Analysis offers potential therapeutic targets for patients with chronic alcohol use disorder
Boston, Mass. – Alcohol use disorder impacts millions of people around the world, including at least 17 million Americans. Nearly 100,000 patients die each year from the consequences of chronic drinking, which induces organ injury throughout the body, particularly to the liver and brain. In a new study, scientists led by Gyongyi Szabo, MD, PhD, Hon. ScD, Chief Academic Officer of Beth Israel Deaconess Medical Center and Beth Israel Lahey Health shed light on the mechanisms by which chronic alcohol consumption causes damage to brain cells and cells of the central nervous system, which in turn potentially triggers addictive behavior. The findings, published in the Journal of Neuroinflammation, also suggest possible targets for a therapeutic approach to chronic alcohol use disorder.
"Chronic alcohol exposure induces a complex, multi-organ response with activation of a variety of immune responses and inflammatory expression," said Szabo. "Our data identifies the signaling pathway by which chronic alcohol consumption promotes inflammation in tissues of the central nervous system and our further analysis suggests a strategy for blocking this alcohol-induced neuroinflammation."
In an experiment conducted at the University of Massachusetts Medical School — where Szabo formerly held the position of Associate Dean for Clinical and Translational Sciences — Szabo and colleagues studied the impact of chronic alcohol-consumption on various regions of the brain in a mouse model. The scientists observed that immune cells called macrophages invaded the brain parenchyma (or tissue), particularly in the hippocampus — a region of the brain critical to learning and memory that is well known to lose volume in patients with chronic alcohol use disorder. Gene expression analysis revealed the signaling pathway by which alcohol consumption promotes neuroinflammation. Moreover, the researchers also demonstrated that blocking immune cell invasion with an investigational drug restored some lost brain cell function; however, administration of the investigational drug did not change the alcohol consumption or preferences of the laboratory animals.
Szabo and colleagues point out that, for decades, scientific dogma held that immune cells could not reach the tissues of the central nervous system (CNS). Researchers subsequently demonstrated the presence of immune cells in CNS tissues in the setting of disease.
"It's only recently that the infiltration of immune cells into the tissues of the central nervous system has been described in the setting of alcohol-induced inflammation," says Szabo. "We and other researchers continue to define the hallmark pathologic features of chronic alcohol consumption on the brain — particularly with respect to inflammation. This present study opens up many interesting areas for future research."
Co-authors included Patrick P. Lowe, Aditya Ambade, Arvin Iracheta-Vlive, Erica Kwiatkowsky, Abhishek Satishchandran, Istvan Furi, Yeonhee Cho, Benedek Gyongyosi and Dorothy O. Schafer of University of Massachusetts Medical School; Caroline Morel and Donna Catalano of BIDMC; Eric Lefebvre, Laurent Fischer and Star Seyedkazemi of Allergan.
This work was supported in part by Tobira Therapeutics, a subsidiary of Allergan, and by the National Institute on Alcohol Abuse and Alcoholism, part of the National Institutes of Health, (F30AA024680 and 5R01AA017729-05).
Dr. Szabo consults for Allergan, Alnylam, Arrow, Durcect Corporation, Generon, Glympse Bio, Terra Firma, Quest Diagnostics, Pandion Therapeutics, Surrozen, and Zomagen. She holds intellectual property rights with Up to Date. The co-authors declare no competing financial interests.
