Heaton Marieta Barrow, Moore D Blaine, Paiva Michael, Madorsky Irina, Mayer Joanne, Shaw Gerry
Department of Neuroscience, McKnight Brain Institute, University of Florida College of Medicine, Gainesville, USA.
Alcohol Clin Exp Res. 2003 Apr;27(4):657-69. doi: 10.1097/01.ALC.0000060527.55252.71.
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.
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).
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.
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.
乙醇会导致发育中的神经系统出现异常，某些区域在特定时期易受影响。新生啮齿动物的小脑在出生后早期（出生后第4 - 5天，即P4 - 5）对乙醇特别敏感，而在稍晚些时候（P7 - 9）该区域对乙醇具有抗性。我们评估了几种可能与新生小脑不同时期乙醇易感性差异有关的物质的基础水平，并分析了早期乙醇暴露后这些物质的变化。
对神经营养因子神经生长因子、脑源性神经营养因子、神经营养素 - 3和神经营养素 - 4；凋亡相关蛋白Bcl - 2、Bcl - xl、Bax、Bcl - xs、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进行评估。这些分析量化了基础水平（在对照组中），以及在小脑易感性和抗性时期（P4、P7）急性乙醇暴露后的连续变化。
比较P4和P7之间所评估分子的基础水平发现，P4时促凋亡的总Bad水平较高，P7时具有保护作用的pAkt激酶水平较高，P7时促凋亡的pJNK水平较低。其他基础水平没有差异。虽然在两个年龄段都发现了乙醇介导的变化，既有促进凋亡的也有促进存活的，但P4时促进凋亡的变化超过了P7时的变化，且大多数变化发生在暴露后的前2小时内，这是一个关键的存活/死亡时期。两个年龄段促进存活的变化数量相似，但在P7时大多数变化发生在暴露后的前2小时内，可能起到保护作用。
新生小脑对乙醇的不同时期易感性差异似乎与神经营养因子、凋亡调节蛋白和/或抗氧化活性的细胞变化并行，这些变化通常在最敏感年龄有利于凋亡，在抗性年龄有利于存活。
