Intravenous administration of anti-inflammatory mesenchymal stem cell spheroids reduces chronic alcohol intake and abolishes binge-drinking

Fernando Ezquer,Yedy Israel,Carolyne Lespay-Rebolledo,María Elena Quintanilla,Daniela Santapau,Marcelo Ezquer,Mario Herrera-Marschitz,Paola Morales

doi:10.1038/s41598-018-22750-7

Fernando Ezquer, Yedy Israel + Show 6 more

Open Access

https://doi.org/10.1038/s41598-018-22750-7

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Abstract

Chronic alcohol intake leads to neuroinflammation and astrocyte dysfunction, proposed to perpetuate alcohol consumption and to promote conditioned relapse-like binge drinking. In the present study, human mesenchymal stem cells (MSCs) were cultured in 3D-conditions to generate MSC-spheroids, which greatly increased MSCs anti-inflammatory ability and reduced cell volume by 90% versus conventionally 2D-cultured MSCs, enabling their intravenous administration and access to the brain. It is shown, in an animal model of chronic ethanol intake and relapse-drinking, that both the intravenous and intra-cerebroventricular administration of a single dose of MSC-spheroids inhibited chronic ethanol intake and relapse-like drinking by 80–90%, displaying significant effects over 3–5 weeks. The MSC-spheroid administration fully normalized alcohol-induced neuroinflammation, as shown by a reduced astrocyte activation, and markedly increased the levels of the astrocyte Na-glutamate (GLT-1) transporter. This research suggests that the intravenous administration of MSC-spheroids may constitute an effective new approach for the treatment of alcohol-use disorders.

Highlights

Alcohol-use disorders constitute a leading cause of morbidity and premature mortality worldwide, accounting for 1 in 10 deaths among working-age adults in the United States[1]
Drug relapse observed for alcohol and other drugs is causally associated with the existence of high levels of extracellular glutamate, since the administration of N-acetyl cysteine or ceftriaxone which increase the level of the astrocyte Na-glutamate transporter-1 (GLT-1) and remove glutamate from the extracellular space, markedly reduce relapse[13,14]
AD-mesenchymal stem cells (MSCs) were isolated from samples of subcutaneous adipose tissue obtained from liposuction aspirates with patient consent and ethical approval

Summary

Introduction

Alcohol-use disorders constitute a leading cause of morbidity and premature mortality worldwide, accounting for 1 in 10 deaths among working-age adults in the United States[1]. Research has indicated that alcohol-induced neuroinflammation remains up-regulated for long periods even after discontinuation of alcohol consumption, whereas the peripheral levels return rapidly to normal, indicating the presence of a potent mechanism of auto-perpetuation of neuroinflammation, which could be related to the lack of regulatory T cells in the brain[9,10] This phenomenon is associated with a marked increase in the risk of relapse in abstinent patients[7,8]. Drug relapse observed for alcohol and other drugs is causally associated with the existence of high levels of extracellular glutamate, since the administration of N-acetyl cysteine or ceftriaxone which increase the level of the astrocyte Na-glutamate transporter-1 (GLT-1) and remove glutamate from the extracellular space, markedly reduce relapse[13,14] These studies further suggest the existence of a common mechanism of addictive drug relapse. This size reduction could allow intravenously administered MSC-spheroids to reach the brain

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