阅读说明：本技术 赛洛西宾抗创伤后应激障碍的医药用途 (Medical application of siloxibin in resisting post-traumatic stress disorder ) 是由 张黎明 姚宜山 李云峰 杜英杰 尹勇玉 代威 于 2021-08-16 设计创作，主要内容包括：本发明公开了赛洛西宾抗创伤后应激障碍的医药用途。赛洛西宾的使用量为0.5-5mg/kg。本发明的研究表明,在小鼠声音线索条件性恐惧行为学模型上,赛洛西宾可增强恐惧消退,显著降低僵住百分比,具有擦除恐惧记忆的作用,提示其具有抗PTSD效应,且起效迅速,作用持久。(The invention discloses a medical application of siloxibin in resisting post-traumatic stress disorder. The usage amount of the siloxibin is 0.5-5 mg/kg. The research of the invention shows that, on a mouse sound cue conditional fear behavioral model, the siloxibin can enhance fear regression, obviously reduce the percentage of catalepsy, has the function of erasing fear memory, and prompts that the compound has the anti-PTSD effect, and has quick response and lasting effect.)

1. Use of siloxibin in the manufacture of a medicament for the treatment of post-traumatic stress disorder.

2. Use of siloxibin according to claim 1 for the preparation of a medicament for the treatment of post-traumatic stress disorder, wherein the siloxibin has the effect of erasing fear memory.

3. Use of siloxibin according to claim 1 in the manufacture of a medicament for the treatment of post-traumatic stress disorder, wherein the amount of siloxibin used is 0.5-5 mg/kg.

Technical Field

The invention belongs to the technical field of post-traumatic stress disorder, and particularly relates to a medical application of siloxibin in resisting post-traumatic stress disorder.

Background

Post Traumatic Stress Disorder (PTSD) refers to a mental disorder that an individual presents with a delay after encountering an extraordinary threat or disaster and continues for a long time, and in recent years, with the continuous occurrence of serious natural disasters, serious epidemic diseases and sudden events worldwide, PTSD has become a serious disease that endangers human health.

At present, the first-line medicament for treating PTSD is an antidepressant represented by 5-HT reuptake inhibitors (SSRIs), only sertraline and paroxetine which are the SSRIs are approved by the FDA in the United states to be used for treating PTSD, unfortunately, the medicaments have the problems of low efficiency, delayed onset (more than 2-4 weeks) and serious adverse reaction, the clinical application of the medicaments is limited, and no anti-PTSD medicament is on the market at present. Siloxibin (psilocybin), also known as nudecoxidin, is a classical hallucinogen, and studies have demonstrated that the duration of hallucinogenic effect of siloxibin is 6-8h, so to rule out the effect of hallucinogenic effect of siloxibin on its fear of memory erasure, the study was initiated 24 hours after a single administration of siloxibin and performed a behavioral test.

Disclosure of Invention

The invention aims to provide a medical application of siloxibin in resisting post-traumatic stress disorder.

Use of siloxibin in the manufacture of a medicament for the treatment of post-traumatic stress disorder.

The siloxibin has the function of erasing fear memory.

The usage amount of the siloxibin is 0.5-5 mg/kg.

The invention has the beneficial effects that: the research of the invention shows that, on a mouse sound cue conditional fear behavioral model, the siloxibin can enhance fear regression, obviously reduce the percentage of catalepsy, has the function of erasing fear memory, and prompts that the compound has the anti-PTSD effect, and has quick response and lasting effect.

Drawings

Fig. 1 is a diagram of scene a.

Fig. 2 is a scene B object diagram.

FIG. 3 is a flow chart of the experimental operation.

Figure 4 is a graph of the effect on withdrawal tests 24h after administration of siloxibin; the results are shown in the figureRepresents;^##p<0.01vs.Control group；*p<0.05vs.Model group,(n＝10-14)。

FIG. 5 is the percent of stiffness in each group at day 7 post-dose; the results are shown in the figureRepresents;^###p<0.001vs.Control group；*p<0.05vs.Model group，(n＝10-14)。

FIG. 6 is the percent of stiffness in each group at day 8 post-dose; the results are shown in the figureRepresents;^###p<0.001vs.Control group；***p<0.001vs.Model group，(n＝10-14)。

Detailed Description

In order that the invention may be more fully understood, reference will now be made to the following description. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.

The following examples use experimental materials:

experimental animals: 8 weeks old C57BL/6 mice, male, SPF grade, initial body weight 20-25 g; purchased from sbefu (beijing) biotechnology limited, license number: SCXK (Jing) 2019-.

An experimental instrument: the system comprises a conditioned fear box (containing a scene box inside) and an automatic video recording device and analysis software.

Conditioned fear box: comprises an electric shock generator (capable of generating electric shocks of various intensities of 0.1-1.0 mA) and a sound generator (capable of generating broadband click sound or low-frequency sound) which are connected with the bottom grating floor and are connected with a computer.

A sound insulation box: a lamp, a small fan (for ventilation and background sound generation) and a loudspeaker in communication with a sound generator are provided.

Scene box:

scene A, made of transparent organic glass, the distance between the grid bars is short enough to prevent the animals from sliding under the grid. The condition box is typically 26cm by 21cm by 10 cm; the grid floor consisted of stainless steel strips (diameter 1.5mm, center-to-center spacing of 0.5cm) (fig. 1).

Scene B is made of organic glass with black and white alternated, and the bottom is a white bottom plate (figure 2).

Automatic video recording device and analysis software: the experimental animals were automatically recorded and analyzed for time to and number of stalls by the professional software Video Freeze.

In addition, there are also a voltmeter and a sound intensity meter for detecting the sound and the stimulation intensity of the electric shock.

Example 1

Conditioned fear of sound cues is a conditioned fear reflex established based on the baroreceptor reflex. The sound clues are used as Conditional Stimuli (CS), aversive stimuli (such as foot shocks) are used as Unconditional Stimuli (US), the conditional stimuli and the unconditional stimuli are paired, and after a plurality of times of CS-US training, the animal learns that the sound is related to the shock. The conditioned fear reflex is a highly conservative associative learning behavior form, and a great deal of research shows that the stiffness (sleeping), namely one of animal defense behaviors, means that an animal does not have any other activities except breathing and becomes motionless, and the conditioned fear reflex is a reliable index for evaluating the fear memory of the rodent. The model is widely applied to the screening of PTSD drugs at present.

The animals were acclimated for 1 week, and were grabbed daily, after which the official experiment was started, with the operational flow shown in figure 3.

Molding: animals were allowed to acclimate to the test room for 1 hour before starting the experiment. The scene used for molding is scene a. Mice were placed in a conditioned fear box for 2min, after which each mouse would receive 5 sound (conditioned stimulus, CS) -shock (unconditioned stimulus, US) pairs of sound and non-evasive plantar shocks. The specific parameters of each CS-US are as follows: the sound lasted 30s (5000Hz, 80dB), followed by a non-evasive foot shock transmitted by the stainless steel fence at the last 2s of the sound (current: 0.8mA, duration: 2s), with an interval (ITI) of 2min per CS-US, repeated 5 times. The Control group (Control group, given physiological saline) was identical to the model group and the administration group except that the sole electric shock was not caused. After each mouse was trained, the faeces were cleaned and the stainless steel fences and trays were wiped with 30% alcohol (environment a) to avoid the smell affecting the fear memory of subsequent mice.

Dosing and withdrawal training: dividing the test period into 2 days, and respectively administering physiological saline (Model group) on the 3 rd day after the Model is manufactured after the electric shock training; the administration mode of the siloxibin administration group (PSY group, 0.1, 0.5 and 2.5mg/Kg) is intraperitoneal injection, and the administration volume is 10 ml/Kg. The first withdrawal training was performed 1h after the intraperitoneal administration. Mice first entered scene B for 2 minutes of acclimation, after which 30s of CS administration was started, with sound parameters identical to those of the first day of modelling, except that the last 2s of sound was no longer accompanied by US, and 30s of sound was followed by 15 repetitions of 30 sscs +30 sITI.

The test regressed again on day 4 after molding, and the procedure was exactly the same as on day three except that no dosing was required.

Spontaneous recovery test: on day 4 after dosing, the test was performed in scene B.

Mice were placed in scene B, acclimated for 2min, followed by 4 CS onsets without shock stimulation with an ITI of 30s, i.e. (30 sscs +30sITI), repeated 5 times.

Fear update test: and performing fear updating test 24h after the spontaneous recovery test is completed, wherein the scene is A, and the rest is the same as the spontaneous recovery test.

Detection indexes are as follows: the recorded data were analyzed by a software analysis system, and the evaluation index was percent catalepsy (%) -time of catalepsy (s)/total time(s) × 100%. Percent catalepsy was calculated within each event and conditioned fear was assessed.

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Data statistics processing: results are expressed as x + -SEM and Student's t test analysis was performed on Control group vs. Model group and one-way anova was performed on Model group vs. each dose PSY group using GraphPad-Prism 8 statistical software.

The experimental results are as follows:

1) resolution test 24h after administration of siloxibin

On day 1 after the administration of siloxibin, when a regression test was performed, the results showed that the percent catalepsy was significantly increased (p <0.01) compared to the control group and the model, indicating that the model was successfully prepared; the 2.5mg/kg dose of siloxibin significantly reduced the percent catalepsy (p <0.05) compared to the Model group, suggesting that siloxibin has a rapid memory-off effect (figure 4).

2) Fear renewal test percentage of catalepsy 7 days after administration of siloxib

The results show that: on the 7 th day after the administration of the siroxibin, when the fear renewal test is carried out by using the scene A, compared with the model, the catalepsy percentage of the control group is obviously increased (p is less than 0.001), and the model is prompted to be effective; the 2.5mg/kg dose of siloxibin group significantly reduced the percent catalepsy (p <0.05) compared to the Model group, suggesting that the siloxibin had a long-lasting effect in erasing fear memory in the fear renewal test index (fig. 5).

3) Fear spontaneous recovery test percent catalepsy at day 8 post-administration of siloxib

The results show that: on the 8 th day after the administration of the siroxibin, when the scene B is used for the fear spontaneous recovery test, compared with the control group and the model, the catalepsy percentage is obviously increased (p is less than 0.001), and the model is prompted to be effective; the 2.5mg/kg siloxibin group significantly reduced the percentage of catalepsy (p <0.001) compared to the Model group, suggesting that the siloxibin has a lasting effect of erasing the fear memory in terms of the indicators of spontaneous recovery of fear (fig. 6).

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.