD, but preterm infants are still under the risk of encountering hypoxia-ischemia (HI) condition. Hypoxic–ischemic brain injury in the preterm infant appears selective for white matter, and 10–15% of preterm infants who have suffer from white matter injury subsequently exhibit cerebral palsy, and 50% have cognitive and behavioral deficits. However, the effect of neonatal DEX exposure on HI-induced white matter injury remains unknown. Thus, the objective of this proposal is to investigate the impact of neonatal DEX treatment on HI-induced white matter damage and characterize the possible underlying causes. Using a HI model of premature brain injury, we found 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) delayed whiter matter development, reduced oligodendrocyte population number and exacerbated HI-induced loss of myelin protein involving MBP, MAG, MOG, PLP in tissues of whiter matter, including cingulum and external capsule. We also found that neonatal DEX treatment exacerbates HI-induced increase in glial fibrillary acidic protein (GFAP) protein expression in the external capsule. In addition, neonatal DEX treatment exacerbates HI-induced microglia activation. Moreover, neonatal DEX treatment exacerbated HI-induced developmental motor deficits before 3-week-old and broken normal neuronal conduction in corpus callosum until 5-week-old. These results revealed that early DEX exposure influence oligodendrocyte lineage growth and delay white matter development and may lead the neonatal brain to be more vulnerable to subsequent HI–induced white matter injury.

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