Docosahexaenoic acid (DHA) is an essential fatty acid modulating key nervous system functions, including neuroinflammation, and regulation of pre- and postsynaptic membrane formation. DHA concentration decreases in the lumbar spinal cord (LSC) of amyotrophic lateral sclerosis (ALS) patients and murine preclinical models. Using a dietary supplementation, we increased DHA levels (2% mean increase, p < 0.01) in the LSC of the familial ALS murine model B6SJL-Tg(SOD1*G93A)1Gur/J. This DHA-enriched diet significantly increases male mouse survival by 7% (average 10 days over 130 days of life expectancy), and delays motor dysfunction (based on stride length) and transgene-associated weight loss (p < 0.01). DHA supplementation led to an increased anti-inflammatory fatty acid profile (ca 30%, p < 0.01) and a lower concentration of circulating proinflammatory cytokine TNF-α (p < 0.001 in males). Furthermore, although DHA-treated mice did not exhibit generally decreased protein oxidative markers (glutamic and aminoadipic semialdehydes, carboxyethyllysine, carboxymethyllysine, and malondialdehydelysine), dietary intake of DHA reduced immunoreactivity towards DNA oxidative damage markers (8-oxo-dG) in the LSC. In vitro we demonstrate that DHA and α-tocopherol addition to a model of motor neuron demise (neonatal rat organotypic spinal cord model under chronic excitotoxicity) also preserves motor neuron number, in comparison with untreated spinal cords. Also, beneficial effects on cell viability were evidenced for the motor neuron cell line NSC-34 in front of H₂O₂ insult (p < 0.001). Globally we show a sex-specific benefit of dietary DHA supplementation in the G93A ALS mouse model, compared with mice fed an isocaloric control or a n-3-depleted diet. These changes were associated with an increased DHA concentration in the LSC and were compatible with in vitro results showing DHA neuroprotective properties. These results suggest the need for further study on the interaction of gender-influenced biological parameters and DHA in ALS pathogenesis.

中文翻译：

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二十二碳六烯酸膳食补充剂对 G93A-SOD1 肌萎缩侧索硬化症小鼠的性别特异性有益作用。


二十二碳六烯酸 (DHA) 是一种调节关键神经系统功能的必需脂肪酸，包括神经炎症以及突触前膜和突触后膜形成的调节。肌萎缩侧索硬化症 (ALS) 患者和小鼠临床前模型的腰脊髓 (LSC) 中 DHA 浓度降低。通过膳食补充剂，我们提高了家族性 ALS 小鼠模型 B6SJL-Tg(SOD1*G93A)1Gur/J 的 LSC 中的 DHA 水平（平均增加 2%， p < 0.01）。这种富含 DHA 的饮食使雄性小鼠的存活率显着提高 7%（预期寿命 130 天平均延长 10 天），并延缓运动功能障碍（基于步幅）和转基因相关的体重减轻 ( p < 0.01)。补充 DHA 导致抗炎脂肪酸谱增加（约30%， p < 0.01）和循环促炎细胞因子 TNF-α 浓度降低（男性中p < 0.001）。此外，虽然 DHA 治疗的小鼠并未表现出普遍降低的蛋白质氧化标记物（谷氨酸和氨基己二酸半醛、羧乙基赖氨酸、羧甲基赖氨酸和丙二醛赖氨酸），但饮食中摄入 DHA 降低了 LSC 中针对 DNA 氧化损伤标记物 (8-oxo-dG) 的免疫反应性。 。在体外，我们证明，与未经治疗的脊髓相比，运动神经元死亡模型（慢性兴奋性毒性下的新生大鼠器官型脊髓模型）中添加 DHA 和 α-生育酚也能保留运动神经元数量。此外，在 H ₂ O ₂损伤之前，运动神经元细胞系 NSC-34 也被证明对细胞活力产生有益影响 ( p < 0.001)。 在全球范围内，我们在 G93A ALS 小鼠模型中展示了膳食 DHA 补充剂的性别特异性益处，与饲喂等热量对照或 n-3 耗尽饮食的小鼠相比。这些变化与 LSC 中 DHA 浓度增加有关，并且与显示 DHA 神经保护特性的体外结果相一致。这些结果表明需要进一步研究性别影响的生物参数和 DHA 在 ALS 发病机制中的相互作用。