Disulfiram is a drug used to treat chronic alcoholism. However, studies suggest that it also inhibits chemokine receptor signaling pathways associated with the regulation of anxiety in rodents.
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A team of researchers from the Tokyo University of Science shows that disulfiram can effectively reduce stress without causing any of the adverse effects linked to other anxiolytic drugs. Thus, disulfiram could potentially become a safe and effective anti-anxiety drug.
Alcoholism, if left untreated, could have dangerous repercussions. Thus, it is no surprise that many drugs have been developed to treat this condition. Of 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 the metabolism of alcohol.
Could the inhibitory effects of DSF extend to signaling molecules as well?
According to recent studies, DSF, in fact, inhibits a cytoplasmic protein known as FROUNT, which controls the direction in which specific immune cells migrate. DSF blocks FROUNT from interacting with two chemokine receptors known as CCR2 and CCR5, which are involved in crucial cellular signaling pathways.
A few studies suggest that chemokine receptors may be involved in regulating 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 comprising Prof. Akiyoshi Saitoh from Tokyo University of Science and other researchers from institutes across Japan conducted a study examining the pharmacological properties of DSF. The study, published online in Frontiers in Pharmacology, describes how the research team used an elevated plus-maze (EPM) test―which is used to screen for anxiolytic drugs―to study the effects of DSF in mice.
The EPM apparatus consists of four arms set in a cross pattern, connected to a central square. Two components are protected by vertical boundaries, whereas two have unprotected edges. Usually, mice with anxiety prefer to spend time in closed arms.
In this case, some mice were administered diazepam (a drug commonly used to treat anxiety) and others, DSF. These mice were then placed in the EPM apparatus, and their activity was monitored. To their surprise, the team found that mice treated with DSF spent significantly more time in the open arms of the apparatus, which indicates that they were less anxious. The team also tested the anxiolytic effects of a more potent FROUNT inhibitor, DSF-41, and observed similar results.
Interestingly, these behavioral changes were similar to those observed in mice treated with diazepam. How exactly did DSF achieve this?
The team had previously discovered that increased extracellular glutamate levels (essential amino acid and neurotransmitter) are associated with increased anxiety in mice.
“We propose that DSF inhibits FROUNT protein and the chemokine signaling pathways under its influence, which may suppress presynaptic glutamatergic transmission in the brain,” says Prof. Saitoh. “This, in turn, attenuates the levels of glutamate in the brain, reducing overall anxiety.”
The team was also pleasantly surprised to find that DSF treatment did not lead to adverse effects such as amnesia, coordination disorders, or sedation in contrast with diazepam.
According to Prof. Saitoh, “These results indicate that DSF can be used safely by elderly patients suffering from 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 clarify further how DSF exerts its pharmaceutical actions. Hopefully, we will also be able to elucidate the exact role of the FROUNT 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 showing any side effects observed with benzodiazepines. Hopefully, DSF's inhibitory activity against FROUNT functioning could be explored for successful anxiolytic drug development.
Source: Tokyo University of Science