Unraveling the molecular mechanism of PTSD treatment

Experimental setup using PTSD mouse model. A) Auditory fear conditioning model, B) Single long-term stress model, and C) Schematic diagram of a single long-term stress applied to an animal. Credit: Institute for Basic Science

Post-traumatic stress disorder (PTSD) is a difficult mental health condition caused by experiencing traumatic events such as interpersonal violence and disasters. Patients with PTSD are present throughout human history and their condition has been observed in animals, but the diagnosis of this condition appeared only in the 1970s after the Vietnam War. Patients with PTSD are widely known to suffer from a variety of symptoms due to recurrent flashbacks, anxiety, and negative cognitive changes.

Currently, various treatment options such as antidepressants and cognitive-behavioral therapy are used to treat PTSD. Selective serotonin reuptake inhibitors (SSRIs) are the only class of antidepressants approved for the treatment of PTSD. However, the drug has the disadvantage of delayed action and is ineffective for some patients.

Cognitive-behavioral therapies such as desensitization and reprocessing (EMDR) of eye movements are also frequently used to treat PTSD. However, such horror extermination therapies are not effective in half of the patients. In addition, PTSD is notorious for recurrence of symptoms, even if treatment is successful. Such a recurrence of previously treated PTSD is called “spontaneous recovery” and has been the subject of much research.

Past studies have pointed out that the activity of glutamatergic neurons is an important part of the pathophysiology of PTSD. Of particular interest is the effect of the N-methyl-D-aspartate receptor (NMDAR) on these neurons. It is involved in the control of synaptic plasticity associated with learning. memory..

Unraveling the molecular mechanism of PTSD treatment

Experimental data for this study. A) Injection of NYX-783 prior to extinction therapy resulted in successful extinction of PTSD memory and impeded spontaneous recovery. Drug treatment is more effective in female mice, suggesting that males and females have different susceptibility to NMDAR modulators. B) When the activity of endogenous BDNF was blocked in the mouse brain using the antibody, PTSD memory spontaneously recovered even after successful extinction. When the activity of endogenous BDNF was blocked, mice injected with NYX-783 did not perform as well as mice injected with saline. Credit: Institute for Basic Science

To address the roots of PTSD, researchers at the Center for Cognitive Sociality within the Institute for Fundamental Sciences (IBS) worked with Yale University to investigate the molecular mechanisms of PTSD treatment. In their latest study, Molecular psychiatry, The IBS team tested a PTSD investigational drug called NYX-783 in mice to investigate the molecular mechanism of its action. NYX-783 is a newly discovered drug known to regulate the NMDAR function of neurons.

There are two established rodent models of PTSD: hearing fear conditioning (AFC) and single prolongation stress (SPS) models. Due to auditory fear conditioning, mice became accustomed to the environment and were exposed to a combination of tone and electric shock for fear conditioning to induce PTSD. To induce a single long-term stress, several mice were exposed to multiple stressors prior to fear conditioning to induce a single long-term stress. It should be noted that the stressful experience prior to fear conditioning is well known to cause additional difficulties in later PTSD treatment.

The mouse was then placed in a new environment and a series of amnesiac procedures were performed to remove traumatic memory. To enhance cognitive-behavioral therapy, researchers tested the performance of NYX-783 with ketamine, a known fast-acting antidepressant. It was found that injecting the drug into mice 1 hour before the horror extinction therapy had the highest treatment success rate.

After treatment, mice were monitored for freezing behavior when they heard the same sound to measure the level of fear they were experiencing. Mice injected with NYX-783 were found to work much better than mice injected. Ketamine Or saline control. This drug was particularly effective in controlling the spontaneous recovery or unwanted recurrence of PTSD. The drug behaved differently depending on the sex of the mice, and female mice responded more positively to treatment than male mice.

Unraveling the molecular mechanism of PTSD treatment

Estimated molecular mechanism of PTSD treatment. A) In normal mice, NYX-783 acts on the GluN2B subunit of the NMDA receptor in glutamatergic neurons, resulting in inhibition of BDNF upregulation and spontaneous recovery of PTSD. B) When GluN2B was knocked down in glutamatergic neurons, NYX-783 lost its effectiveness because there were no effective targets for the drug. C) When GluN2B is knocked down in GABAergic neurons, the degree of inhibition of glutamatergic neurons is reduced. More glutamate is released, postsynaptic pyramidal neurons are activated, and the baseline of spontaneous recovery is reduced. Credit: Institute for Basic Science

These experiments were repeated in combination with genetic engineering to explore the therapeutic mechanism. First, NYX-783 was found to suppress fear memory and suppress the spontaneous recovery of those memories by regulating NMDA receptors, especially by acting on the GluN2B subunit. To test this, researchers knocked down the GluN2B subunit of the NMDAR by manipulating the Grin2b gene using a viral vector. As expected, the efficacy of the drug was largely diminished when the receptor was knocked down on glutamatergic neurons in the medial prefrontal cortex. In particular, the Grin2b knockdown mutant showed spontaneous recovery even when injected with NYX-783.

On the other hand, drug performance was unaffected when the same receptor was knocked down in GABAergic interneurons. Interestingly, we found that simply knocking down the NMDA receptors in interneurons can reduce spontaneous recovery. The group believed that this was most likely by reducing the inhibitory effect of interneurons on the main neuron.

However, this does not completely rule out the possibility that NYX-783 may act on inhibitory interneurons. The authors state that “Grin2b knockdown in interneurons without NYX-783 indicates that freezing during spontaneous recovery is already low. Due to this floor effect, NYX-783 is GluN2B in glutamatergic neurons. The activity of the drug on glutamatergic neurons is thought to be more important for behavioral output, but further research may be needed to confirm this.

Finally, the team discovered it Brain-derived neurotrophic factor Very important for synaptic plasticity (BDNF) is required for memory disappearance. When the author used antibody therapy to suppress BDNF activity in the brain of mice, it blunted most of NYX-783’s effect on inhibiting spontaneous recovery.

Lee Boyoung, the corresponding author of the Center for Cognition and Sociality, commented: That the development of NMDAR modulators could be a viable strategy for treating PTSD. ”

Potential advances in the treatment of PTSD and PTSD-related cardiovascular disease

For more information:
Positive regulation of the N-methyl-D-aspartate receptor of mPFC reduces the spontaneous recovery of fear, Molecular psychiatry (2022).

Quote: Https: // unlocks the molecular mechanism of PTSD treatment obtained on April 13, 2022 (April 2022) The 13th)

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Unraveling the molecular mechanism of PTSD treatment

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