Intranasal delivery of mesenchymal stem cell-derived exosomes reduces oxidative stress and markedly inhibits ethanol consumption and post-deprivation relapse drinking.
Intranasal delivery of mesenchymal stem cell-derived exosomes reduces oxidative stress and markedly inhibits ethanol consumption and post-deprivation relapse drinking.
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DOI：
10.1111/adb.12675
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发表时间：
2019-09-01
影响因子：
3.4
通讯作者：
Israel, Yedy
中科院分区：
文献类型：
--
作者：
Ezquer, Fernando;Elena Quintanilla, Maria;Israel, Yedy
慢性酒精消耗导致大脑氧化应激和神经炎症，已知这些条件相互增强和延续。一些研究表明，神经炎症导致慢性乙醇消耗量增加。最近的报告显示，向长期饮酒的大鼠脑室内给予间充质干细胞显著抑制氧化应激，消除神经炎症，并大大减少慢性酒精摄入和剥夺后复发样酒精摄入。然而，活细胞的脑室内施用不适合作为慢性病症的治疗。本研究旨在通过非侵入性鼻内施用人间充质干细胞产物来抑制乙醇摄入：从间充质干细胞中挤出的具有显著抗氧化活性的外泌体、微泡（40至150 nm）。外泌体膜可以与不同组织中细胞的质膜融合，从而将其内容物递送到细胞内。该研究表明，每周鼻内给予长期饮酒的大鼠间充质干细胞衍生的外泌体（1）抑制了84%的乙醇摄入量，并减弱了酒精剥夺期和乙醇重新获得后的复发性“狂欢”饮酒。(2)（3）完全逆转了酒精诱导的海马氧化应激（通过氧化型谷胱甘肽与还原型谷胱甘肽的较低比率证明）和神经炎症（通过减少的星形胶质细胞活化和小胶质细胞密度显示）;（4）谷氨酸转运体GLT 1在丘脑核中的表达增加，抵消谷氨酸转运体活性的抑制，据报道，在氧化应激条件下抑郁。设想可能的翻译影响。
Chronic ethanol consumption leads to brain oxidative stress and neuroinflammation, conditions known to potentiate and perpetuate each other. Several studies have shown that neuroinflammation results in increases in chronic ethanol consumption. Recent reports showed that the intra-cerebroventricular administration of mesenchymal stem cells to rats consuming alcohol chronically markedly inhibited oxidative-stress, abolished neuroinflammation and greatly reduced chronic alcohol intake and post deprivation relapse-like alcohol intake. However, the intra-cerebroventricular administration of living cells is not suitable as a treatment of a chronic condition. The present study aimed at inhibiting ethanol intake by the non-invasive intranasal administration of human mesenchymal stem cell products: exosomes, microvesicles (40 to 150 nm) with marked antioxidant activity extruded from mesenchymal stem cells. The exosome membrane can fuse with the plasma membrane of cells in different tissues, thus delivering their content intracellularly. The study showed that the weekly intranasal administration of mesenchymal stem cell-derived exosomes to rats consuming alcohol chronically (1) inhibited their ethanol intake by 84 percent and blunted the relapse-like 'binge' drinking that follows an alcohol deprivation period and ethanol re-access. (2) Intranasally administered exosomes were found in the brain within 24 hours; (3) fully reversed both alcohol-induced hippocampal oxidative-stress, evidenced by a lower ratio of oxidized to reduced glutathione, and neuroinflammation, shown by a reduced astrocyte activation and microglial density; and (4) increased glutamate transporter GLT1 expression in nucleus accumbens, counteracting the inhibition of glutamate transporter activity, reportedly depressed under oxidative-stress conditions. Possible translational implications are envisaged.