Institute of Pharmacology and Toxicology, Tzu Chi University, Hualien, Taiwan.
J Biomed Sci. 2011 Sep 21;18(1):69. doi: 10.1186/1423-0127-18-69.
Perinatal brain injury is the leading cause of subsequent neurological disability in both term and preterm baby. Glutamate excitotoxicity is one of the major factors involved in perinatal hypoxic-ischemic encephalopathy (HIE). Glutamate transporter GLT1, expressed mainly in mature astrocytes, is the major glutamate transporter in the brain. HIE induced excessive glutamate release which is not reuptaked by immature astrocytes may induce neuronal damage. Compounds, such as ceftriaxone, that enhance the expression of GLT1 may exert neuroprotective effect in HIE.
We used a neonatal rat model of HIE by unilateral ligation of carotid artery and subsequent exposure to 8% oxygen for 2 hrs on postnatal day 7 (P7) rats. Neonatal rats were administered three dosages of an antibiotic, ceftriaxone, 48 hrs prior to experimental HIE. Neurobehavioral tests of treated rats were assessed. Brain sections from P14 rats were examined with Nissl and immunohistochemical stain, and TUNEL assay. GLT1 protein expression was evaluated by Western blot and immunohistochemistry.
Pre-treatment with 200 mg/kg ceftriaxone significantly reduced the brain injury scores and apoptotic cells in the hippocampus, restored myelination in the external capsule of P14 rats, and improved the hypoxia-ischemia induced learning and memory deficit of P23-24 rats. GLT1 expression was observed in the cortical neurons of ceftriaxone treated rats.
These results suggest that pre-treatment of infants at risk for HIE with ceftriaxone may reduce subsequent brain injury.
围产期脑损伤是导致足月和早产儿随后发生神经功能障碍的主要原因。谷氨酸兴奋性毒性是围产期缺氧缺血性脑病（HIE）的主要因素之一。谷氨酸转运体 GLT1 主要在成熟星形胶质细胞中表达，是大脑中主要的谷氨酸转运体。HIE 诱导的过量谷氨酸释放，如果不成熟的星形胶质细胞不能重新摄取，可能会导致神经元损伤。增强 GLT1 表达的化合物，如头孢曲松，可能在 HIE 中发挥神经保护作用。
我们使用单侧颈总动脉结扎和随后在出生后第 7 天（P7）暴露于 8%氧气 2 小时的新生大鼠模型来建立 HIE。新生大鼠在实验性 HIE 前 48 小时给予三种剂量的抗生素头孢曲松。用神经行为学测试评估治疗大鼠的情况。用尼氏染色和免疫组织化学染色以及 TUNEL 检测法检查 P14 大鼠的脑切片。通过 Western blot 和免疫组织化学法评估 GLT1 蛋白表达。
200mg/kg 头孢曲松预处理可显著降低海马区的脑损伤评分和凋亡细胞，恢复 P14 大鼠外囊的髓鞘形成，并改善 P23-24 大鼠缺氧缺血诱导的学习和记忆缺陷。在头孢曲松处理的大鼠皮质神经元中观察到 GLT1 表达。
这些结果表明，对有 HIE 风险的婴儿进行头孢曲松预处理可能会减轻随后的脑损伤。
