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Written byWang CongEditor
Wang Duoyu typesettingDepression
is a common mental disorder, mainly manifested as low mood, reduced interest, and slow thinking Symptoms such as poor diet and sleep can also produce pessimism and misanthropy and even suicidal tendencies
.
In addition, depression has been linked to
increased rates of cardiovascular disease, diabetes, and Alzheimer's disease.
According to the World Health Organization (WHO), depression has become the fourth most common disease in the world, and more than 350 million people worldwide suffer from depression, and it is growing rapidly
.
As early as the 50s of the last century, the monoamine hypothesis was proposed and became a classic theory of the onset of depression, which believed that the onset of depression was related to the deficiency of monoamine neurotransmitters (including serotonin, dopamine and norepinephrine), which led to the development of a series of antidepressant drugs
。
Selective serotonin reuptake inhibitors (SSRIs) are the latest generation of antidepressants that inhibit the use of serotonin (also known as serotonin) by selectively blocking serotonin transporters (SERT) , increase the level of serotonin in the brain, thereby improving depressive symptoms
.
This is currently the first-line treatment for
depression.
But they take weeks or even longer to show efficacy
in people with depression.
In addition, these drugs have a range of potential side effects and, for many patients, do not work at
all.
On October 28, 2022, Professor Zhou Qigang, Professor Zhu Yaya, and Professor Li Tingyou, State Key Laboratory of Reproductive Medicine, School of Pharmacy, Nanjing Medical University, teamed up, Published a research paper titled: Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN in the top international academic journal Science.
The study developed a compound, ZZL-7, that selectively uncouples the middle suture dorsal nuclear region (DRN) serotonin transporter (SERT) complex with neuronal nitric oxide synthase (nNOS), in mice, two hours after injection administration, quickly exerts antidepressant effects without any side effects
observed.
This research not only brings new insights into the classic theory of depression, the monoamine hypothesis, but also develops a fast-acting drug
candidate for depression.
The results were highly praised by the journal Science and presented as highlight
.
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 proposed, and the classical antidepressant fluoxetine (an SSRI drug) was discovered for 50 years.
It is also the first time that the scientific research results of Nanjing Medical University with completely independent intellectual property rights have been published
in Science journals.
Selective serotonin reuptake inhibitors (SSRIs) are thought to act in part through effects on 5-HT1a receptors, in certain parts of the brain (such as the cortex and hippocampus) bind to this receptor, allowing cells to send signals using serotonin (5-HT, also known as serotonin) to improve symptoms of
depression.
The dorsal nucleus region (DRN) of the middle suture is the main source of serotonin (5-HT) in the brain, where 5-HT1a receptors work differently
.
The binding of SSRIs to 5-HT1a receptors prevents cells from firing, which affects the concentration of serotonin (5-HT) downstream because the signal emitted by the DRN promotes the release
of serotonin (5-HT) in the cortex.
This also explains why antidepressants such as SSRIs take a long time to work, and within a few weeks of starting SSRIs, the 5-HT1a receptor in the DRN becomes desensitized before it is more favorable Serotonin (5-HT) signaling is transmitted, and patients begin to feel relief
from SSRIs.
The joint research team of Professor Zhou Qigang, Professor Zhu Dongya and Professor Li Tingyou believes that the time between medication and onset of action can be shortened by releasing serotonin (5-HT) in DRN neurons
。
To do this, they looked at neuronal type nitric oxide synthase (nNOS), which forms complexes with serotonin transporters (SERT) on the surface of neurons in the dorsal nucleus region (DRN) of the middle slit
。 Previous studies have shown that when SERT and nNOS interact, the 5-HT1a receptor prevents cells from firing
.
Therefore, the research team believes that SERT-nNOS interaction blockers, or SNIBs, can release SERTs and reduce the inhibition of 5-HT1a receptors, resulting in faster symptom
relief in patients with depression.
The team first evaluated whether the coupling between SERT and nNOS played a role in depressive behavior, using a mouse model under long-term mild stress, and found that the higher the concentration of the SERT-nNOS complex in the dorsal nucleus region (DRN) of the middle slit, the more
depressive behavior there was.
Knocking out the nNOS gene produced the opposite result: mice that knocked out the nNOS gene showed more antidepressant behavior
under the same conditions.
To investigate how the uncoupling of the SERT-nNOS complex affects the serotonin (5-HT) pathway, the team injected a chemical directly into itThe dorsal nucleus region (DRN) of the middle suture to uncouple the SERT-nNOS complex, and within two hours, an increase in SERT activity and an increase
in antidepressant behavior were observed.
An increase in serotonin (5-HT) in the prefrontal cortex was also observed, suggesting that the uncoupling of the SERT-nNO S complex has a rapid antidepressant effect
.
Based on the above results, the research team developed a small molecule compound, ZZL-7, to specifically uncouple the SERT-nNOS complex, and after intravenous injection of ZZL-7 into a group of depressed mouse models, the depressive behavior of these mice was reversed
within two hours.
Other tests have shown that the compound has no effect on memory, cognition or aggression in mice, and does not produce abnormal brain activity
.
Comparison of the mechanism of action of selective serotonin reuptake inhibitors (SSRIs) with SERT-nNOS interaction blockers (SNIBs) contrasts with other fast-acting drugs being tested for the treatment of
depression, such as ketamine, which is still under development, Ketamine works quickly in the treatment of depression, but it is short-lived, addictive, and can also induce schizophrenia
.
Overall, this study brings new insights into the classic theory of depression, the monoamine hypothesis, showing that uncoupling SERT-nNOS can rapidly reverse depressive behavior in mice, opening up new avenues
for the development of mood disorder therapies.
The research team says "it should now be tested in humans.
"
As the incidence of depression continues to increase, more and more researchers have joined the ranks
of developing rapid antidepressant drugs.
In August, Axsome Therapeutics' NMDA receptor antagonist, Auvelity, received FDA approval for the treatment of major depressive disorder, with depressive symptoms relieved within a week of medication and complete relief
by week 2.
In 2019, Johnson & Johnson's nasal spray, ketamine, an isomer of ketamine, received FDA approval for the rapid treatment of acute episodes of major depression or suicidal thoughts
.
And in October of this year, researchers at the College of Medicine of Connecticut published a paper in the journal JAMA Psychiatry [2] showing that electroconvulsive therapy (ECT) is better than ketamine/esketamine Faster relief of major depressive disorder
.
Links to papers: 1.
https:
//www.
science.
org/doi/10.
1126/science.
abo3566 2.
https://jamanetwork.
com/journals/jamapsychiatry/article-abstract/2797209
open for reprinting welcome to forward to the circle of friends and WeChat group
Wang Duoyu typesettingDepression
is a common mental disorder, mainly manifested as low mood, reduced interest, and slow thinking Symptoms such as poor diet and sleep can also produce pessimism and misanthropy and even suicidal tendencies
.
In addition, depression has been linked to
increased rates of cardiovascular disease, diabetes, and Alzheimer's disease.
According to the World Health Organization (WHO), depression has become the fourth most common disease in the world, and more than 350 million people worldwide suffer from depression, and it is growing rapidly
.
As early as the 50s of the last century, the monoamine hypothesis was proposed and became a classic theory of the onset of depression, which believed that the onset of depression was related to the deficiency of monoamine neurotransmitters (including serotonin, dopamine and norepinephrine), which led to the development of a series of antidepressant drugs
。
Selective serotonin reuptake inhibitors (SSRIs) are the latest generation of antidepressants that inhibit the use of serotonin (also known as serotonin) by selectively blocking serotonin transporters (SERT) , increase the level of serotonin in the brain, thereby improving depressive symptoms
.
This is currently the first-line treatment for
depression.
But they take weeks or even longer to show efficacy
in people with depression.
In addition, these drugs have a range of potential side effects and, for many patients, do not work at
all.
On October 28, 2022, Professor Zhou Qigang, Professor Zhu Yaya, and Professor Li Tingyou, State Key Laboratory of Reproductive Medicine, School of Pharmacy, Nanjing Medical University, teamed up, Published a research paper titled: Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN in the top international academic journal Science.
The study developed a compound, ZZL-7, that selectively uncouples the middle suture dorsal nuclear region (DRN) serotonin transporter (SERT) complex with neuronal nitric oxide synthase (nNOS), in mice, two hours after injection administration, quickly exerts antidepressant effects without any side effects
observed.
This research not only brings new insights into the classic theory of depression, the monoamine hypothesis, but also develops a fast-acting drug
candidate for depression.
The results were highly praised by the journal Science and presented as highlight
.
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 proposed, and the classical antidepressant fluoxetine (an SSRI drug) was discovered for 50 years.
It is also the first time that the scientific research results of Nanjing Medical University with completely independent intellectual property rights have been published
in Science journals.
Selective serotonin reuptake inhibitors (SSRIs) are thought to act in part through effects on 5-HT1a receptors, in certain parts of the brain (such as the cortex and hippocampus) bind to this receptor, allowing cells to send signals using serotonin (5-HT, also known as serotonin) to improve symptoms of
depression.
The dorsal nucleus region (DRN) of the middle suture is the main source of serotonin (5-HT) in the brain, where 5-HT1a receptors work differently
.
The binding of SSRIs to 5-HT1a receptors prevents cells from firing, which affects the concentration of serotonin (5-HT) downstream because the signal emitted by the DRN promotes the release
of serotonin (5-HT) in the cortex.
This also explains why antidepressants such as SSRIs take a long time to work, and within a few weeks of starting SSRIs, the 5-HT1a receptor in the DRN becomes desensitized before it is more favorable Serotonin (5-HT) signaling is transmitted, and patients begin to feel relief
from SSRIs.
The joint research team of Professor Zhou Qigang, Professor Zhu Dongya and Professor Li Tingyou believes that the time between medication and onset of action can be shortened by releasing serotonin (5-HT) in DRN neurons
。
To do this, they looked at neuronal type nitric oxide synthase (nNOS), which forms complexes with serotonin transporters (SERT) on the surface of neurons in the dorsal nucleus region (DRN) of the middle slit
。 Previous studies have shown that when SERT and nNOS interact, the 5-HT1a receptor prevents cells from firing
.
Therefore, the research team believes that SERT-nNOS interaction blockers, or SNIBs, can release SERTs and reduce the inhibition of 5-HT1a receptors, resulting in faster symptom
relief in patients with depression.
The team first evaluated whether the coupling between SERT and nNOS played a role in depressive behavior, using a mouse model under long-term mild stress, and found that the higher the concentration of the SERT-nNOS complex in the dorsal nucleus region (DRN) of the middle slit, the more
depressive behavior there was.
Knocking out the nNOS gene produced the opposite result: mice that knocked out the nNOS gene showed more antidepressant behavior
under the same conditions.
To investigate how the uncoupling of the SERT-nNOS complex affects the serotonin (5-HT) pathway, the team injected a chemical directly into itThe dorsal nucleus region (DRN) of the middle suture to uncouple the SERT-nNOS complex, and within two hours, an increase in SERT activity and an increase
in antidepressant behavior were observed.
An increase in serotonin (5-HT) in the prefrontal cortex was also observed, suggesting that the uncoupling of the SERT-nNO S complex has a rapid antidepressant effect
.
Based on the above results, the research team developed a small molecule compound, ZZL-7, to specifically uncouple the SERT-nNOS complex, and after intravenous injection of ZZL-7 into a group of depressed mouse models, the depressive behavior of these mice was reversed
within two hours.
Other tests have shown that the compound has no effect on memory, cognition or aggression in mice, and does not produce abnormal brain activity
.
Comparison of the mechanism of action of selective serotonin reuptake inhibitors (SSRIs) with SERT-nNOS interaction blockers (SNIBs) contrasts with other fast-acting drugs being tested for the treatment of
depression, such as ketamine, which is still under development, Ketamine works quickly in the treatment of depression, but it is short-lived, addictive, and can also induce schizophrenia
.
Overall, this study brings new insights into the classic theory of depression, the monoamine hypothesis, showing that uncoupling SERT-nNOS can rapidly reverse depressive behavior in mice, opening up new avenues
for the development of mood disorder therapies.
The research team says "it should now be tested in humans.
"
As the incidence of depression continues to increase, more and more researchers have joined the ranks
of developing rapid antidepressant drugs.
In August, Axsome Therapeutics' NMDA receptor antagonist, Auvelity, received FDA approval for the treatment of major depressive disorder, with depressive symptoms relieved within a week of medication and complete relief
by week 2.
In 2019, Johnson & Johnson's nasal spray, ketamine, an isomer of ketamine, received FDA approval for the rapid treatment of acute episodes of major depression or suicidal thoughts
.
And in October of this year, researchers at the College of Medicine of Connecticut published a paper in the journal JAMA Psychiatry [2] showing that electroconvulsive therapy (ECT) is better than ketamine/esketamine Faster relief of major depressive disorder
.
Links to papers: 1.
https:
//www.
science.
org/doi/10.
1126/science.
abo3566 2.
https://jamanetwork.
com/journals/jamapsychiatry/article-abstract/2797209
open for reprinting welcome to forward to the circle of friends and WeChat group
