A new candidate for antidepressants
The Japanese have tested an antidepressant for resistant to SSRIs
Denis Strigun, Naked Science
Japanese scientists have discovered that a new 5-HT3R receptor agonist surpasses the antidepressant properties of the selective serotonin reuptake inhibitor (SSRI) fluoxetine as part of depression therapy in mice. Article by Kondo et al. A novel 5HT3 receptor–IGF1 mechanism distinct from SSRI-induced antidepressant effects is published in the journal Molecular Psychiatry.
According to According to the World Health Organization (WHO), around 350 million people suffer from depression worldwide. First-line antidepressants include SSRIs, the mechanism of action of which is based on blocking the reuptake of serotonin by neurons, which theoretically increases the level of the neurotransmitter and improves the patient's mood. However, often drugs of this type do not lead to remission, so scientists are looking for alternative ways to treat the disease. Past studies have shown that antidepressant effects may depend on the processes of adult neurogenesis: for example, with successful treatment, SSRIs stimulate the proliferation of neuronal progenitor cells in the dentate gyrus of the hippocampus. In this case, the target of such substances, for example fluoxetine, are metabotropic 5-HT1AR receptors.
In 2015, experts from Osaka University found out that 5-HT3R receptor agonists expressed in the hippocampus, amygdala and prefrontal cortex also have an antidepressant effect, but, unlike the targets of SSRIs, they have other structures and functions. The exact role of 5-HT3R receptors is unknown, it is assumed that they are involved in the regulation of cognitive and emotional processes. To clarify the molecular mechanisms of agonists of these receptors, the authors of the new article compared their effects with fluoxetine. At the first stage, the researchers bred mice with a lack of 5-HT3R receptors, after which they and healthy individuals were injected with SR 57227A (4-amino-1-(6-chloro-2-pyridine)-piperidine hydrochloride), fluoxetine or a mixture of drugs.
The scheme of the agonist's action (from an article in Molecular Psychiatry)
After assessing motor activity, the scientists conducted a blood test and studied the hippocampal neurons of the animals using immunochemical staining and an optical microscope. Additionally, they studied the dynamics of the effect of drugs in vivo by microdialysis: for this, a probe was inserted into the ventral hippocampus of live mice and injections of a 5-HT3R receptor agonist, fluoxetine or saline solution were made. The results showed that the agonist had a significant antidepressant effect on animals (they had previously shown motor activity when hanging by the tail) regardless of the administration of fluoxetine. At the same time, the experimental compound had no effect on healthy individuals whose motor activity increased after SSRI injections.
The agonist effect persisted for three weeks and was earlier and more pronounced than that of fluoxetine: for example, a significant increase in the proliferation of neuronal progenitor cells in the hippocampus of the experimental group was observed three days after treatment. Despite the fact that the combination with fluoxetine enhanced the effect, the authors note that the data obtained indicate a high independent effect of the agonist. Notably, neurons that expressed the 5-HT3R receptor also expressed insulin-like growth factor 1 (IFG1), a protein involved in the regulation of cell differentiation and development. At the same time, activation of IFG1 was necessary for cell proliferation associated with the 5-HT3R receptor.
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26.04.2017