The role of neurotrophic factors, apoptosis-related proteins, and endogenous antioxidants in the differential temporal vulnerability of neonatal cerebellum to ethanol
The role of neurotrophic factors, apoptosis-related proteins, and endogenous antioxidants in the differential temporal vulnerability of neonatal cerebellum to ethanol
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DOI：
10.1111/j.1530-0277.2003.tb04402.x
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发表时间：
2003-04-01
影响因子：
3.2
通讯作者：
Shaw, G
中科院分区：
文献类型：
--
作者：
Heaton, MB;Moore, DB;Shaw, G
背景：酒精会在发育中的神经系统中产生异常，某些区域在明确的时期内容易受到攻击。新生啮齿动物的小脑在出生后早期[出生后4-5天(P4-5)]对乙醇特别敏感，而这一区域在稍晚的时候对乙醇具有抵抗力(P7-9)。方法：检测神经营养因子神经生长因子、脑源性神经营养因子、神经营养因子-3和神经营养因子-4；细胞凋亡相关蛋白Bcl2、Bclxl、Bax、Bclxs、Bad、磷酸化Bad、磷酸化Akt和磷酸化c-Jun N末端激酶；以及抗氧化剂超氧化物歧化酶、谷胱甘肽还原酶和过氧化氢酶。这些分析量化了基础水平(在对照组中)，以及在急性酒精暴露后的连续变化(P4，P7)。结果：比较P4和P7之间评估的分子基础水平发现，在P4时总促凋亡Bad水平较高，在P7时保护性Pakt激酶水平较高，而在P7时促凋亡pJNK水平较低。其他基础水平也没有不同。虽然在两个年龄段都发现了有利于细胞凋亡和存活的乙醇介导的变化，但P4产生的促进凋亡的变化超过了P7，而且大多数发生在暴露后的第一个2小时内，这是一个关键的生存/死亡时期。在两个年龄段，有利于存活的改变的数量相似，但在P7，大多数发生在暴露后的第一个2小时内，可能是一种保护性的行为。结论：新生儿小脑对乙醇的不同时间脆弱性似乎与神经营养因子、凋亡调节蛋白和/或抗氧化剂活性的细胞变化平行，后者通常有利于最敏感年龄的细胞凋亡和抵抗年龄的存活。
Background: Ethanol produces abnormalities in the developing nervous system, with certain regions being vulnerable during well-defined periods. Neonatal rodent cerebellum is particularly susceptible to ethanol during the early postnatal period [on postnatal days 4-5 (P4-5)], while this region is resistant to ethanol at a slightly later time (P7-9). We assessed basal levels of several substances which may be involved in differential temporal ethanol vulnerability in neonatal cerebellum, and analyzed alterations in these substances after early ethanol exposure.Methods: Assessments were made of neurotrophic factors nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4; apoptosis-related proteins Bcl-2, Bcl-xl, Bax, Bcl-xs, Bad, phosphorylated-Bad, phosphorylated-Akt, and phosphorylated-c-Jun N-terminal kinase; and the antioxidants superoxide dismutase, glutathione reductase, and catalase. These analyses quantified basal levels (in controls), and sequential changes following acute ethanol exposure at the vulnerable and resistant cerebellar periods (P4, P7).Results: Comparisons of basal levels of the molecules assessed between P4 and P7 revealed higher levels of total proapoptotic Bad at p4, higher levels of the protective pAkt kinase at P7, and lower levels of proapoptotic pJNK at P7. Other basal levels did not differ. While ethanol-mediated alterations were found at both ages favoring both apoptosis and survival, the apoptosis-promoting changes produced on P4 exceeded those on P7, and most occurred within the first 2 hr after exposure, a critical survival/death period. The number of alterations favoring survival were similar at the two ages, but at P7 most occurred within the first 2 hr after exposure, possibly acting in a protective manner.Conclusions: Differential temporal vulnerability to ethanol in the neonatal cerebellum appears to be paralleled by cellular alterations in neurotrophic factors, apoptosis-regulatory proteins, and/or antioxidant activities which generally favor apoptosis at the most sensitive age and survival at the resistant age.