Drew Paul D, Johnson Jennifer W, Douglas James C, Phelan Kevin D, Kane Cynthia J M
Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Alcohol Clin Exp Res. 2015 Mar;39(3):445-54. doi: 10.1111/acer.12639. Epub 2015 Feb 19.
Fetal alcohol spectrum disorders (FASD) result from fetal exposure to alcohol and are the leading cause of mental retardation in the United States. There is currently no effective treatment that targets the causes of these disorders. Thus, novel therapies are critically needed to limit the neurodevelopmental and neurodegenerative pathologies associated with FASD.
A neonatal mouse FASD model was used to examine the role of the neuroimmune system in ethanol (EtOH)-induced neuropathology. Neonatal C57BL/6 mice were treated with EtOH, with or without pioglitazone, on postnatal days 4 through 9, and tissue was harvested 1 day post treatment. Pioglitazone is a peroxisome proliferator-activated receptor (PPAR)-γ agonist that exhibits anti-inflammatory activity and is neuroprotective. We compared the effects of EtOH with or without pioglitazone on cytokine and chemokine expression and microglial morphology in the hippocampus, cerebellum, and cerebral cortex.
In EtOH-treated animals compared with controls, cytokines interleukin-1β and tumor necrosis factor-α mRNA levels were increased significantly in the hippocampus, cerebellum, and cerebral cortex. Chemokine CCL2 mRNA was increased significantly in the hippocampus and cerebellum. Pioglitazone effectively blocked the EtOH-induced increase in the cytokines and chemokine in all tissues to the level expressed in handled-only and vehicle-treated control animals. EtOH also produced a change in microglial morphology in all brain regions that was indicative of microglial activation, and pioglitazone blocked this EtOH-induced morphological change.
These studies indicate that EtOH activates microglia to a pro-inflammatory stage and also increases the expression of neuroinflammatory cytokines and chemokines in diverse regions of the developing brain. Further, the anti-inflammatory and neuroprotective PPAR-γ agonist pioglitazone blocked these effects. It is proposed that microglial activation and inflammatory molecules expressed as a result of EtOH treatment during brain development contribute to the sequelae associated with FASD. Thus, pioglitazone and anti-inflammatory pharmaceuticals more broadly have potential as novel therapeutics for FASD.
胎儿酒精谱系障碍（FASD）是胎儿暴露于酒精所致，是美国智力迟钝的主要原因。目前尚无针对这些障碍病因的有效治疗方法。因此，迫切需要新的疗法来限制与FASD相关的神经发育和神经退行性病变。
使用新生小鼠FASD模型来研究神经免疫系统在乙醇（EtOH）诱导的神经病理学中的作用。在出生后第4至9天，对新生C57BL/6小鼠给予EtOH治疗，同时或不同时给予吡格列酮，治疗后1天采集组织。吡格列酮是一种过氧化物酶体增殖物激活受体（PPAR）-γ激动剂，具有抗炎活性且具有神经保护作用。我们比较了有或没有吡格列酮的EtOH对海马体、小脑和大脑皮质中细胞因子和趋化因子表达以及小胶质细胞形态的影响。
与对照组相比，在接受EtOH治疗的动物中，海马体、小脑和大脑皮质中细胞因子白细胞介素-1β和肿瘤坏死因子-α的mRNA水平显著升高。趋化因子CCL2的mRNA在海马体和小脑中显著增加。吡格列酮有效地将所有组织中EtOH诱导的细胞因子和趋化因子增加阻断至仅接受处理和接受赋形剂治疗的对照动物所表达的水平。EtOH还在所有脑区引起小胶质细胞形态变化，这表明小胶质细胞被激活，而吡格列酮阻断了这种EtOH诱导的形态变化。
这些研究表明，EtOH将小胶质细胞激活至促炎阶段，并增加发育中大脑不同区域神经炎症细胞因子和趋化因子的表达。此外，具有抗炎和神经保护作用的PPAR-γ激动剂吡格列酮阻断了这些作用。有人提出，在大脑发育过程中，EtOH治疗导致的小胶质细胞激活和炎症分子表达促成了与FASD相关的后遗症。因此，吡格列酮和更广泛的抗炎药物有潜力成为FASD的新型治疗药物。
