CN111658677B - Application of chemical genetics medicine composition in preparation of medicine for preventing and treating propofol addiction - Google Patents
Application of chemical genetics medicine composition in preparation of medicine for preventing and treating propofol addiction Download PDFInfo
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- CN111658677B CN111658677B CN202010512865.1A CN202010512865A CN111658677B CN 111658677 B CN111658677 B CN 111658677B CN 202010512865 A CN202010512865 A CN 202010512865A CN 111658677 B CN111658677 B CN 111658677B
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Abstract
The invention discloses application of a chemical genetics medicine composition in preparing a medicine for preventing and treating propofol addiction. The propofol addiction mainly relates to behavior sensitization and self administration of two classical addiction behaviors. The invention fully proves that the rats can generate addiction behaviors after long-term repeated use of propofol, which is mainly caused by excitation of neurons of the medial prefrontal cortex (mPF region) of the cortex; the utilization of the chemical genetic pharmaceutical composition can effectively inhibit the hyperphagic state of the mPF region caused by propofol, thereby inhibiting the addicted behavior of the propofol in rats. The chemical genetics medicine composition provided by the invention has the advantages of good effect, strong controllability and the like, and provides a new treatment medicine for treating, researching and developing propofol addiction prevention and treatment.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to application of a chemical genetic pharmaceutical composition in propofol addiction behaviors, and particularly relates to application of the chemical genetic pharmaceutical composition in preparation of a medicine for preventing and treating propofol addiction.
Background
Propofol is widely used in clinical anesthesia, painless outpatient clinic and tranquilization of ICU patients due to its advantages of quick action, quick elimination and no accumulation. With the widespread use of propofol, some of its potential problems have been increasingly appreciated: part of patients have pleasure, excitement and euphoria after use, and have potential mental dependence. Clinical investigation has found that propofol has mental dependence and certain abuse phenomena, and is mainly suitable for the mismanagement of propofol. Therefore, in recent years, propofol is listed in the control drug catalogue by the U.S. drug administration, but the management of propofol in China has not been regarded yet, and propofol has not been included in the catalog of narcotic drug varieties 2013 and the catalog of psychotropic drug varieties 2013. This lack of control provides a possibility for the abuse of propofol. In animal experiments, propofol has been shown to induce multiple addiction behavioral models, such as self-administration (SA), Conditioned Place Preference (CPP), and relapse models, indicating that propofol has some mental dependence.
Chemical genetic technology (Chemogenetic) is a process by which known biological macromolecules (e.g., various metabolic enzymes, nucleic acid hybrids, kinases, G-protein coupled receptors, etc.) are engineered to interact with unknown small molecule compounds. The application of the technology can artificially regulate and control the conversion of neuron and non-neuron signals in a certain specific cell, thereby controlling the behavior of animals, having controllability and reversibility, and being widely applied to the research of various brain diseases such as addiction, pain and the like.
At present, although the addictive behavior of propofol is studied, its intrinsic mechanisms and therapeutic approaches have not been extensively explored. Therefore, the patent explores a propofol addiction mechanism, proposes an assumption that a chemical genetic pharmaceutical composition modified by a chemical genetic technology is used for treating propofol addiction behaviors, and develops a safe and efficient pharmaceutical composition for inhibiting cortical neuron excitability, and the pharmaceutical composition has wide market value and application prospect.
Disclosure of Invention
The invention aims to solve the technical problem of providing an application of a chemical and genetic pharmaceutical composition in preparing a drug for preventing and treating propofol addiction. The chemical genetics medicine composition comprises adeno-associated virus carrying chemical genetics genes and a medicine azido flat-N-oxide solution (CNO) for activating the chemical genetics genes, and can be used for inhibiting the high excitation state of neurons of the medial prefrontal cortex (mPF C region) caused by propofol addiction. Wherein the optimum amount of adeno-associated virus in the chemical genetic pharmaceutical composition is 0.3 ul/side and CNO is 0.1 ug/side in rat model. The propofol addiction mainly relates to two classic addiction behaviors of behavior sensitization and self administration, namely the propofol addiction can be established by two classic addiction models, namely a behavior sensitization model and a self administration model. The pharmaceutical composition must be present at the same time to exert its prophylactic and therapeutic effects.
Through intensive research, the invention discovers that: two classical addiction behaviors (self-administration model and behavior sensitization model) fully prove that the addiction behavior can be generated after long-term use of the propofol, namely, the propofol has certain addiction. Simultaneously, electrophysiological detection is carried out on the cortical mPF area of the addicted and normal rats, and the generation of propofol addicted behaviors is found to be related to the increase of neuron excitability in the cortical mPF area for the first time; after the chemogenetic pharmaceutical composition is used for inhibiting the excitability of neurons in the mPF region, the behavior sensitization and the self-administration behavior of the propofol of the rat can be inhibited. Therefore, the cellular excitability change of the mPF region is considered to regulate the addicting behavior of propofol, and the chemical genetic pharmaceutical composition provided by the invention can regulate the cellular excitability of the mPF region. The adeno-associated virus carrying the chemical genetic gene has high safety and low immunogenicity, and the spontaneous activity and the like of the mPF region are not changed after the mPF region is subjected to positioning microinjection; the dose and concentration of CNO used simultaneously did not affect the spontaneous activity of the rats.
The invention is realized by the following technical scheme: after 3 weeks of expression, a rat propofol behavior sensitization and self-administration training is applied to prepare a rat propofol addiction model by microinjecting the adeno-associated virus in the pharmaceutical composition in a rat mPF region through a brain stereotaxic injection instrument, CNO is given to the rat brain after the model is successfully prepared to match the adeno-associated virus, and corresponding behavioral changes and related pharmacological research on the propofol addiction prevention and treatment effect of the chemical genetics pharmaceutical composition are monitored.
The invention has the beneficial technical effects that: the inhibitory chemical genetic pharmaceutical composition has obvious anti-propofol addiction effect, and the mechanism of the inhibitory chemical genetic pharmaceutical composition is mainly related to the inhibition of the excitability of neurons in the cortical mPF region; the pharmaceutical composition and the application thereof are safe and stable, have no toxicity to neurons, have high expression efficiency and obvious effect, can be used for preventing and treating propofol addiction, and have huge application prospects.
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FIG. 1 is a diagram showing the location and function verification of a chemical genetic pharmaceutical composition, wherein A is a representative diagram of the injection location of the chemical genetic pharmaceutical composition, B is a representative diagram of the function verification under patch clamp, and C is a statistical diagram of the result of the function verification.
FIG. 2 is a graph for verifying the effect of the chemical genetic pharmaceutical composition in a propofol behavior sensitization model, wherein A is a graph for comparing the moving distances of two groups of rats in behavior sensitization training, B and C are a representation graph and a result statistical graph for comparing the cellular excitability of mPF C regions of two groups of rats after behavior sensitization training, and D is a result statistical graph for the moving distances of the rats after the chemical genetic pharmaceutical composition is injected.
FIG. 3 is a graph for verifying the effect of the chemogenetic pharmaceutical composition on self-administration behavior, wherein A and B are the results of effective nasal contact times and pump injection times of two groups of rats in self-administration training, C and D are the results of comparison of cellular excitability of mPF C zone of two groups of rats after self-administration training and a statistical result graph, and E and F are the results of effective nasal contact times and pump injection times of each group of rats after the chemogenetic pharmaceutical composition is injected.
Detailed Description
In order to further illustrate the technical means adopted by the invention and the effects thereof, the invention is further explained with reference to the drawings and the embodiments, but the invention is not limited to the embodiments.
In order to detect the propofol addiction behavior, a self-administration model and a behavior sensitization model are established. In a self-administration model, the effective nasal contact times and the pump injection times are compared; in the behavioral sensitization model, we measure the distance of movement per unit time.
In order to detect the function and position of the chemical genetic pharmaceutical composition injected into the brain of the rat, the function of the chemical genetic pharmaceutical composition is detected by a patch clamp technology; the injection and transfection sites were also observed by fluorescence microscopy.
Example 1 construction and validation of a pharmaceutical composition for chemical genetics
The chemical genetics medicine composition provided by the invention consists of adeno-associated virus carrying chemical genetics genes and medicine CNO activating the chemical genetics genes, and the specific preparation and verification operations are as follows:
(1) constructing a virus: and constructing a chemical genetic gene, a green fluorescent gene and a nerve cell specific promoter on the pAAV virus to obtain pAAV-hSyn-hM4 Di-GFP.
(2) Transfection of virus and verification of its location: injecting the adeno-associated virus obtained in the step (1) into the mPF area of the SD rat by using a brain stereotaxic instrument, wherein the optimal amount of virus injection is 0.3ul per side mPF area. After injection of adeno-associated virus, neurons in the relevant brain region at the injection site are infected. The optimal time for infection was 3-4 weeks, and after 4 weeks, verification and soma location labeling were performed. The position was verified by making SD rat brain into brain slices containing mPFC regions with a thickness of 300um, observing the brain slices under a fluorescence microscope, and expressing green fluorescence if transfection was successful, as shown in fig. 1A.
(3) Verifying the function of the chemical genetics pharmaceutical composition: selecting cells expressing green fluorescence under a fluorescence microscope, clamping the cells under current clamp by using a whole-cell patch clamp technology, applying current stimulation to observe and record the condition of action potential emission. The perfusion system then administers the drug CNO which activates the chemogenetic genes, and the changes in the action potential delivery of the cells are observed and recorded. The virus carries an inhibitory chemical genetic group, and action potential of cortical neurons infected with the virus is reduced under the action of CNO. As shown in FIGS. 1B and C, it was revealed that the chemical genetic pharmaceutical composition functions normally and effectively inhibits excitability of cortical neurons. The CNO concentration used in the perfusion was 10 uM.
Example 2 Effect of a pharmaceutical composition in chemical genetics in a model of Propofol behavioral sensitization
The invention firstly detects the formation of sensitization behavior induced by long-term repeated injection of propofol, which is mainly related to the increase of excitability of neurons in a cortical mPF region. 17 healthy male SD rats of 7-8 weeks old are selected and divided into two groups of propofol group and normal saline control group, and are respectively given to the abdominal cavity for 7 days of propofol injection or normal saline injection. After the injection of propofol or physiological saline on the last day, the propofol or physiological saline is placed in an open field device to observe the sensitization behavior by detecting the movement distance, namely the spontaneous activity, in unit time. After the detection is finished, isoflurane is anesthetized, the NMDG liquid in an ice-water mixed state is used for perfusion to take brains, the rat brains are cut into coronal sections with the thickness of 300um in a concussion microtome, the brain sections containing the mPF area are collected to be incubated in a constant-temperature water bath kettle at 34 ℃ again, after incubation is carried out for 60 minutes, the rat brains are moved to a recording tank to detect the action potential distribution condition of the rat brains to compare the excitability of two groups of rat neurons, and the mixed gas containing 95% oxygen and 5% carbon dioxide is continuously introduced in the whole process to ensure the cell activity.
Secondly, the present invention finds that the formation of propofol sensitization can be inhibited by using a chemogenetic pharmaceutical composition. 28 healthy male SD rats of 7-8 weeks of age were injected with the site-specific mPF region in the brain with adeno-associated virus containing the chemical genetic genes, and the rats were randomly divided into 4 groups: the group of normal saline injected in the abdominal cavity + CNO injected in the brain (saline + CNO group, n ═ 5), the group of normal saline injected in the abdominal cavity + vehicle injected in the brain (saline + vehicle group, n ═ 5), the group of propofol injected in the abdominal cavity + CNO injected in the brain (propofol + CNO group, n ═ 9), and the group of propofol injected in the abdominal cavity + vehicle injected in the brain (propofol + vehicle group, n ═ 9). According to grouping requirements, after the rats are injected with propofol or physiological saline in the abdominal cavity and CNO or solvent control vehicle is administered intracerebrally, the effect of the chemogenetic pharmaceutical composition on the propofol sensitization behavior is observed by detecting the spontaneous activity. The injection amount of adeno-associated virus containing chemical genetic genes is 0.3ul per side mPF region. The CNO injection volume was 0.3ul per side mPF zone, containing 0.1ug CNO.
The results are shown in FIG. 2, which shows: propofol can remarkably increase the movement distance of a rat, namely, the propofol can successfully establish a behavior sensitization model and is related to the increase of excitability of neurons in a cortical mPF region; after the chemogenetic medicine composition is used for selectively inhibiting the excitation of neurons in the mPF region, the sensitization behavior can be inhibited.
Example 3 Effect of a pharmaceutical composition in chemical genetics on Propofol self-administration behavior
The invention firstly detects that the self-administration behavior of propofol can be successfully established by repeatedly injecting propofol for a long time, and is mainly related to the increase of excitability of neurons in a cortical mPF region. Selecting 16 healthy male SD rats with the age of 7-8 weeks, dividing the rats into two groups, namely a propofol group and a normal saline control group, carrying out external jugular vein catheterization operation on the rats, and recovering intravenous self-administration training of 14 days in behavior period after one week. In the training process, the computer automatically records the times of effective nasal touch and pumping of the rat so as to observe the self administration training condition. After training, isoflurane anesthesia and pouring by using NMDG liquid in an ice-water mixed state to take brains, cutting rat brains into coronal sections with the thickness of 300um in a concussion microtome, collecting the brains containing mPF areas, carrying out rewarming incubation in a constant-temperature water bath kettle at 34 ℃, moving the brains into a recording tank after incubation for 60 minutes to detect the action potential distribution condition of the brains so as to compare the excitability of two groups of rat neurons, and continuously introducing mixed gas containing 95% of oxygen and 5% of carbon dioxide in the whole process to ensure the cell activity.
Secondly, the invention finds that the self-administration behavior of propofol can be inhibited by utilizing a chemical genetic pharmaceutical composition. 26 healthy male SD rats of 7-8 weeks of age were injected with site-specific injection of adeno-associated virus containing chemical genetic genes (hM4Di-GFP virus) or control virus containing fluorescent groups only and no chemical genetic groups (GFP virus) into the mPF region in the brain, and the rats were randomly divided into 4 groups: (1) hM4Di + vehicle group: hM4Di-GFP virus is injected into the mPF region, and vehicle is injected into a drug administration tube 30min before training; (2) hM4Di + CNO group: hM4Di-GFP virus is injected into the mPF region, and CNO is injected into the administration tube 30min before training; (3) GFP + vehicle group: control virus is injected into the mPF area, and vehicle is injected into a drug administration tube 30min before training; (4) GFP + CNO group: control virus was injected in the mPFC region and CNO was injected in the administration tube 30min before training. After the rats are treated according to the grouping requirements, the effect of the chemical genetic pharmaceutical composition on the administration behavior of propofol per se is observed by detecting the change of the effective nasal contact and the pumping times of the rats. The injection amount of adeno-associated virus containing chemical genetic genes is 0.3ul per side mPF region. The CNO injection volume was 0.3ul per side mPF zone, containing 0.1ug CNO.
The results are shown in fig. 3, and show that propofol can successfully establish a self-administration model and is related to the increase of excitability of neurons in the cortical mPFC region; after the chemogenetic medicine composition is used for selectively inhibiting the excitation of neurons in the mPF region, the self-administration behavior can be inhibited.
The results show that the chemical genetic pharmaceutical composition can effectively inhibit the addiction behavior of propofol. The above embodiments are intended to illustrate rather than to limit the invention, and any modifications and variations of the present invention are within the spirit of the invention and the scope of the claims.
Claims (2)
1. The application of a chemical genetic pharmaceutical composition in preparing a medicine for treating propofol addiction is characterized in that the chemical genetic pharmaceutical composition comprises an adeno-associated virus carrying a chemical genetic gene of hM4Di and a medicine azido-N-oxide solution for activating the chemical genetic gene; the optimal amount of injection of the adeno-associated virus positioning mPF region is 0.3ul per lateral cerebrum, and the solution of the drug azidoping-N-oxide is 0.1ug per lateral cerebrum; the propofol addiction is a behavior sensitization addiction and a self-administration addiction, and the pharmaceutical composition can play a role in preventing and treating the propofol addiction by simultaneously existing.
2. The use of claim 1, wherein said treatment of propofol addiction is by use of a chemogenetic pharmaceutical composition for altering excitability of medial frontal lobe cortical neurons in rats.
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Citations (4)
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| WO2015079439A1 (en) * | 2013-11-26 | 2015-06-04 | Technion Research And Development Foundation Limited | Neuronal modulation |
| CN107929753A (en) * | 2017-11-24 | 2018-04-20 | 深圳先进技术研究院 | A kind of pharmaceutical composition and its application |
| CN108348528A (en) * | 2015-09-17 | 2018-07-31 | 科达生物治疗公司 | Treat the composition and method of neurological disorder |
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| WO2019113538A2 (en) * | 2017-12-07 | 2019-06-13 | California Institute Of Technology | Methods and systems for noninvasive control of brain cells and related vectors and compositions |
| CN108853509A (en) * | 2018-05-03 | 2018-11-23 | 浙江大学 | The treatment and pharmaceutical composition of depression |
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| WO2015079439A1 (en) * | 2013-11-26 | 2015-06-04 | Technion Research And Development Foundation Limited | Neuronal modulation |
| CN108348528A (en) * | 2015-09-17 | 2018-07-31 | 科达生物治疗公司 | Treat the composition and method of neurological disorder |
| CN107929753A (en) * | 2017-11-24 | 2018-04-20 | 深圳先进技术研究院 | A kind of pharmaceutical composition and its application |
| CN208902655U (en) * | 2018-09-27 | 2019-05-24 | 温州医科大学附属第二医院、温州医科大学附属育英儿童医院 | Concentration of propofol real time on-line monitoring device in a kind of anaesthesia patient exhaled gas |
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| Self-administration of propofol is mediated by dopamine D1 receptors in nucleus accumbens in rats;Q Lian等;《Neuroscience》;20121129;第231卷;373-383 * |
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