Centro de Medicina Regenerativa, Facultad de Medicina Clínica Alemana-Universidad del Desarrollo, Chile.
Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Chile.
Addict Biol. 2019 Sep;24(5):994-1007. doi: 10.1111/adb.12675. Epub 2018 Sep 21.
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.
慢性乙醇摄入会导致大脑氧化应激和神经炎症，已知这些条件会相互增强和持续。多项研究表明，神经炎症会导致慢性乙醇摄入增加。最近的报告显示，向慢性饮酒的大鼠脑室内给予间充质干细胞会显著抑制氧化应激，消除神经炎症，并大大减少慢性酒精摄入和断酒后的复发样酒精摄入。然而，脑室内给予活细胞并不适合作为慢性疾病的治疗方法。本研究旨在通过非侵入性的鼻腔内给予人骨髓间充质干细胞产物（具有显著抗氧化活性的外泌体和微囊泡（40 至 150nm））来抑制乙醇摄入。外泌体膜可以与不同组织的细胞膜融合，从而将其内容物递送到细胞内。研究表明，每周向慢性饮酒的大鼠鼻腔内给予间充质干细胞衍生的外泌体（1）可抑制其 84%的乙醇摄入，并减轻断酒后的复发样“狂饮”，（2）鼻腔内给予的外泌体在 24 小时内即可在大脑中发现；（3）完全逆转了酒精引起的海马氧化应激，表现为氧化型谷胱甘肽与还原型谷胱甘肽的比值降低，以及神经炎症，表现为星形胶质细胞激活和小胶质细胞密度降低；（4）增加了伏隔核中的谷氨酸转运体 GLT1 表达，抵消了谷氨酸转运体活性的抑制，据报道，氧化应激条件下会抑制谷氨酸转运体活性。可以预见其具有潜在的转化意义。
