Polyamines in neonatal alcohol neurotoxicity

描述(由申请人提供)： 虽然众所周知，产前接触乙醇(Etoh)对 发展中的中枢神经系统，关于其背后的机制仍有许多问题 观察到中枢神经系统损伤。乙醇对谷氨酸/NMDA受体的影响如下 久负盛名。乙醇诱导的NMDAR功能在发育过程中的变化 至少由两种机制造成的海马区损伤；在存在期间NMDAR功能降低 无水乙醇(通过细胞凋亡)和在无水乙醇戒断期间NMDAR功能增强(通过 兴奋性毒性)。这些机制中哪一种占主导地位可能与年龄有关 抑制NMDAR活性在早期发育阶段具有更大的破坏性 Etoh WD期间的过度兴奋在较老的文化中是更主要的成分。 多胺是普遍存在的化合物，在中枢神经系统中也发挥着重要的营养作用 多胺的发展及其作用机制之一是通过增强 NMDAR。由于海马神经元NMDAR亚型及其对多胺的反应在 在大鼠出生的第一周，接触乙醇的时间可能会有显著的意义 对多胺反应、NMDAR和结局的影响。这些假说是可以检验的。 使用器官型细胞培养模型直接在体外培养，并比较从 新生大鼠在PND 2和PND 8。具体目标是1)检查如何发育 在我们的体外器官移植中，通过细胞损伤来衡量年龄对乙醇反应的影响 海马区模型；2)研究发育年龄和乙醇暴露如何与 在体外海马区模型中通过细胞损伤来测量多胺和3)评估 体内乙醇暴露是否与体外暴露的结果相关。模型 本申请的提出将为利用海马区提供一种创新和新颖的方法 器官型细胞培养以解决与Etoh效应相关的特定发育问题 并评估该模型的预测有效性，以预测体内结果。有了这些发现，它 也可能对一些潜在的机制有更好的了解 新生儿乙醇暴露和多胺的作用，这将为减少某些乙醇影响的药物干预提供依据。

DESCRIPTION (provided by applicant): While it is well known that prenatal ethanol (ETOH) exposure has detrimental effects on the developing CNS, there are still numerous questions regarding the mechanisms underlying the CNS damage observed. The effects of ETOH on the glutamate/NMDA receptor (NMDAR) are well established. ETOH-induced alterations in NMDAR function during development causes hippocampal damage by at least two mechanisms; reduced NMDAR function during the presence of ETOH (via apoptosis) and enhanced NMDAR function during ETOH withdrawal (via excitotoxicity). Which of these mechanisms predominates may be age- dependent with suppression of NMDAR activity being more damaging at earlier developmental stages and overexcitation during ETOH WD being a more dominant component in older cultures. Polyamines are ubiquitous compounds that also play an important trophic role during CNS development and one of the mechanisms by which polyamines work is by potentiation of the NMDAR. Since hippocampal NMDAR subtypes and their response to polyamines change during the first neonatal weeks in rats, the timing when ETOH exposure occurs may have significant influences on response to polyamines, NMDAR and outcome. These hypotheses can be tested directly in vitro using the organotypic cell culture model and comparing cultures obtained from neonatal rats at PND 2 versus PND 8. The specific aims are 1) to examine how developmental age affects the response to ETOH as measured by cell damage in our in vitro organotyplc hippocampal model; 2) to examine how developmental age and ETOH exposure interact with polyamines as measured by cell damage in the in vitro hippocampal model and 3) To assess whether in vivo ETOH exposure correlates with the findings from in vitro exposure. The model proposed in this application will provide an innovative and novel approach for using hippocampal organotypic cell cultures to address specific developmental questions related to ETOH's effects and to assess the predictive validity of the model to predict in vivo results. With these findings, it may also be possible to gain a better understanding of some of the mechanisms underlying neonatal ETOH exposure and the role of polyamines that will provide grounds for pharmacological interventions that will reduce some of ETOH effects.