Department of Orthopedics, The First Hospital of China Medical University, Shenyang, China.
Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, Université de Bordeaux, Bordeaux, France.
J Neurotrauma. 2021 Feb;38(3):373-384. doi: 10.1089/neu.2020.7166. Epub 2020 Nov 12.
Spinal cord injury (SCI) is one of the leading causes of neurological disability and death. So far, there is no satisfactory treatment for SCI, because of its complex and ill-defined pathophysiology. Recently, autophagy has been implicated as protective in acute SCI rat models. Here, we investigated the therapeutic value of a dietary intervention, namely, intermittent fasting (IF), on neuronal survival after acute SCI in rats, and its underlying mechanism related to autophagy regulation. We found remarkable improvement in both behavioral performance and neuronal survival at the injured segment of the spinal cord of animals previously subjected to IF. Western blotting revealed a marked decrease in apoptosis-related markers such as cleaved caspase 3 levels and the bax/bcl-2 ratio in the IF group, which suggested an inhibition of the intrinsic apoptosis pathway. In addition, the expression of the autophagy markers LC3-II and beclin 1 was also increased in the IF group compared with fed animals. In parallel, IF decreased the levels of the substrate protein of autophagy, p62, indicative of an upregulation of the autophagic processes. Treatment with 3-methyladenine (3-MA), a selective inhibitor of autophagy, reversed the downregulated apoptosis-related markers by IF. Finally, IF could activate the adenosine monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway and enhance lysosome function by upregulating transcription factor (TF)EB expression. Altogether, the present findings suggest that IF exerts a neuroprotective effect after acute SCI via the upregulation of autophagy, and further points to dietary interventions as a promising combinatorial treatment for SCI.
脊髓损伤 (SCI) 是导致神经功能障碍和死亡的主要原因之一。到目前为止，由于其复杂且定义不明确的病理生理学，还没有令人满意的 SCI 治疗方法。最近，自噬被认为在急性 SCI 大鼠模型中具有保护作用。在这里，我们研究了饮食干预（即间歇性禁食 (IF)）对大鼠急性 SCI 后神经元存活的治疗价值，及其与自噬调节相关的潜在机制。我们发现，与之前接受 IF 的动物相比，IF 可显著改善行为表现和损伤脊髓节段的神经元存活。Western blot 显示，IF 组中凋亡相关标志物Cleaved caspase 3 水平和 bax/bcl-2 比值明显降低，提示内源性凋亡途径受到抑制。此外，IF 组自噬标志物 LC3-II 和 beclin 1 的表达也高于喂食组。平行地，IF 降低了自噬底物蛋白 p62 的水平，表明自噬过程上调。用 3-甲基腺嘌呤 (3-MA) 处理，一种选择性自噬抑制剂，逆转了 IF 下调的凋亡相关标志物。最后，IF 可以通过上调转录因子 (TF) EB 的表达来激活腺苷单磷酸 (AMP)-激活的蛋白激酶 (AMPK)/雷帕霉素靶蛋白 (mTOR) 通路并增强溶酶体功能。总之，这些发现表明 IF 通过上调自噬在急性 SCI 后发挥神经保护作用，并进一步指出饮食干预作为 SCI 的一种有前途的联合治疗方法。
