Inhibition of fatty acid synthesis (FAS) stimulates tumor cell death and reduces angiogenesis. When SH-SY5Y cells or primary neurons are exposed to hypoxia only, inhibition of FAS yields significantly enhanced cell injury. The pathophysiology of stroke, however, is not only restricted to hypoxia but also includes reoxygenation injury. Hence, an oxygen-glucose-deprivation (OGD) model with subsequent reoxygenation in both SH-SY5Y cells and primary neurons as well as a murine stroke model were used herein in order to study the role of FAS inhibition and its underlying mechanisms. SH-SY5Y cells and cortical neurons exposed to 10 h of OGD and 24 h of reoxygenation displayed prominent cell death when treated with the Acetyl-CoA carboxylase inhibitor TOFA or the fatty acid synthase inhibitor cerulenin. Such FAS inhibition reduced the reduction potential of these cells, as indicated by increased NADH2 +/NAD+ ratios under both in vitro and in vivo stroke conditions. As observed in the OGD model, FAS inhibition also resulted in increased cell death in the stroke model. Stroke mice treated with cerulenin did not only display increased brain injury but also showed reduced neurological recovery during the observation period of 4 weeks. Interestingly, cerulenin treatment enhanced endothelial cell leakage, reduced transcellular electrical resistance (TER) of the endothelium and contributed to poststroke blood-brain barrier (BBB) breakdown. The latter was a consequence of the activated NF-κB pathway, stimulating MMP-9 and ABCB1 transporter activity on the luminal side of the endothelium. In conclusion, FAS inhibition aggravated poststroke brain injury as consequence of BBB breakdown and NF-κB-dependent inflammation.

中文翻译：

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在鼠中风模型中抑制脂肪酸合成会加重脑损伤、降低血脑屏障完整性并损害神经功能恢复。

脂肪酸合成 (FAS) 的抑制刺激肿瘤细胞死亡并减少血管生成。当 SH-SY5Y 细胞或原代神经元仅暴露于缺氧时，FAS 的抑制会显着增强细胞损伤。然而，中风的病理生理不仅限于缺氧，还包括复氧损伤。因此，本文使用了随后在 SH-SY5Y 细胞和原代神经元中进行再充氧的氧-葡萄糖剥夺 (OGD) 模型以及鼠中风模型，以研究 FAS 抑制的作用及其潜在机制。SH-SY5Y 细胞和皮层神经元暴露于 10 小时的 OGD 和 24 小时的再充氧，当用乙酰辅酶 A 羧化酶抑制剂 TOFA 或脂肪酸合酶抑制剂蔚蓝素处理时，显示出显着的细胞死亡。这种 FAS 抑制降低了这些细胞的还原潜力，正如在体外和体内中风条件下增加的 NADH2 +/NAD+ 比率所表明的那样。正如在 OGD 模型中观察到的，FAS 抑制也导致中风模型中细胞死亡的增加。在 4 周的观察期内，用蔚蓝素治疗的中风小鼠不仅表现出增加的脑损伤，而且表现出减少的神经功能恢复。有趣的是，蔚蓝素治疗增强了内皮细胞渗漏，降低了内皮细胞的跨细胞电阻 (TER)，并有助于中风后血脑屏障 (BBB) 的破坏。后者是激活 NF-κB 通路的结果，刺激内皮腔侧的 MMP-9 和 ABCB1 转运蛋白活性。综上所述，