Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
Centro de Medicina Regenerativa, Facultad de Medicina Clínica Alemana-Universidad del Desarrollo, Santiago, Chile.
Gene Ther. 2019 Nov;26(10-11):407-417. doi: 10.1038/s41434-019-0064-9. Epub 2019 Feb 28.
Studies reviewed show that lentiviral gene therapy directed either at inhibiting the synthesis of brain acetaldehyde generated from ethanol or at degrading brain acetaldehyde fully prevent ethanol intake by rats bred for their high alcohol preference. However, after animals have chronically consumed alcohol, the above gene therapy did not inhibit alcohol intake, indicating that in the chronic ethanol intake condition brain acetaldehyde is no longer the compound that generates the continued alcohol reinforcement. Oxidative stress and neuroinflammation generated by chronic ethanol intake are strongly associated with the perpetuation of alcohol consumption and alcohol relapse "binge drinking". Mesenchymal stem cells, referred to as guardians of inflammation, release anti-inflammatory cytokines and antioxidant products. The intravenous delivery of human mesenchymal stem cells or the intranasal administration of mesenchymal stem cell-generated exosomes reverses both (i) alcohol-induced neuro-inflammation and (ii) oxidative stress, and greatly (iii) inhibits (80-90%) chronic alcohol intake and relapse binge-drinking. The therapeutic effect of mesenchymal stem cells is mediated by increased levels of the brain GLT-1 glutamate transporter, indicating that glutamate signaling is pivotal for alcohol relapse. Human mesenchymal stem cells and the products released by these cells may have translational value in the treatment of alcohol-use disorders.
研究表明，无论是针对抑制由乙醇生成的脑乙醛合成的慢病毒基因治疗，还是针对降解脑乙醛的慢病毒基因治疗，均能完全阻止通过高酒精偏好培育的大鼠摄入乙醇。然而，在动物长期摄入酒精后，上述基因治疗并不能抑制酒精摄入，这表明在慢性乙醇摄入条件下，脑乙醛不再是产生持续酒精强化的化合物。慢性乙醇摄入引起的氧化应激和神经炎症与酒精持续摄入和酒精复饮“狂饮”密切相关。间充质干细胞被称为炎症的守护者，它们释放抗炎细胞因子和抗氧化产物。人骨髓间充质干细胞的静脉内递送或间充质干细胞衍生的外泌体的鼻内给药，逆转了（i）酒精引起的神经炎症和（ii）氧化应激，并大大（iii）抑制了（80-90%）慢性酒精摄入和复饮狂饮。间充质干细胞的治疗效果是通过增加脑 GLT-1 谷氨酸转运体的水平来介导的，这表明谷氨酸信号对酒精复饮至关重要。人骨髓间充质干细胞及其细胞释放的产物在治疗酒精使用障碍方面可能具有转化价值。
