Researchers have developed a highly accurate fluorescent probe to visualize serotonin in living cells and organisms, providing new insights into its role in depression. The study revealed that although the amounts of serotonin inside healthy and “depressed” cells are similar, the big difference lies in the release of this substance: depressed cells release significantly less serotonin. This reduction in release is associated with the activity of the molecule mTOR, which is crucial for cellular communication. These findings suggest that the main problem in depression may be the difficulty of cells in releasing serotonin, and not just its quantity, which could open the way for new, more effective treatments.
The link between depression and serotonin (5-HT) has been widely discussed, with major implications for the diagnosis and treatment of neurological disorders.
A team of Chinese researchers has developed a highly sensitive and selective fluorescent probe for serotonin, allowing for more accurate visualization of this substance in animal cells and tissues. The problem with this is that the structure and chemistry of serotonin closely resemble other biomolecules, such as melatonin and tryptophan. The first results were published in the journal Angewandte Chemie.
Depression is a global public health problem, and current treatments are still limited, partly because the exact mechanisms of depression are difficult to understand. Recent studies have shown that depression may not be caused solely by decreased serotonin levels in the brain.
The team’s goal was to further investigate how serotonin plays a role in depression, using this new fluorescent probe.
Until now, developing molecular tools to detect serotonin has been a challenge. The team designed a special reactive group (3-mercaptopropionate) that can react very selectively with serotonin through a cascade reaction. They attached this reactive building block to a fluorescent dye (a dicyanomethylene benzopyran derivative).
The researchers developed an innovative fluorescent probe that, initially “off”, turns on when it encounters serotonin, allowing its precise detection. This process occurs in two steps: first, a part of the probe reacts with serotonin (a chemical bond between the SH group of the probe and a double bond of serotonin, called a thiol-ene click reaction).
Then, a second bond is formed between an amino group of serotonin and a carbonyl group of the probe, activating the fluorescence of the probe. This mechanism allows serotonin to be identified selectively and sensitively, even inside cells.
Mechanism of action of a highly selective molecular probe based on thiol-ene click cascade nucleophilic reactions that enables real-time imaging of brain tissue in depression. https://doi.org/10.1002/anie.202407308
The team used this probe to study neuronal cells that had been transformed into a model of depression by administering corticosterone. Interestingly, they found that the level of serotonin in the “depressed” and normal cells was nearly the same.
However, the depressed cells released much less serotonin when stimulated. When traditional antidepressants, such as serotonin reuptake inhibitors, were administered, the release increased slightly, but not significantly.
The research also suggests that the molecule mTOR, involved in many cellular functions, may be linked to the low serotonin release capacity. They observed that when using mTOR activators, depressed cells significantly increased serotonin release, while mTOR inhibitors reduced this release in normal cells. These findings were confirmed in mouse models.
With this innovation, they were able to observe that, although serotonin levels in the brains of people with depression may be similar to those in normal brains, the difference lies in the ability of depressed cells to release serotonin.
Furthermore, this release capacity is strongly linked to the activity of a molecule called mTOR, which is involved in cellular communication. These findings offer new clues about the mechanisms of depression and pave the way for the development of more effective antidepressant treatments, focusing on the action of serotonin and the role of mTOR.
READ MORE:
Development of a Fluorescent Probe with High Selectivity based on Thiol-ene Click Nucleophilic Cascade Reactions for Delving into the Action Mechanism of Serotonin in Depression
Lizhou Yue, Huawei Huang, Weiying Lin
Abstract:
The intrinsic correlation between depression and serotonin (5-HT) is a highly debated topic, with significant implications for the diagnosis, treatment, and advancement of drugs targeting neurological disorders. To address this important question, it is of utmost priority to understand the action mechanism of serotonin in depression through fluorescence imaging studies. However, the development of efficient molecular probes for serotonin is hindered by the lack of responsive sites with high selectivity for serotonin at present. Herein, we developed the first highly selective serotonin-responsive site, 3-mercaptopropionate, utilizing thiol-ene click cascade nucleophilic reactions. The novel responsive site was then employed to construct the powerful molecular probe SJ-5-HT for imaging the serotonin level changes in the depression cells and brain tissues. Importantly, imaging studies reveal that the level of serotonin in patients with depression may not be the primary factor, while the ability of neurons in patients with depression to release serotonin appears to be more critical. Additionally, this serotonin release capability correlates strongly with the levels of mTOR (intracellular mammalian target of rapamycin). These discoveries could offer valuable insights into the molecular mechanisms underpinning depression and furnish mTOR as a novel direction for the advancement of antidepressant therapies.
Comments