Department of Cancer Biology, Wake Forest Baptist Medical Center, United States.
Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, United States; Proteomics and Metabolomics Shared Resource, Wake Forest Baptist Health, United States.
EBioMedicine. 2021 Jan;63:103192. doi: 10.1016/j.ebiom.2020.103192. Epub 2021 Jan 6.
The United States is currently facing an opioid crisis. Novel tools to better comprehend dynamic molecular changes in the brain associated with the opioid abuse are limited. Recent studies have suggested the usefulness of plasma exosomes in better understanding CNS disorders. However, no study has ever characterized exosomes (small extracellular vesicles of endocytic origin) secreted by brain cells to understand the potential neurodegenerative effects of long-term oxycodone self-administration (SA).
MRI of Cynomolgus monkeys (Macaca fascicularis) was performed to assess alterations in gray matter volumes with oxycodone SA. We isolated total exosomes (TE) from the plasma of these monkeys; from TE, we pulled-out neuron-derived exosomes (NDE), astrocytes-derived exosomes (ADE), and microglia-derived exosomes (MDE) using surface biomarkers L1CAM (L1 cell adhesion molecule), GLAST (Glutamate aspartate transporter) and TMEM119 (transmembrane protein119), respectively.
We observed a significantly lower gray matter volume of specific lobes of the brain (frontal and parietal lobes, and right putamen) in monkeys with ∼3 years of oxycodone SA compared to controls. Higher expression of neurodegenerative biomarkers (NFL and α-synuclein) correlates well with the change in brain lobe volumes in control and oxycodone SA monkeys. We also identified a strong effect of oxycodone SA on the loading of specific miRNAs and proteins associated with neuro-cognitive disorders. Finally, exosomes subpopulation from oxycodone SA group activated NF-κB activity in THP1- cells.
These results provide evidence for the utility of brain cells-derived exosomes from plasma in better understanding and predicting the pro-inflammatory and neurodegenerative consequence of oxycodone SA.
NIH.
美国目前正面临阿片类药物危机。缺乏新工具来更好地了解与阿片类药物滥用相关的大脑动态分子变化。最近的研究表明，血浆外泌体在更好地了解中枢神经系统疾病方面具有一定作用。然而，目前尚无研究描述过由脑细胞分泌的外泌体（内体起源的小细胞外囊泡），以了解长期羟考酮自我给药（SA）的潜在神经退行性效应。
对恒河猴（Macaca fascicularis）进行 MRI 检查，以评估羟考酮 SA 引起的灰质体积变化。我们从这些猴子的血浆中分离出总外泌体（TE）；通过表面标志物 L1CAM（L1 细胞黏附分子）、GLAST（谷氨酸-天冬氨酸转运蛋白）和 TMEM119（跨膜蛋白 119），从 TE 中提取出神经元衍生的外泌体（NDE）、星形胶质细胞衍生的外泌体（ADE）和小胶质细胞衍生的外泌体（MDE）。
与对照组相比，接受约 3 年羟考酮 SA 的猴子大脑特定脑叶（额叶、顶叶和右侧壳核）的灰质体积明显较低。神经退行性生物标志物（NFL 和 α-突触核蛋白）的高表达与对照组和羟考酮 SA 猴子脑叶体积变化密切相关。我们还发现，羟考酮 SA 对与神经认知障碍相关的特定 miRNA 和蛋白质的载量有强烈影响。最后，来自羟考酮 SA 组的外泌体亚群可激活 THP1-细胞中的 NF-κB 活性。
这些结果为更好地了解和预测羟考酮 SA 的促炎和神经退行性后果，提供了来自血浆的脑细胞衍生外泌体的效用证据。
NIH。
