The Burke Medical Research Institute, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, White Plains, NY 10605, USA.
J Neurochem. 2013 Feb;124(4):536-47. doi: 10.1111/jnc.12107. Epub 2013 Jan 3.
Astrocytes are critical for the antioxidant support of neurons. Recently, we demonstrated that low level hydrogen peroxide (H(2) O(2) ) facilitates astrocyte-dependent neuroprotection independent of the antioxidant transcription factor Nrf2, leaving the identity of the endogenous astrocytic Nrf2 activator to question. In this study, we show that an endogenous electrophile, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), non-cell autonomously protects neurons from death induced by depletion of the major antioxidant glutathione. Nrf2 knockdown in astrocytes abrogated 15d-PGJ2's neuroprotective effect as well as 15d-PGJ2 facilitated Nrf2-target gene induction. In contrast, knockdown of the transcription factor peroxisome proliferator activated-receptor gamma (PPARγ), a well-characterized 15d-PGJ2 target, did not alter 15d-PGJ2 non-cell autonomous neuroprotection. In addition, several PPARγ agonists of the thiazolidinedione (TZD) family failed to induce neuroprotection. Unexpectedly, however, the TZD troglitazone (which contains a chromanol moiety found on vitamin E) induced astrocyte-mediated neuroprotection, an effect which was mimicked by the vitamin E analogs alpha-tocopherol or alpha-tocotrienol. Our findings lead to two important conclusions: (i) 15d-PGJ2 induces astrocyte-mediated neuroprotection via an Nrf2 but not PPARγ mediated pathway, suggesting that 15d-PGJ2 is a candidate endogenous modulator of Nrf2 protective pathways in astrocytes; (ii) selective astrocyte treatment with analogs or compounds containing the chromanol moiety of vitamin E facilitates non-cell autonomous neuroprotection.
星形胶质细胞对神经元的抗氧化支持至关重要。最近，我们证明低水平的过氧化氢 (H(2) O(2) ) 促进星形胶质细胞依赖性神经保护，而不依赖于抗氧化转录因子 Nrf2，使得内源性星形胶质细胞 Nrf2 激活剂的身份成为问题。在这项研究中，我们表明一种内源性亲电体，15-去氧-Δ12,14-前列腺素 J2（15d-PGJ2），非自主地保护神经元免受主要抗氧化剂谷胱甘肽耗竭诱导的死亡。星形胶质细胞中 Nrf2 的敲低消除了 15d-PGJ2 的神经保护作用以及 15d-PGJ2 促进的 Nrf2 靶基因诱导。相比之下，转录因子过氧化物酶体增殖物激活受体 γ（PPARγ）的敲低，一个经过充分研究的 15d-PGJ2 靶标，并没有改变 15d-PGJ2 的非自主神经保护作用。此外，几种噻唑烷二酮 (TZD) 家族的 PPARγ 激动剂未能诱导神经保护。然而，出乎意料的是，TZD 曲格列酮（含有维生素 E 上的色满醇部分）诱导星形胶质细胞介导的神经保护，维生素 E 类似物α-生育酚或α-生育三烯醇模拟了这种作用。我们的发现得出了两个重要结论：（i）15d-PGJ2 通过 Nrf2 而不是 PPARγ 介导的途径诱导星形胶质细胞介导的神经保护，表明 15d-PGJ2 是星形胶质细胞中 Nrf2 保护途径的候选内源性调节剂；（ii）选择性地用维生素 E 的色满醇部分的类似物或化合物处理星形胶质细胞促进非自主神经保护。
