Biol Chem. 2013 Dec;394(12):1553-70. doi: 10.1515/hsz-2013-0215.
Overwhelming evidence shows that oxidative stress is a major cause in development of brain disorders. Low activity of the reactive oxygen species (ROS)-degrading system as well as high levels of oxidative damage markers have been observed in brain tissue of patients with neurodegenerative and other brain diseases to a larger extent than in healthy individuals. Many studies aimed to develop effective and safe antioxidant strategies for the therapy or prevention of brain diseases. Nevertheless, it became clear that rigorous suppression of ROS is deleterious for normal cell functioning. Thus, approaches that can regulate the ROS levels over a wide range, from inhibition to induction, will be a powerful tool for neuroprotection. A most prominent target for such ROS management is the family of peroxisome proliferator-activated receptors (PPARs). All three members (PPAR-α, -β/δ and -γ) of this nuclear receptor subfamily form a tightly connected triad. For individual PPAR isoforms, neuroprotective properties have been well proven. Their involvement in regulation of ROS production and degradation underlies the therapeutic effects. Nevertheless, the current paradigms of the involvement of PPAR in neuroprotective therapy ignore such interconnections of PPARs and aim at antioxidant effects of individual PPAR isoforms, but do not take into account the necessity of careful regulation of ROS levels. The present review (i) summarizes the data, which support the concept of the PPAR triad in brain, (ii) demonstrates that usage of the PPAR triad allows the regulation of PPAR-dependent genes over a wide range, from inhibition to upregulation, and (iii) summarizes the known data concerning the PPAR triad involvement in regulation of ROS. Our report opens new directions in the field of PPAR/ROS-related neuroscience research.
大量证据表明，氧化应激是大脑疾病发展的主要原因。与健康个体相比，神经退行性和其他脑部疾病患者的脑组织中观察到活性氧（ROS）降解系统活性降低以及氧化损伤标志物水平升高的程度更大。许多研究旨在开发有效和安全的抗氧化策略，用于治疗或预防脑部疾病。然而，事实已经很清楚，严格抑制 ROS 对正常细胞功能是有害的。因此，能够在从抑制到诱导的广泛范围内调节 ROS 水平的方法将成为神经保护的有力工具。这种 ROS 管理的一个最突出的目标是过氧化物酶体增殖物激活受体（PPAR）家族。该核受体亚家族的所有三个成员（PPAR-α、-β/δ 和 -γ）形成一个紧密连接的三联体。对于单个 PPAR 同工型，已经很好地证明了其具有神经保护特性。它们在调节 ROS 产生和降解中的参与是其治疗效果的基础。然而，目前涉及 PPAR 的神经保护治疗的范例忽略了 PPAR 之间的这种相互联系，并旨在针对单个 PPAR 同工型的抗氧化作用，而没有考虑到仔细调节 ROS 水平的必要性。本综述（i）总结了支持大脑中 PPAR 三联体概念的相关数据，（ii）表明使用 PPAR 三联体可以在从抑制到上调的广泛范围内调节 PPAR 依赖性基因，（iii）总结了已知的有关 PPAR 三联体参与 ROS 调节的数据。我们的报告为与 PPAR/ROS 相关的神经科学研究领域开辟了新的方向。
