Protection of neurons and microglia against ethanol in a mouse model of fetal alcohol spectrum disorders by peroxisome proliferator-activated receptor-γ agonists.
Protection of neurons and microglia against ethanol in a mouse model of fetal alcohol spectrum disorders by peroxisome proliferator-activated receptor-γ agonists.
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DOI：
10.1016/j.bbi.2011.02.016
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发表时间：
2011-06
影响因子：
15.1
通讯作者：
Drew, Paul D.
中科院分区：
文献类型：
--
作者：
Kane, Cynthia J. M.;Phelan, Kevin D.;Han, Lihong;Smith, Renea R.;Xie, Jin;Douglas, James C.;Drew, Paul D.
关键词：
胎儿酒精谱系障碍（FASD）是由于发育中的胎儿暴露于乙醇而引起的，是美国智力迟钝的最常见原因。这些疾病的特征是各种神经发育和神经退行性异常，导致严重的终身残疾。因此，需要新的疗法来限制FASD的破坏性后果。与FASD相关的神经病理学可发生在整个中枢神经系统（CNS），但在发育中的小脑中特别明显。FASD的啮齿动物模型先前已经证明，浦肯野细胞和颗粒细胞，这是小脑中的两种主要类型的神经元，对乙醇的毒性作用高度敏感。目前的研究表明，乙醇降低培养的小脑颗粒细胞和小胶质细胞的活力。有趣的是，小胶质细胞在CNS中具有双重功能。它们为神经元提供营养和保护支持。然而，它们也可能被病理激活并产生对包括神经元在内的实质细胞有毒的炎性分子。这项研究的结果表明，过氧化物酶体增殖物激活受体-γ激动剂15-脱氧-Δ 12，15前列腺素J2和吡格列酮保护培养的颗粒细胞和小胶质细胞免受乙醇的毒性作用。此外，使用新开发的FASD小鼠模型和小脑体视学细胞计数方法进行的研究阐明，新生儿乙醇给药对浦肯野细胞神经元和小胶质细胞均有毒性，体内给予PPAR-γ激动剂可保护这些细胞。总之，这些研究表明，PPAR-γ激动剂可有效限制乙醇诱导的CNS发育毒性。
Fetal alcohol spectrum disorders (FASD) result from ethanol exposure to the developing fetus and are the most common cause of mental retardation in the United States. These disorders are characterized by a variety of neurodevelopmental and neurodegenerative anomalies which result in significant lifetime disabilities. Thus, novel therapies are required to limit the devastating consequences of FASD. Neuropathology associated with FASD can occur throughout the central nervous system (CNS), but is particularly well characterized in the developing cerebellum. Rodent models of FASD have previously demonstrated that both Purkinje cells and granule cells, which are the two major types of neurons in the cerebellum, are highly susceptible to the toxic effects of ethanol. The current studies demonstrate that ethanol decreases the viability of cultured cerebellar granule cells and microglial cells. Interestingly, microglia have dual functionality in the CNS. They provide trophic and protective support to neurons. However, they may also become pathologically activated and produce inflammatory molecules toxic to parenchymal cells including neurons. The findings in this study demonstrate that the peroxisome proliferator-activated receptor-γ agonists 15-deoxy-Δ12,15 prostaglandin J2 and pioglitazone protect cultured granule cells and microglia from the toxic effects of ethanol. Furthermore, investigations using a newly developed mouse model of FASD and stereological cell counting methods in the cerebellum elucidate that ethanol administration to neonates is toxic to both Purkinje cell neurons as well as microglia, and that in vivo administration of PPAR-γ agonists protects these cells. In composite, these studies suggest that PPAR-γ agonists may be effective in limiting ethanol-induced toxicity to the developing CNS.
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