Peroxisome Proliferator-Activated Receptor γ Agonists Accelerate Oligodendrocyte Maturation and Influence Mitochondrial Functions and Oscillatory Ca2+ Waves
Peroxisome Proliferator-Activated Receptor γ Agonists Accelerate Oligodendrocyte Maturation and Influence Mitochondrial Functions and Oscillatory Ca2+ Waves
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DOI：
10.1097/nen.0b013e3182309ab1
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发表时间：
2011-10-01
影响因子：
3.2
通讯作者：
Minghetti, Luisa
中科院分区：
文献类型：
--
作者：
De Nuccio, Chiara;Bernardo, Antonietta;Minghetti, Luisa
我们之前已经证明，天然的(15-脱氧- δ（12,14)-前列腺素J(2)）和合成的（吡格列酮）过氧化物酶体增殖激活受体γ (ppar - γ)激动剂增强了保护少突胶质细胞（OL）祖细胞（OPs）免受氧化损伤并促进其分化的内在细胞机制。在这里，我们证明了ppar - γ激动剂对OP培养物的重复管理加速了它们向OLs的分化，正如O-4和o -1阳性细胞数量的增加所表明的那样，这些细胞表现出髓鞘碱性蛋白表达增加、胆固醇富集膜的细化和过氧化物酶体的增加。此外，ppar - γ激动剂处理的OLs显示线粒体呼吸链复合体IV的活性增加，对环境信号（如二磷酸腺苷（ADP））的响应能力增加，具有振荡Ca2+波；后者与线粒体的存在密切相关，并被线粒体呼吸链复合体I抑制剂鱼藤酮抑制。由于Ca2+振荡和线粒体呼吸链活性在OL分化中起关键作用，这些发现表明ppar - γ激动剂可以通过多种机制保护OL并促进髓鞘形成，包括那些涉及线粒体功能的机制。我们的研究支持ppar - γ激动剂在线粒体改变、氧化应激和脱髓鞘发生的脑部疾病中的治疗潜力，并指出需要更好地理解ppar - γ及其激动剂在OL生物学中的作用。
We have previously shown that natural (15-deoxy-Delta(12,14)-prostaglandin J(2)) and synthetic (pioglitazone) agonists of peroxisome proliferator-activated receptor gamma (PPAR-gamma) strengthen the intrinsic cellular mechanisms protecting oligodendrocyte (OL) progenitors (OPs) from oxidative insults and promote their differentiation. Here, we demonstrate that repeated administrations of PPAR-gamma agonists to OP cultures accelerate their differentiation to OLs, as indicated by increased numbers of O-4- and O-1-positive cells that show increased myelin basic protein expression, elaborated cholesterol-enriched membranes and have increased peroxisomes. Moreover, PPAR-gamma agonist-treated OLs show increased activity of the mitochondrial respiratory chain Complex IV and an increased ability to respond to environmental signals, such as adenosine diphosphate (ADP), with oscillatory Ca2+ waves; the latter closely correlated with the presence of mitochondria and were inhibited by the mitochondrial respiratory chain Complex I inhibitor rotenone. Because Ca2+ oscillations and mitochondrial respiratory chain activity play crucial roles in OL differentiation, these findings suggest that PPAR-gamma agonists could protect OLs and promote myelination through several mechanisms, including those involving mitochondrial functions. Our studies support the therapeutic potential of PPAR-gamma agonists in brain diseases in which mitochondrial alteration, oxidative stress, and demyelination occur and point to the need for a better understanding of the role of PPAR-gamma and its agonists in OL biology.