Abstract: 【Objective】 To investigate the time dependent manner of glutamate concentration in brain tissues of rodent model in different postnatal days and its intervention study. 【Methods】 Total 128 neonatal SD rats were divided into 4 groups according to postnatal days(P)∶P2, P6, P12, P18(n=32). Each group were randomly divided into 4 groups: hypoxic-ischemic brain damage(HIBD) group(H), α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate(AMPA) group(A), GYKI52466 group(G) and normal control group(N) (n=8). Standard HIBD models were set up according to Rice methods on rats of H, A, G groups. Rats of the A and G groups were injected drugs immediately after modeling. Brain tissue of all groups was collected to detect the glutamate concentration and observe the pathological changes. 【Results】 The results showed that there was a negative correlation between glutamate concentrations and postnatal ages (r=0.81, P<0.01). The glutamate concentration in brain tissues of P2 group was the maximum and was dramatically higher than those of P6 group, P12 group and P18 group, respectively[(670.2±139.4) μmol/gprot vs(576±139 )μmol/gprot,(670.2±139.4) μmol/gprot vs(441.9±114.9) μmol/gprot and(670.2±139.4) μmol/gprot vs(287.0±82.8) μmol/gprot, q=3.88,9.41,15.80,P<0.05 or 0.01]. The glutamate concentration in brain tissues of G group was the minimum and there were significant differences compared with those of A, H and N groups[(348.6±128.5) μmol/gprot vs(608.6±176.7) μmol/gprot, (348.6±128.5) μmol/gprot vs(554.2±206.2) μmol/gprot, (348.6±128.5) μmol/gprot vs(463.8±167.1) μmol/gprot, q=10.72,8.49,4.75,P<0.01]. Pathological changes were consistent with the changes of glutamate concentration in each group. 【Conclusions】 Glutamate concentration shows time dependent in brain tissue of different postnatal days represent to different developmental level of neonatal brain. There is a negative correlation between glutamate concentrations and postnatal days. Glutamate concentrations increase in HIBD cases and decrease with treatment of GYKI52466. Neuroprotective effect of GYKI52466 is more obvious in relative early stage of gestational age. Early intervention with GYKI52466 is expected to prevent and cure neonatal brain damage resulted from premature birth or asphyxia.

Key words: cerebral anoxia, cerebral ischemia, glutamate, AMPA, GYKI52466

摘要： 【目的】 研究代表不同胎龄新生儿缺氧缺血性脑病(hypoxic ischemic encephalopathy, HIE)的模型鼠脑组织中谷氨酸(glutamate, Glu)含量变化的时间依从性及干预措施。 【方法】 将128只新生SD大鼠按出生日龄(postnatal age, P)分为P2、P6、P12、P18 4组,每组32只;各组按不同干预措施分为缺氧缺血性脑损伤(hypoxic ischemic brain damage, HIBD)模型对照组(H)、α-氨基羟甲基恶唑丙酸(AMPA)干预组(A)、GYKI52466干预组(G)与空白对照组(N),每组8只。除N组外,各组参照Rice方法建立HIBD标准模型,A、G组于造摸后立即给药。用药6 h后采集标本,检测各组脑组织Glu含量,同时做病理学检查。 【结果】 各日龄组脑组织中Glu含量比较,Glu含量与日龄呈负相关(r=0.81,P<0.01),P2组含量最高,与P6、P12、P18组比较差异均有统计学意义[(670.2±139.4) μmol/gprot vs (576±139) μmol/gprot,(670.2±139.4) μmol/gprot vs(441.9±114.9) μmol/gprot,(670.2±139.4) μmol/gprot vs(287.0±82.8) μmol/gprot, Q=3.88,9.41,15.80,P<0.05或<0.01]。各日龄组内比较,G组脑组织中Glu含量明显低于A组、H组和N组[(348.6±128.5) μmol/gprot vs(608.6±176.7)μmol/gprot,(348.6±128.5) μmol/gprot vs(554.2±206.2) μmol/gprot,(348.6±128.5) μmol/gprot vs(463.8±167.1) μmol/gprot,Q=10.72,8.49,4.75,P均<0.01]。病理学改变与Glu含量变化呈一致性。 【结论】 不同日龄新生大鼠脑组织中,Glu的含量具有时间依从性,与日龄呈负相关;HIBD可导致Glu含量明显增加而加重脑损伤;而GYKI52466可显著降低Glu含量,从而发挥神经保护作用,且胎龄越小,效果越明显。故应用GYKI52466早期干预可望有效防治因早产、窒息导致新生儿脑损伤。

关键词: 脑缺氧, 脑缺血, 谷氨酸, AMPA, GYKI52466