Mol Psychiatry︱ Frontier Review: The latest progress in the molecular mechanism of ketamine against depression

Written by Zhao Xinnan, edited by Zhao Xinnan, Wang Sizhen Ketamine is an antagonist of N-methyl-ᴅ-aspartate (NMDA) receptor (NMDAR)
.

Since the 1960s, ketamine has been mainly used as an anesthetic and analgesic, and it is also the main ingredient of the drug "K powder"
.

Racemic ketamine (namely (R,S)-ketamine) is composed of S-ketamine (esketamine, that is right-handed ketamine) and R-ketamine (arketamine, that is left-handed ketamine) two optical enantiomers 1:1 Proportion
.

 In 2019, the U.
S.
FDA formally approved the use of S-ketamine nasal spray as the standard treatment for refractory depression.
However, more and more evidence has shown that sub-narcotic doses of R-ketamine have a rapid and rapid effect on refractory depression.
Long-lasting antidepressant effect [1-3]
.

Preclinical studies have also shown that, compared with S-ketamine, although R-ketamine has a weaker binding force to NMDAR, its antidepressant effect on mice is stronger and the drug effect is longer [1-3]
.

However, other clinical trials have shown that non-ketamine NMDAR-related compounds cannot show the potent antidepressant effect similar to ketamine in human patients with depression [4, 5]
.

 In other words, due to the complexity of human mental illness, rodent data may not be applicable to humans
.

Existing studies have shown that the exact molecular mechanism of the antidepressant effects of racemic ketamine and its enantiomers is still unclear, and NMDAR is unlikely to play a major role in the antidepressant effects of racemic ketamine and its enantiomers
.

 On May 7, 2021, in a review article published on Molecular Psychiatry titled Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor, Dr.
Wei Yan, a visiting scholar at the Institute of Cardiovascular Medicine, Southwest Medical University and the Faculty of Medicine, Chiba University (Yan Wei), Dr.
Lijia Chang and Professor Kenji Hashimoto (corresponding author) of the Social and Mental Health Education Research Center of Chiba University The molecular mechanisms of antidepressant and derivatives, and discussed the brain-gut axis, brain-spleen axis in stress-related depression and the role of R-ketamine in antidepressant.
The author also recognizes the role of R-ketamine in the treatment of non-depressive mental illness.
The potential of barriers to knowledge is discussed
.

 Background depression is currently the most common mental illness.
More than 2 billion people are sickened worldwide, and nearly 800,000 people die of suicide due to depression each year.
It has become a global public health problem
.

Now mainstream antidepressant drugs, such as serotonin reuptake inhibitor (SSRI), serotonin reuptake inhibitor (SNRI), etc.
, all have delayed effects (lag time) and (treatment failure) Problems such as high non-response rate [6, 7]
.

Therefore, it is very important to develop antidepressant drugs with fast onset and long acting time
.

 Abnormal binding of glutamatergic neurotransmitters and NMDA receptors in the central nervous system is involved in a variety of mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BD)
.

A study by Berman et al.
in 2000 showed that a single intravenous administration of sub-anaesthetic dose (0.
5 mg/kg) of racemic ketamine in MDD patients can have an antidepressant effect within a few hours and last for at least 72 hours [ 8]
.

A series of subsequent clinical experiments also showed that racemic ketamine can have a strong anti-depressant and anti-suicide effect on MDD and BD patients who are ineffective in conventional treatment
.

Although S-ketamine has been approved by the FDA as an antidepressant into clinical treatment, experiments have shown that the antidepressant effect of R-ketamine is better than that of S-ketamine
.

 In addition, although the antidepressant effect of racemic ketamine is currently believed to be through antagonizing NMDAR, more and more experimental results show that NMDAR antagonism is not the main way for ketamine to resist depression
.

In conclusion, the molecular mechanism of (R,S)-ketamine (racemic ketamine) against depression is still unclear
.

 Progress 1.
NMDAR inhibition and antidepressant Many studies have reported that ketamine can play an antidepressant effect on animal models with depression, and the antidepressant effect and duration of R-ketamine are better than that of S-ketamine
.

The main pharmacological effect of racemic ketamine is to antagonize NMDAR (inhibition constant Ki = 0.
53μM)
.

Does the antidepressant effect of racemic ketamine stem from its inhibitory effect on NMDAR? Masaki et al.
verified it on animal models by fMRI [9]
.

In the study, rats were given therapeutic doses of racemic ketamine, two enantiomers of ketamine, and NMDAR inhibitor (+)-MK-801
.

The fMRI results of racemic ketamine, S-ketamine and (+)MK-801 groups all showed positive reactions, while the R-ketamine group showed negative fMRI reactions [9]
.

This implies that the antidepressant effect of a certain therapeutic dose of R-ketamine may not depend on the inhibitory effect on NMDAR
.

In addition, it has also been reported that racemic ketamine exerts antidepressant effects through cAMP-dependent pathways instead of inhibiting NMDAR [12]
.

Studies on the metabolites of racemic ketamine (such as (2R,6R)-HNK, (2S,6S)-HNK, (S)-norketamine, etc.
) have shown that these metabolites have no obvious antidepressant effect, and ketamine On the contrary, the metabolites may cause depression in healthy people
.

Racemic ketamine will dissociate in the human body, and produce side effects such as hallucinations, dissociative effects, etc.
, which are all related to the increase of dopamine release from the presynaptic terminal mediated by S-ketamine
.

Taken together, at present, NMDAR inhibition, or ketamine inhibition of NMDAR, does not show an antidepressant effect, but further research is still needed in the future [11]
.

The main metabolite of the enantiomer of ketamine (picture quoted from: Wei, Y.
, Chang, L.
& Hashimoto, K.
Mol Psychiatry (2021)) 2.
AMPAR activation and antidepressant Depression is achieved by inhibiting NMDA receptors on GABAergic neurons, and subsequent activation of AMPAR is an important part of the antidepressant effect of ketamine [11, 12]
.

Experiments have confirmed that giving the AMPAR antagonist NBQX in advance can block the rapid and long-lasting antidepressant effect of (R,S)-ketamine [13]
.

In addition, NBQX can also simultaneously block the antidepressant effects of R- and S-ketamine on chronic social defeated stress (CSDS) mice (a model of depression), indicating that AMPAR activation may mediate two The antidepressant effect of the patient [14]
.

Therefore, the role of AMPAR activation in the antidepressant effect of racemic ketamine and its metabolites remains to be further studied
.

  3.
Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase B (TrkB) pathway and antidepressant BDNF-TrkB pathway research found that ketamine can up-regulate the content of BDNF in the rat brain, and ketamine is knocked out in the BDNF gene The antidepressant effect in mice indicates that the synthesis of BDNF is necessary for the antidepressant effect of ketamine [15]
.

After pre-administration of ANA-12, an inhibitor of BDNF receptor TrkB, the antidepressant effects of R- and S-ketamine disappeared [16]
.

These results suggest that the activation of the BDNF-TrkB signaling pathway is necessary for the antidepressant effect of ketamine.
However, the specific mechanism of the BDNF-TrkB signaling pathway needs further study, including antidepressant drugs and the TrkB transmembrane domain.
Is binding a common mechanism for all antidepressants
.

 TGF-β1 system RNA sequencing of the prefrontal cortex of CSDS mice found that transforming growth factor β1 (TGF-β1) plays an important role in the antidepressant effect of R-ketamine [17]
.

 In CSDS mice, the expression level of TGF-β1 in different brain regions has decreased, and the decrease of TGF-β1 expression level has also been reported in patients with MDD [18]
.

TGF-β1 and its receptors are mainly expressed in microglia.
When the brain microglia is cleared, the antidepressant effect of R-ketamine is weakened.
However, injection of TGF-β1 into the middle and lateral ventricle of CSDS mice can produce It has a rapid and long-lasting antidepressant effect similar to R-ketamine treatment [18]
.

In addition, the TrKB inhibitor ANA-12 can inhibit the antidepressant effect of TFG-β1 [19]
.

In summary, the BDNF-TrkB pathway, the antidepressant effect of TFG-β1 and the relationship between them may become new drug targets for antidepressant therapy
.

Potential signaling pathways of R-ketamine and TGF-β1 antidepressant (picture quoted from: Wei, Y.
, Chang, L.
& Hashimoto, K.
Mol Psychiatry (2021)) 4.
mTORC1, ERK, eEF2K, 4E-BPs and Neuregulin-1 pathway and antidepressant It has been reported that mTORC1 and its downstream are involved in the antidepressant effect mediated by ketamine, but the application of rapamycin in MDD patients can alleviate the symptoms of depression.
Therefore, the antidepressant effect of ketamine through mTORC1 needs to be further explored.

.

Studies have shown that the antidepressant effect of R-ketamine is mediated by extracellular signal-regulated kinase (ERK) [20]
.

In addition, eukaryotic elongation factor 2 kinase (eEF2K) plays an important role in the elongation phase of protein synthesis
.

Monteggia et al.
speculate that eEF2K is involved in the antidepressant process mediated by ketamine, because in the mouse depression model of eEF2K knockout, ketamine has no antidepressant effect [21]
.

As we all know, mTORC1 regulates a variety of biological processes through the translation regulation of the eukaryotic initiation factor 4E-Bps (4E-Bps)
.

Aguilar-Valles et al.
reported that 4E-BPs are involved in the process of ketamine antidepressant [22]
.

In addition, ketamine can regulate the excitatory and inhibitory neuronal functions of the prefrontal cortex (PFC).
Recent studies have found that the rapid and sustained antidepressant-like effects of (R,S)-ketamine may be specific to PV inside the PFC.
The neuregulin-1 (NRG1) signaling pathway de-inhibits cortical nerve cells to exert its antidepressant effect [23].
However, the mechanism and function of neuregulin-1 and its signaling pathway in ketamine antidepressant need to be further confirmed
.

 5.
Brain-gut axis, brain-spleen axis and antidepressant In recent years, some studies have found that brain-gut-microbiota axis and brain-spleen axis participate in the mechanism of depression through the vagus nerve
.

The use of racemic ketamine and R-ketamine can improve the depressive phenotype caused by abnormal intestinal flora composition [24]
.

The spleen is a large immune organ.
When the spleen of the mouse is removed, the composition of the intestinal flora of the mouse becomes abnormal, and the spleen volume of the depression mouse model (CSDS mouse) increases.
R-ketamine treatment can make the CSDS mouse The weight of the spleen is reduced [25]
.

When the mouse subdiaphragmatic vagus nerve is removed, the injection of lipopolysaccharide can alleviate the depressive behavior of mice, reduce the volume of the spleen, and improve the intestinal microbiota [26]
.

In the biopsy specimens, it was also found that the brain BDNF level of depressed patients was positively correlated with the spleen BDNF level, while the colony stimulating factor 1 receptor (CSF1R) level was negative [27], which further suggests that the brain-spleen axis is more frequent.
It plays a regulatory role in a variety of mental illnesses (including depression)
.

The role of brain-gut-bacteria axis and brain-spleen axis in stress-related mental disorders and the benefits of R-ketamine treatment (picture quoted from: Wei, Y.
, Chang, L.
& Hashimoto, K.
Mol Psychiatry (2021)) Six.
Depression and other diseases.
R-ketamine also has a good effect on the cognitive impairment of non-depressive mental illness, which can improve such as schizophrenia, post-traumatic stress disorder (PTSD), and major depression ( MDD) and cognitive disorders such as bipolar disorder (BD), general anxiety disorder, obsessive-compulsive disorder, autism spectrum disorder, attention deficit hyperactivity disorder and panic disorder [28]
.

In the Parkinson's disease (PD) model, R-ketamine can reduce the neurotoxicity of MPTP to dopaminergic neurons in the substantia nigra of the midbrain [29]
.

R-ketamine can also improve the symptoms of osteoporosis by inhibiting the level of RANKL in plasma [30]
.

Continuous administration of R-ketamine in a DSS (dextran sodium sulfate)-induced inflammatory bowel disease (IBD) mouse model can significantly reduce inflammation and enteritis by activating the TrkB signaling pathway [31]
.

Administration of R-ketamine after middle cerebral artery occlusion in mice can effectively improve brain damage and behavioral dysfunction caused by ischemia, suggesting that R-ketamine may be used as a new treatment for ischemic stroke and post-stroke depression New treatment drugs [32]
.

The potential effect of R-ketamine on cognitive impairment in mental disorders and other diseases (picture quoted from: Wei, Y.
, Chang, L.
& Hashimoto, K.
Mol Psychiatry (2021)) Conclusions and prospects This review discusses (R , S)-ketamine (racemic ketamine) and its two enantiomers (R-, S-ketamine) are the main antidepressant mechanism, which emphasizes that R-ketamine is faster and more durable than S-ketamine.
Depressive effect, and its mechanism of action is not through the current mainstream NMDAR antagonism
.

Considering the pre-clinical stage studies of the two enantiomers of ketamine and the inability of non-ketamine NMDAR inhibitors to reproduce the same effects of racemic ketamine in patients with MDD, NMDAR is unlikely to be used in racemic ketamine and R-ketamine antidepressants Play an antidepressant effect, but the specific mechanism needs further research
.

At present, the main molecular mechanism and main targets of R-ketamine's antidepressant effect are still unclear.
Therefore, new technologies need to be used for further research to fully understand the molecular mechanism of R-ketamine's antidepressant effect and determine new targets for disease intervention and treatment.
Point
.

Some clinical studies on R-ketamine have found that R-ketamine has a strong antidepressant effect and a low adverse reaction rate
.

In addition, in addition to its antidepressant effect, R-ketamine may also be used in the future to treat BD, PTSD, cognitive impairment in mental illness, and diseases such as PD, osteoporosis, IBD, and stroke.
It has broad application prospects
.

Original link: https:// Dr.
Wei Yan (left), Professor Kenji Hashimoto (middle) and Dr.
Chang Lijia (right) (Image source: Kenji Hashimoto Lab ) Selected articles from previous issues [1] Long article by BRAIN︱Hu Hao laboratory reveals the molecular cause of cerebral palsy, which is actually a genetic disease [2] Breakthrough in Neuron︱ optical genetic technology! PPO can achieve rapid and reversible neuronal optogenetic inhibition operations [3] PNAS︱ He Shujun’s research group reveals a new mechanism for glial cells to provide time signals to regulate neuron development [4] PNAS︱ the network balance mechanism for the formation of rich cognitive functions in the brain [5] Cell︱ breakthrough! New mechanisms of human brain spatial navigation and memory: high-quality research training courses recommended for phase precession of hippocampus and entorhinal cortex [1] "Scientific Research Image Processing and Mapping" off-line: June 26-27 Shanghai; July 10-11, Beijing [2] Patch clamp and optogenetics and calcium imaging technology seminar (June 26-27, two days and one night) [3] Single-cell sequencing data analysis and project design network implementation Daoban (July 24-25) References (swipe up and down to view) [1] Zarate CA Jr.
, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al.
A randomized trial of an N- methyl-Daspartate antagonist in treatment-resistant major depression.
Arch Gen Psychiatry.
2006;63:856–64【2】Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, et al.
A randomized add- on trial of an N-methyl-Daspartate antagonist in treatment-resistant bipolar depression.