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The incidence of depression has increased year by year in recent years and has received extensive attention
.
On October 28, 2022, Science published online a study by Professor Zhou Qigang, Professor Zhu Dongya and Professor Li Tingyou of the State Key Laboratory of Reproductive Medicine of Nanjing Medical University, School of Pharmacy: Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN, the study is revolutionary for the classic hypothesis of depression, the monoamine theory
.
Since the first antidepressant drug promethazine was discovered clinically in 1954, scientists have gradually realized that depression is mainly due to a decrease in serotonin neurotransmitters in the synaptic cleft in the brain, and increasing the synaptic cleft serotonin can treat depression
.
Drugs that act by inhibiting monoamine oxidase are classified as first-generation antidepressants
.
However, the monoamine oxidase target lacks specificity and can lead to serious side effects
.
Promethazine was also decommissioned early in 1961, and the first generation of antidepressants was largely no longer used
.
The discovery of promethazine inspired scientists to develop antidepressants, and soon a second antidepressant, imiprazine, was screened in
1956.
Because this class of drugs has a phenothiazide tricyclic structure, it is called a tricyclic antidepressant and is also a second-generation antidepressant
.
Later studies found that second-generation antidepressants mainly exerted antidepressant effects by inhibiting the reabsorption of serotonin and norepinephrine in the synaptic cleft by serotonin transporters (SERT) and norepinephrine transporters (NETs), and increasing the concentration of serotonin and norepinephrine in the synaptic cleft.
However, second-generation antidepressants have more side effects, such as imipramine poisoning
when used incorrectly.
However, on this basis, scientists have proposed the classic "monoamine hypothesis" of depression: the concentration of monoamine neurotransmitters that can be effectively used in the synaptic cleft in depressed patients is significantly reduced; Increasing synaptic cleft monoamine transmitter concentrations (mainly 5-HT) exerts antidepressant effects
.
Subsequently, based on the "monoamine hypothesis", Eli Lilly of the United States developed the selective serotonin transporter (SERT) inhibitor fluoxetine, which shocked the market
when it was launched in 1987.
Fluoxetine has more significant clinical antidepressant effect and fewer side effects, and is a blockbuster drug with annual sales of more than 10 billion US dollars, so far it is a first-line clinical antidepressant
.
Therefore, drugs based on selective inhibition of SERT are classified as third-generation antidepressants
.
However, antidepressants developed based on the "monoamine hypothesis" have a drawback, which is that they delay the onset of effect
.
For example, it takes 2-4 weeks for patients to take the selective SERT inhibitor fluoxetine to begin to show efficacy, which seriously hinders the treatment
of the acute phase of the episode in patients with major depression.
In addition, this class of drugs also has low efficacy, only some patients are effective, the efficacy is unstable, some patients are ineffective, and even aggravate symptoms and lead to suicide
.
The main reason for these side effects is to block serotonin transporters in postsynaptic tissues (including cortex, hippocampus, etc.
), increase serotonin concentration, activate serotonin receptors, and exert antidepressant effects; However, at the same time, it blocks the serotonin transporter of serotoninergic neurons in the dorsal nucleus of the middle suture, increases serotonin in the dorsal nucleus of the middle suture, activates the negative feedback effect of serotonin own receptors, and induces depression
.
This balance leads to early effects such as fluoxetine, and it is necessary to wait until the serotonin receptors of the dorsal nucleus of the middle suture are desensitized to the antidepressant effect
.
In addition, the instability of serotonin self-receptor desensitization in the dorsal nucleus of the middle suture has also led to other defects
such as ineffectiveness and unstable efficacy in some patients.
How to overcome this problem? Through years of research, the joint research team of Professor Zhou Qigang, Professor Zhu Dongya, and Professor Li Tingyou found that SERT is highly colocalized with neuronal nitric oxide synthase (nNOS) in the dorsal nucleus region of the middle suture, while SERT-nNOS colocalization is basically absent in the postsynaptic site
。 After chronic stress, the coupling of the dorsal nucleus of the middle suture SERT to nNOS increases, resulting in a decrease in the localization of the cell membrane SERT membrane, an increase in the concentration of serotonin between cells, activation of serotonin autoreceptors, and increased negative feedback to inhibit serotonergic neuronal firing, resulting in a decrease in serotonin in the postsynaptic cleft and inducing depression
。 Unhook the SERT-nNOS coupling, increase the middle suture dorsal nucleus cell membrane SERT, reduce intercellular serotonin, reduce negative feedback, stimulate serotoninergic neuronal firing, resulting in a sharp increase in serotonin concentration in the postsynaptic cleft, does not depend on serotonin self-receptor desensitization, exerts rapid antidepressant effect
.
Based on this new target, the team synthesized the selective SERT-nNOS uncoupling lead compound ZZL-7 and found that ZZL-7 exerts antidepressant effects 2 hours after injection and is a new candidate with rapid onset of action
.
In recent years, ketamine has been found to exert rapid-acting antidepressant effects
by blocking NMDA receptors.
However, ketamine, known as "K powder," is a drug that has serious side effects such as addiction and hallucinogenic, severely limiting its use
.
This study has found a new fast-acting antidepressant target with a decoupling agent that can act quickly without ketamine-like side effects, and may overcome the defect of third-generation antidepressants relying on serotonin self-receptor desensitization and develop a new generation of antidepressants
.
The journal Science listed the study as Highlight, and international peers and media also highly praised the study, believing that this is a major theoretical breakthrough
in antidepressant research in the nearly 60 years since the "monoamine hypothesis" was put forward and fluoxetine has been on the market for 50 years.
Original link:
http://doi.
org/10.
1126/science.
abo3566
Pattern maker: Eleven
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