Kim Do Young, Davis Laurie M, Sullivan Patrick G, Maalouf Marwan, Simeone Timothy A, van Brederode Johannes, Rho Jong M
Barrow Neurological Institute and St. Joseph's Hospital & Medical Center, Phoenix, Arizona 85013, USA.
J Neurochem. 2007 Jun;101(5):1316-26. doi: 10.1111/j.1471-4159.2007.04483.x. Epub 2007 Mar 30.
Ketone bodies (KB) have been shown to prevent neurodegeneration in models of Parkinson's and Alzheimer's diseases, but the mechanisms underlying these effects remain unclear. One possibility is that KB may exert antioxidant activity. In the current study, we explored the effects of KB on rat neocortical neurons exposed to hydrogen peroxide (H(2)O(2)) or diamide - a thiol oxidant and activator of mitochondrial permeability transition (mPT). We found that: (i) KB completely blocked large inward currents induced by either H(2)O(2) or diamide; (ii) KB significantly decreased the number of propidium iodide-labeled cells in neocortical slices after exposure to H(2)O(2) or diamide; (iii) KB significantly decreased reactive oxygen species (ROS) levels in dissociated neurons and in isolated neocortical mitochondria; (iv) the electrophysiological effects of KB in neurons exposed to H(2)O(2) or diamide were mimicked by bongkrekic acid and cyclosporin A, known inhibitors of mPT, as well as by catalase and DL - dithiothreitol, known antioxidants; (v) diamide alone did not significantly alter basal ROS levels in neurons, supporting previous studies indicating that diamide-induced neuronal injury may be mediated by mPT opening; and (vi) KB significantly increased the threshold for calcium-induced mPT in isolated mitochondria. Taken together, our data suggest that KB may prevent mPT and oxidative injury in neocortical neurons, most likely by decreasing mitochondrial ROS production.
酮体（KB）已被证明在帕金森病和阿尔茨海默病模型中可预防神经退行性变，但其潜在机制仍不清楚。一种可能性是KB可能具有抗氧化活性。在本研究中，我们探讨了KB对暴露于过氧化氢（H₂O₂）或二酰胺（一种硫醇氧化剂和线粒体通透性转换（mPT）激活剂）的大鼠新皮质神经元的影响。我们发现：（i）KB完全阻断了由H₂O₂或二酰胺诱导的大内向电流；（ii）在暴露于H₂O₂或二酰胺后，KB显著减少了新皮质切片中碘化丙啶标记的细胞数量；（iii）KB显著降低了原代神经元和分离的新皮质线粒体中的活性氧（ROS）水平；（iv）已知的mPT抑制剂缬氨霉素和环孢素A以及已知的抗氧化剂过氧化氢酶和DL-二硫苏糖醇模拟了KB对暴露于H₂O₂或二酰胺的神经元的电生理作用；（v）单独的二酰胺并未显著改变神经元中的基础ROS水平，支持先前的研究表明二酰胺诱导的神经元损伤可能由mPT开放介导；（vi）KB显著提高了分离线粒体中钙诱导的mPT阈值。综上所述，我们的数据表明KB可能通过降低线粒体ROS产生来预防新皮质神经元中的mPT和氧化损伤。
