Alcoholism, if left untreated, can have dangerous repercussions. So, it’s no surprise that there is a range of drugs developed to treat this condition. Among these drugs, disulfiram (DSF) is approved by the Food and Drug Agency (FDA) for the treatment of alcoholism. DSF primarily inhibits the enzyme aldehyde dehydrogenase (ALDH), which is responsible for alcohol metabolism.
Could the inhibitory effects of DSF also extend to signaling molecules?
According to recent studies, DSF actually inhibits a cytoplasmic protein called FROUNT, which controls the direction of migration of certain immune cells. DSF prevents FROUNT from interacting with two chemokine receptors called CCR2 and CCR5, which are involved in important cell signaling pathways.
A few studies suggest that chemokine receptors may be involved in the regulation of emotional behaviors in rodents. However, there is a lack of data on the exact association between FROUNT-chemokine signaling and DSF. To clarify this link, a team including Professor Akiyoshi Saitoh of Tokyo University of Science and other researchers from institutes across Japan conducted a study examining the pharmacological properties of DSF. The study, published online March 7, 2022 in Frontiers in pharmacologydescribes how the research team used an elevated plus maze (EPM) test – which is used to screen for anti-anxiety drugs – to study the effects of DSF in mice.
The EPM device consists of four arms arranged in a cross, connected to a central square. Two arms are protected by vertical boundaries, while two have unprotected edges. Usually, anxious mice prefer to spend time in closed arms.
In this case, some mice were given diazepam (a drug commonly used to treat anxiety) and others were given DSF. These mice were then placed in the EPM device, and their activity was monitored. To their surprise, the team found that the DSF-treated mice spent significantly more time in the open arms of the device, indicating that they were less anxious. The team also tested the anxiolytic effects of a more potent FROUNT inhibitor, known as DSF-41, and observed similar results.
Interestingly, these behavioral changes were similar to those seen in diazepam-treated mice. How exactly did DSF achieve this?
The team had previously found that increased levels of extracellular glutamate (which is an important amino acid and neurotransmitter) are associated with increased anxiety in mice.
“We propose that DSF inhibits the FROUNT protein and the chemokine signaling pathways under its influence, which may suppress presynaptic glutamatergic transmission in the brain,” Professor Saitoh said. “This, in turn, dampens glutamate levels in the brain, thereby reducing overall anxiety.”
The team was also pleasantly surprised to find that, unlike diazepam, DSF treatment did not cause adverse effects such as amnesia, impaired coordination or sedation.
According to Professor Saitoh, “These results indicate that DSF can be used safely by elderly patients with anxiety and insomnia and has the potential to become a breakthrough psychotropic drug.”
What are the long-term implications of these results? Dr. Saitoh explains: “We plan to further clarify how DSF carries out its pharmaceutical actions. Hopefully we will also be able to elucidate the exact role of the FRONT molecule in the central nervous system.
This is one of the first studies to reveal that DSF exhibits anti-anxiety properties comparable to existing benzodiazepines without exhibiting the side effects seen with benzodiazepines. Hopefully, the inhibitory activity of DSF against FROUNT functioning could be explored for the successful development of anxiolytic drugs.
On Tokyo University of Science
Tokyo University of Science (TUS) is a well-known and respected university, and the largest private research university specializing in science in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Founded in 1881, the university has continuously contributed to the scientific development of Japan by instilling a love of science in researchers, technicians and educators.
With a mission to “create science and technology for the harmonious development of nature, human beings and society”, TUS has undertaken a wide range of research from basic science to applied science. TUS has taken a multidisciplinary approach to research and undertaken intensive studies in some of today’s most vital areas. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel laureate and the only private university in Asia to produce Nobel laureates within the field of natural sciences.
About Professor Akiyoshi Saitoh of Tokyo University of Science
Dr. Akiyoshi Saitoh is a professor at the Faculty of Pharmaceutical Sciences, Tokyo University of Science. He is a senior researcher with over 20 years of experience in the fields of medicinal pharmacology, behavioral pharmacology and neuroscience. His research also focuses on the role of the amygdala in fear memory extinction in rodents and the development of a novel delta opioid receptor agonist for antidepressants/anxiolytics. Dr. Saitoh has contributed to over 100 research publications and is the first author of this study.
This study was partially funded by the Tsukuba Clinical Research and Development Organization (T-CReDO) of the Japanese Agency for Medical Research and Development (AMED).
Frontiers in pharmacology
The title of the article
Disulfiram Produces Potent Anxiolytic Effects Without Benzodiazepine Anxiolytic-Related Adverse Effects in Mice
Publication date of articles
March 7, 2022
Conflict of Interest Statement
The authors of this article declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest.
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