| Summary: | 碩士 === 國立成功大學 === 藥理學研究所 === 100 === The synthetic glucocorticoid dexamethasone (DEX) is frequently used to prevent or lessen the morbidity of chronic lung disease (CLD) by facilitating surfactant synthesis in pulmonary alveolus in premature infants. Typically, high doses of DEX are administered for several weeks, notably during a period of life that is critical for the development of the infant brain. 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 management of CLD, but preterm infants are still under the risk of encountering hypoxic-ischemic stress. Based on our cDNA microarray data, we have found that DEX administration during neonatal development may alter the expression pattern of several genes associated with neurotrophic and neuroprotective functions. Thus, the objective is to evaluate the impact of neonatal DEX treatment on hypoxic-ischemic brain damage and characterize the possible underlying mechanisms.
Using a schedule of tapering doses of DEX similar to that used in premature infants, we demonstrate that neonatal DEX treatment exacerbates hypoxic-ischemic brain damage in the immature rats through a glucocorticoid receptor-mediated mechanism. The influence of neonatal DEX treatment on hypoxic-ischemic brain damage was correlated with a decrease in glutamate reuptake. Furthermore, neonatal DEX treatment decreased the expression of GLT-1 and GLAST mRNA and protein in the cerebral cortex. The expression level of the NMDA receptor subunits NR2A and NR2B was not significantly altered by neonatal DEX treatment. By using promoter luciferase assay, we identified that the decrease of GLT-1 transcriptional activity after DEX treatment was associated to the GLT-1 promoter region form -956 to -306. Pretreatment with ceftriaxone effectively increased the expression of GLT-1 protein and rescued exacerbated hypoxic-ischemic brain damage by neonatal DEX treatment.
In conclusion, these results suggest that neonatal DEX treatment before an episode of hypoxic-ischemia actually enhances the brain injury through an enhanced glutamate-mediated excitotoxicity.
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