The COVID-19 pandemic has significantly affected the mental health and emotional well-being of the general population, but people who already suffered from a mental disorder have also in many cases experienced a worsening of their illness. This is the case, for example, of major depressive disorder, one of the most frequent psychiatric pathologies in developed countries, since in 2020 it was estimated that 5.4% of the world population presented some type of depressive disorder, of which that 230,000 are considered serious.
The treatment of depression includes psychological support with psychotherapy, but antidepressant medications are also key to managing the problem, however, the available drugs have adverse side effects and can cause addiction, and even, in extreme cases, induce schizophrenia. Therefore, the development of rapid-onset antidepressants without causing adverse effects is an important neuropharmacological goal.
And this is what scientists from the Department of Clinical Pharmacology of the Faculty of Pharmacy, a key laboratory in research and evaluation of narcotic and psychotropic drugs, of the Nanjing Medical University, in China, led by Nan Sun, since they have synthesized a compound for the treatment of depression called ZZL-7 that induces a response just two hours after its administration in the animal model designed to analyze major depression, and without have produced apparent side effects.
This drug “could be of great help to those suffering from depression and should be developed as a new rapid-onset antidepressant candidate”
These researchers have carried out a test in an experimental mouse model that has allowed them to discover that the dissociation of the serotonin transporter, called SERT, which forms the basis of classic antidepressants, from neuronal nitric oxide synthase (nNOS), specifically decreased the intercellular serotonin concentration in a region of the brain called the dorsal raphe nucleus.
The effects of the antidepressant are noticeable in just two hours
The findings have been published in Science and represent a breakthrough because currently used antidepressants do not have an immediate action, but it can take approximately four weeks for patients to experience their pharmacological effects. In addition, and according to the results published in the journal, they have not observed any adverse effect associated with the tested molecule, which does not affect locomotor or general activity, nor memory or cognition, nor has it induced aggressive behavior, nor has it caused abnormal brain waves.
The researchers administered the compound intravenously to mice that had been subjected to chronic mild stress in the previous 28 days, and found that two hours after administration, the compound reversed the SERT-nNOS complex in the dorsal raphe nucleus , and had a similar effect on stress-related depressive behaviors, persisting for the next 24 hours.
“Disruption of this interaction of transporters enhanced the activity of serotonergic neurons in this area–dorsal raphe nucleus–and significantly promoted serotonin release in the medial prefrontal cortex, thus producing a rapid-onset antidepressant effect,” explained Sun, who believes that “the discovery of this small molecule compound – ZZL-7, which caused an antidepressant effect two hours after treatment without undesirable side effects -, or similar reagents, may serve as a new route for the treatment of this disease.
“Another important fact is that the molecule was already detectable in the dorsal nucleus of the raphe half an hour after its administration, which is a sign that it is capable of crossing the blood-brain barrier,” explains Qi-Ganz Zhou, one of the researchers. authors of the work, who, thanks to the use of mass spectrometry technology, verified that the experimental molecule also penetrated the cell membrane.
ZZL-7 decreases intercellular serotonin levels in a region of the brain called the dorsal raphe nucleus, a mechanism that “manages to improve the serotonergic activity of neurons in this area. In addition, it increases the release of serotonin in the medial prefrontal cortex, “said Sun. According to the team of scientists, the results obtained suggest that this drug “could be of great help for those who suffer from depression and that it should be developed as a new rapid-onset antidepressant candidate.”
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