Application of combined adenosine A1 receptor stimulant and dopamine D2 receptor stimulant in preparation of medicine or food for preventing oxygen poisoning of central nervous system

Abstract

The invention relates to the technical field of medicines, in particular to application of combination of an adenosine A1 receptor stimulant and a dopamine D2 receptor stimulant in preparation of a medicine or food for preventing oxygen poisoning of a central nervous system. The invention provides a new application of a combined adenosine A1 receptor stimulant and a dopamine D2 receptor stimulant. Animal experiments prove that the combined adenosine A1 receptor stimulant CCPA and the dopamine D2 receptor stimulant bromocriptine can effectively delay the oxygen poisoning phenomenon of a central nervous system. Compared with the traditional method for preventing oxygen only by strictly limiting the pressure and time of oxygen inhalation, the method provided by the invention can be used for inhaling oxygen for a longer time under higher pressure, so that the application of hyperbaric oxygen in diving and hyperbaric medicine is further expanded.

Description

Technical Field

[0001] The invention relates to the field of medical technology, in particular to the application of a combined adenosine A1 receptor agonist and a dopamine D2 receptor agonist in the preparation of a medicine or food for preventing central nervous system oxygen poisoning. Background Art

[0002] In the central nervous system, adenosine is a substance with multiple activities. It mainly exerts neuromodulatory effects through different receptors distributed on the cell membranes of various nerve cells. Adenosine A1 receptor is the most important receptor for adenosine, and has a very high affinity with adenosine. When adenosine is at a low concentration, it can produce effects through A1 receptors. A1 receptors are widely distributed in various areas of the brain, and are concentrated in the excitatory nerve endings. They are distributed on both the presynaptic and postsynaptic membranes, and mainly play a central inhibitory function to control the excessive release of excitatory neurotransmitters (Edward Beamer, Manvitha Kuchukulla, Detlev Boison, Tobias Engel. ATP and adenosine-Two players in the control of seizures and epilepsy development. Prog Neurobiol, 2021, 204: 102105. Doi: 10.1016 / j.pneurobio.2021.102105.).

[0003] Dopamine is also a very important neurotransmitter in the brain, participating in a variety of physiological and pathological processes of the body. It can participate in the regulation of the body's motor function through two types of receptors, D1 and D2, specifically by regulating the excitatory neurotransmitter glutamate and the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in the neural circuit to which it belongs, to maintain normal neuromuscular activity. Studies have shown that dopamine is an important neuromodulator in the cortex-basal ganglia-thalamus-cortex neural circuit, and the threshold of epileptic seizures is regulated by it to a certain extent. D2 receptors are coupled to intracellular inhibitory G proteins (Gi), which can inhibit adenylate cyclase and activate K +channel; dopamine can exert anti-epileptic effects through D2 receptors. In addition, D2 receptor stimulation can antagonize excitatory neurotoxicity caused by glutamate and muscarinic, reducing the incidence of epilepsy; D2 receptor blocking can lower the threshold of epileptic seizures and induce epilepsy (Gao Min, Zhang Jingjun. Research on the relationship between dopamine and epilepsy. Chinese Journal of Brain Diseases and Rehabilitation, 2017, 7(2): 83-86; J Vuong, Annaelle Devergnas. The role of the basal ganglia in the control of seizure. J Neural Transm, 2018, 125(3): 531-545. Doi: 10.1007 / s00702-017-1768-x.; Yuri Bozzi, Emiliana Borrelli. The role of dopamine signaling in epileptogenesis. Front Cell Neurosci,2013,7:157.Doi:10.3389 / fncel.2013.00157.).

[0004] In the brain, adenosine and dopamine are closely connected. Adenosine receptors and dopamine receptors coexist on the nerve cell membrane in the form of heterodimers, and are coupled to different intracellular G protein receptors, respectively, and then play opposite regulatory roles on intracellular adenylate cyclase (AC) and subsequent signal transduction molecules such as protein kinase A (PKA), thus forming a mutually antagonistic coexistence relationship. Among them, the adenosine A1 receptor coupled to the intracellular inhibitory G protein (Gi) and the dopamine D1 receptor coupled to the excitatory G protein (Gs) form a dimer; the adenosine A2 receptor coupled to Gs and the dopamine D2 receptor of Gi form a dimer. Through their synergistic cooperation, they jointly maintain normal neural activity (Sun Wanchun, Zhu Xingzu. Dimerization of dopamine and adenosine receptors in basal ganglia and their pharmacological significance. Life Science, 2004: 193-199. Fuxe K, et al. Adenosine-dopamine interactions in the pathophysiology and treatment of CNS disorders. CNS Neuroscience & Therapeutics, 2010, 16: e18-e42.). Therefore, activating A1 receptors and D2 receptors can produce the effect of inhibiting intracellular signal pathways, and activating A2 receptors and D1 receptors can produce the effect of exciting intracellular signal pathways. Based on the coexistence of A1 receptors and D1 receptors, the coexistence of A2 receptors and D2 receptors, and the opposite effects after activating different receptors, for different purposes of use, the agonists and antagonists of these two types of receptors can be combined to produce a synergistic effect and achieve twice the result with half the effort.

[0005] Since A1 receptors coexist with D1 receptors, A2 receptors coexist with D2 receptors, and activation of different receptors may produce opposite effects, therefore, interventions on the two types of receptors cannot be combined arbitrarily. It is necessary to combine their regulatory effects and selectively intervene simultaneously to achieve beneficial results; otherwise, the established goals cannot be achieved, and it may even have the opposite effect. For example, by antagonizing A2A receptors, the regulatory function of D2 receptors is released, which is a hot topic in recent years in the prevention and treatment of neurodegenerative diseases directly affected by dopamine (Pinna A, et al. Role of adenosine A(2A) receptors in motor control: relevance to Parkinson's disease and dyskinesia. Journal of Neural Transmission, 2018, 125: 1273-1286. Ferre S, et al. Essential control of the function of the striatopallidal neuron by pre-coupled complexes of adenosine A(2A)-dopamine D(2) receptor heterotetramers and adenylyl cyclase. Frontiers in Pharmacology, 2018, 9: 243.). If D2 receptors are antagonized at the same time as A2A receptors, the effect of antagonizing A2A will be offset. On the other hand, if both A2A receptors are stimulated and D2 receptors are antagonized at the same time, more serious damaging consequences may occur.

[0006] Adenosine A1 receptor agonist CCPA (English name: 2-chloro-N 6 -cyclopentyladenosine; Chinese name: 2-chloro-N 6 -Cyclopentyl adenosine; CAS registration number: 37739-05-2) is a potent and highly selective adenosine A1 receptor agonist, and its molecular structure is shown below:

[0007]

[0008] Dopamine D2 receptor agonist bromocriptine (English name: Bromocriptine mesylate; CAS registration number: 22260-51-1) is a potent and highly selective dopamine D2 receptor agonist. Its molecular structure is shown below:

[0009]

[0010] So far, there has been no research report on the combined use of CCPA and bromocriptine.

[0011] Central nervous system oxygen poisoning refers to the toxic effects on the central nervous system of the body after the body inhales oxygen above a certain pressure for a certain period of time. It mainly occurs in military and civilian diving, high-pressure operations, and the use of hyperbaric oxygen to treat diseases. When the body inhales gas with an oxygen partial pressure exceeding 280kPa (equivalent to 18 meters deep), toxic reactions will occur in a relatively short period of time, and as the pressure increases, the incubation period of the attack will be further shortened. During an attack, the most violent reaction is a systemic convulsion, called oxygen convulsion, which seriously threatens the life safety of personnel breathing hyperbaric oxygen and greatly limits the efficiency of diving and hyperbaric operations. At present, there is a lack of active and effective prevention measures for central nervous system oxygen poisoning, mainly passively limiting the pressure and duration of oxygen inhalation, such as intermittent oxygen inhalation. Finding measures that can actively prevent oxygen convulsions so as to achieve safe use of oxygen at higher pressures (greater depths) is of great significance for diving, hyperbaric operations, and hyperbaric oxygen therapy. (Reference: Xu Weigang. Diving Medicine. Beijing, Science Press, 2016:145-154).

[0012] To date, there is no recognized drug to prevent CNS oxygen toxicity.

[0013] The inventor has long been committed to the research on oxygen poisoning of the central nervous system. In the patent document with Chinese patent application number: CN201210157924.3, publication number: CN102697798A, invention name: Use of adenosine (ADO) in preparing drugs or foods for preventing oxygen poisoning of the central nervous system, the inventor verified through animal (BALB / C mice, male) experiments that adenosine can effectively prevent the occurrence of oxygen poisoning of the central nervous system, and disclosed the use of adenosine in preparing drugs or foods for preventing oxygen poisoning of the central nervous system. In the patent document of Chinese patent application number: CN201610980086.8, patent number: ZL201610980086.8, invention name: Combination of adenosine and nNOS inhibitors to prevent central nervous system oxygen poisoning, the inventor verified through animal (Sprague-Dawley rats, male) experiments that the combination of adenosine and nNOS inhibitor 7-nitroindazole can effectively delay the occurrence of central nervous system oxygen poisoning.

[0014] Since the occurrence of central nervous system oxygen poisoning involves multiple different cell signaling pathways, the use of combined response measures targeting different targets and pathways may be superior to single preventive measures and may even produce a 1+1>2 effect.

[0015] The technical field has been searching for drugs that can prevent the occurrence of oxygen toxicity in the central nervous system. Summary of the invention

[0016] The purpose of the present invention is to solve the problem of the lack of effective measures that can actively prevent oxygen poisoning of the central nervous system. Based on the original work of the inventor, in the present invention, a substance that has an inhibitory effect on oxygen poisoning of the central nervous system, adenosine A1 receptor agonist, and a substance that has an inhibitory effect on central excitatory neurotoxicity, dopamine D2 receptor agonist, are simultaneously used to find a more powerful measure to prevent oxygen poisoning of the central nervous system through a multi-target joint intervention method.

[0017] The first aspect of the present invention provides the use of an adenosine A1 receptor agonist in combination with a dopamine D2 receptor agonist in the preparation of a drug or food for preventing oxygen poisoning of the central nervous system.

[0018] Adenosine can exert a central inhibitory effect by binding to the A1 receptor, and adenosine A1 receptor agonists have the effect of counteracting central nervous system oxygen toxicity attacks. Changes in dopamine content in the brain are closely related to central nervous system oxygen toxicity attacks. Dopamine can exert a central inhibitory effect by binding to the D2 receptor, and dopamine D2 receptor agonists have the effect of counteracting epileptic seizures. The combined use of adenosine A1 receptor agonists and dopamine D2 receptor agonists may produce a more effective effect of counteracting central nervous system oxygen toxicity.

[0019] Preferably, the adenosine A1 receptor agonist is selected from CCPA (2-chloro-N 6 -cyclopentyladenosine, 2-chloro-N 6 -cyclopentyl adenosine), CPA(N 6 -cyclopentyl adenosine), 2'-MeCCPA, S(–)ENBA, (±)-5'-Chloro-5'-deoxy-ENBA, SDZ WAG 994, CVT510, ADCAC, etc., one or two or more thereof; CCPA is more preferred.

[0020] Preferably, the dopamine D2 receptor agonist is selected from one or two or more of Bromocriptine mesylate, Sumanirole maleate (1-CBZ-3-piperidinecarboxaldehyde; alias: (R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]quinoline-2(1H)-one maleate), Quinelorane hydrochloride, Cabergoline, (-)-Quinpirole hydrochloride, Ropinirole, Aripiprazole, etc.; more preferably Bromocriptine.

[0021] The present invention selects to combine CCPA and bromocriptine for animal experiments. The experimental results show that low-dose CCPA or bromocriptine has no effect of delaying the occurrence of oxygen convulsions, but after their combined use, they can significantly resist the occurrence of oxygen convulsions, with an effect of 1+1>2.

[0022] Preferably, the drug or food for preventing oxygen poisoning of the central nervous system is used to prevent oxygen convulsions caused by oxygen poisoning of the central nervous system. The present invention verifies through animal experiments that the combination of CCPA and bromocriptine can effectively prevent oxygen poisoning of the central nervous system, especially the occurrence of oxygen convulsions.

[0023] Preferably, the drug has CCPA and bromocriptine as active ingredients, or is a pharmaceutical composition comprising CCPA and bromocriptine.

[0024] Preferably, in the pharmaceutical composition, the dosage of CCPA is 2.5-20 μg, and the dosage of bromocriptine is 2.5-10 μg. Within the above range, the dosages of the two can be arbitrarily matched. For example, the dosage of CCPA can be formulated as 2.5 μg, 3 μg, 4 μg, 5 μg, 10 μg, 20 μg or any other point value within the above range; the dosage of bromocriptine can be formulated as 2.5 μg, 3 μg, 4 μg, 5 μg, 10 μg or any other point value within the above range.

[0025] The dosage refers to the dosage in rats, and the rat weight is calculated based on 250g, that is, the dosage of CCPA is 2.5-20μg / 250g wt, and the dosage of bromocriptine is 2.5-10μg / 250g wt. This dosage is for one-time use. If converted to other animal species, it needs to be adjusted according to pharmacological regulations, body weight, and purpose of use.

[0026] Further preferably, based on the consideration of minimizing the dosage of the drug while achieving the best drug efficacy, the dosages of CCPA and bromocriptine in the pharmaceutical composition are CCPA 2.5-5 μg and bromocriptine 2.5-5 μg, respectively.

[0027] Preferably, the drug also includes commonly used pharmaceutical excipients. The pharmaceutical excipients are one or more of diluents, excipients, adhesives, fillers, disintegrants, flavoring agents, and sweeteners. The drug is in the form of an oral preparation or an injection.

[0028] Preferably, the food is a daily food containing CCPA and bromocriptine. The food is in a solid or liquid state. The food can also be used as a health food.

[0029] The second aspect of the present invention provides a drug for preventing oxygen poisoning of the central nervous system, wherein the drug is a pharmaceutical composition with CCPA and bromocriptine as active ingredients, or a pharmaceutical composition comprising CCPA and bromocriptine.

[0030] The medicine also includes commonly used pharmaceutical excipients. The pharmaceutical excipients are one or more of diluents, excipients, adhesives, fillers, disintegrants, flavoring agents, and sweeteners. The dosage form of the medicine is oral or injection.

[0031] The third aspect of the present invention provides a food for preventing oxygen poisoning of the central nervous system, wherein the food is prepared by adding CCPA and bromocriptine to daily food. The food is in a solid or liquid state. The food can also be used as a health food.

[0032] The advantages of the present invention are:

[0033] 1. The present invention provides a new use of CCPA and bromocriptine: the use in the preparation of drugs or foods for preventing oxygen poisoning of the central nervous system solves the problem of the current lack of effective measures that can actively prevent oxygen poisoning of the central nervous system. The present invention proves through animal experiments that the combination of CCPA and bromocriptine can effectively delay the occurrence of oxygen poisoning of the central nervous system. Compared with the traditional method of prevention by strictly limiting the pressure and time of oxygen inhalation, the method of the present invention can inhale oxygen at a higher pressure and for a longer time, thereby further expanding the use of hyperbaric oxygen in diving and hyperbaric medicine.

[0034] 2. When CCPA and bromocriptine are used together, a stronger effect of preventing oxygen poisoning can be achieved while reducing the dosage of the drugs, achieving a prevention effect of 1+1>2, proving that the two have a synergistic effect;

[0035] 3. Compared with the use of either substance alone, combined use can effectively prevent the occurrence of central nervous system oxygen poisoning. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 Comparison of the latency of central nervous system oxygen toxicity seizures in rats treated with different dose combinations of CCPA and bromocriptine.

[0037] Figure 2 This is a comparison of the latency of central nervous system oxygen poisoning convulsions in rats treated with 5μg CCPA or 5μg bromocriptine alone, or with a combination of 5μg CCPA and 5μg bromocriptine.

[0038] Figure 3 This is a comparison of the latency of central nervous system oxygen poisoning convulsions in rats treated with 2.5μg CCPA or 2.5μg bromocriptine alone, or with a combination of 2.5μg CCPA and 2.5μg bromocriptine.

[0039] Figure 4 To compare the latency of central nervous system oxygen poisoning seizures in rats treated with 20μg CCPA or 10μg bromocriptine alone, or with a combination of 20μg CCPA and 10μg bromocriptine. DETAILED DESCRIPTION

[0040] The following embodiments of the present invention are described in detail with reference to the accompanying drawings. The following embodiments are implemented based on the technical solution of the present invention and provide detailed implementation methods, but the protection scope of the present invention is not limited to the following embodiments. The following reagents are commercially available unless otherwise specified.

[0041] Experimental data description: The latency of oxygen convulsion in rats was recorded in the experiment. If convulsion did not occur at 60 minutes of hyperbaric oxygen exposure, the latency was recorded as 60 minutes. The experimental results were statistically analyzed using the Kaplan-Meier method and the Log-rank test was used for comparison of samples among multiple groups, and GraphPad Prism 8.0 software was used for graphical presentation.

[0042] Example 1 Effects of different doses of CCPA and bromocriptine on the convulsion latency of rats

[0043] (1) Preparation of injection solution

[0044] 1.1) Prepare 20% DMSO artificial cerebrospinal fluid

[0045] Artificial cerebrospinal fluid (ACSF) was purchased from Kingclone (Beijing) Biotechnology Co., Ltd.

[0046] Dimethyl sulfoxide (DMSO) was purchased from Sinopharm Chemical Reagent Co., Ltd. with a purity of >99%.

[0047] Take 0.4 mL of pure DMSO, add 1.6 mL of artificial cerebrospinal fluid, shake and mix well.

[0048] 1.2) Prepare 60% DMSO artificial cerebrospinal fluid

[0049] Take 3 mL of pure DMSO, add 2 mL of artificial cerebrospinal fluid, shake and mix well.

[0050] 1.3) Prepare 4 mg / mL CCPA solution

[0051] CCPA was purchased from Sigma-Aldrich with a purity of >98%.

[0052] Accurately weigh 8 mg of CCPA and add it to 2 mL of 20% DMSO artificial cerebrospinal fluid prepared in step 1.1. Vortex and mix to completely dissolve CCPA to prepare a 4 mg / mL CCPA solution.

[0053] 1.4) Prepare 1 mg / mL CCPA solution

[0054] Take 1 mL of the 4 mg / mL CCPA solution prepared in step 1.3, add 3 mL of 20% DMSO artificial cerebrospinal fluid, and vortex to mix to make a 1 mg / mL CCPA solution.

[0055] 1.5) Prepare 2 mg / mL bromocriptine solution

[0056] Bromocriptine was purchased from Tocris Bioscience with a purity of >98%.

[0057] Accurately weigh 10 mg of bromocriptine and add it to 5 mL of 60% DMSO artificial cerebrospinal fluid prepared in step 1.2. Vortex and mix to completely dissolve the bromocriptine to prepare a 2 mg / mL bromocriptine solution.

[0058] 1.6) Prepare 1 mg / mL bromocriptine solution

[0059] Take 1 mL of the 2 mg / mL bromocriptine solution prepared in step 1.5, add 1 mL of 60% DMSO artificial cerebrospinal fluid, and vortex to mix to prepare a 1 mg / mL bromocriptine solution.

[0060] (2) Comparative study on the effects of combined CCPA and bromocriptine on the latency of oxygen seizures in rats

[0061] Twenty male Sprague-Dawley (SD) rats, weighing 250±10 g, were obtained from Shanghai Xipu-Bikai Experimental Animal Co., Ltd. They were randomly divided into 4 groups, namely, solvent control group, 2.5μg CCPA+2.5μg bromocriptine group, 5μg CCPA+5μg bromocriptine group, and 20μg CCPA+10μg bromocriptine group. There were 5 rats in each group.

[0062] 2.1) After the rats were anesthetized by intraperitoneal injection of 3% pentobarbital, they were fixed on a brain stereotaxic instrument. The top of the head was kept horizontal, the hair was removed, and the skin was disinfected with 75% alcohol cotton balls. The skin on the top of the head was cut along the anterior midline, the subcutaneous tissue was separated, the periosteum was peeled off and scraped, and the anterior fontanelle was exposed. The injection point of the lateral ventricle was taken 2mm behind the anterior fontanelle and 1.5mm to the right of the midline. A small hole with a diameter of 0.5mm was drilled at this point with a skull drill. The lateral ventricle injection outer tube fixed to the vertical arm of the lateral ventricle locator was inserted into this hole with a depth of 2mm. It was fixed to the skull with dental cement and the skin was sutured. All the processes were performed aseptically. The rats were kept after the operation.

[0063] 2.2) Three days after the catheter implantation surgery, the rats were placed on an animal anesthesia machine and anesthetized with isoflurane, and then a sterile microsyringe was used to inject the control solvent or the test drug into the cerebral ventricle through the pre-placed catheter at a rate of 1 μL / min.

[0064] The solvent control group was injected with 10 μL of 60% DMSO artificial cerebrospinal fluid.

[0065] In the 2.5μg CCPA+2.5μg bromocriptine experimental group, 2.5μL of 1mg / mL CCPA solution was injected first, and then 2.5μL of 1mg / mL bromocriptine solution was injected.

[0066] In the 5μg CCPA+5μg bromocriptine experimental group, 5μL of 1mg / mL CCPA solution was injected first, and then 5μL of 1mg / mL bromocriptine solution was injected.

[0067] In the 20 μg CCPA+10 μg bromocriptine experimental group, 5 μL of 4 mg / mL CCPA solution was first injected, followed by 5 μL of 2 mg / mL bromocriptine solution.

[0068] 2.3) 30 minutes after the intraventricular injection, when the rats are fully awake, each group of rats is placed in a pressurized chamber, one rat at a time. The air in the chamber is replaced with pure oxygen. When the oxygen meter shows that the oxygen concentration in the chamber reaches 99% or above, the chamber is pressurized at a rate of 1 ATA / min to 6 ATA. The pressure is kept stable and the behavioral changes of the rats are closely observed. When the rats show neck stiffness, opisthotonos and other symptoms, it indicates that a major seizure has occurred. (This standard is a recognized behavioral standard for judging central nervous system oxygen poisoning attacks at home and abroad. Reference: Domachevsky L, Rachmany L, Barak Y, Rubovitch V, Abramovich A, Pick CG. Hyperbaric oxygen-induced seizures cause a transient decrement in cognitive function. Neuroscience, 2013, 247: 328-34.) The time from the time when the chamber pressure reaches 6 ATA to the occurrence of a major seizure is recorded as the oxygen seizure latency. After the rat had its first major seizure, the pressure in the chamber was reduced at a rate of 1 ATA / min until the pressure in the chamber returned to normal atmospheric pressure. Figure 1 .

[0069] Figure 1 The results showed that during the 60-minute hyperbaric oxygen exposure, rats in the solvent control group all had convulsions. The convulsion latency of rats in the experimental groups of 2.5μg CCPA+2.5μg bromocriptine, 5μg CCPA+5μg bromocriptine, and 20μg CCPA+10μg bromocriptine was significantly prolonged, which was significantly different from the latency of the control group, and there was no significant difference between the different dose combination groups. This shows that CCPA and bromocriptine can effectively fight convulsions induced by hyperbaric oxygen exposure when used in combination within a certain dose range.

[0070] The above animal experiments show that the combined use of CCPA and bromocriptine, after direct central administration, can significantly prolong the latency period of convulsive seizures caused by hyperbaric oxygen exposure, and the preventive effect of the combined application is significantly better than the effect of using CCPA or bromocriptine alone, and has a very good synergistic effect, and can be used to prepare drugs or foods for preventing oxygen poisoning of the central nervous system.

[0071] Example 2 Effects of 2.5 μg CCPA and 2.5 μg bromocriptine alone and in combination on oxygen convulsions in rats

[0072] According to the method shown in Example 1, rats in the control group were injected with 10 μL of 60% DMSO artificial cerebrospinal fluid through the lateral ventricle; rats in the CCPA experimental group were injected with 2.5 μL of 1 mg / mL CCPA solution; rats in the bromocriptine experimental group were injected with 2.5 μL of 1 mg / mL bromocriptine solution; the 2.5 μg CCPA+2.5 μg bromocriptine experimental group was first injected with 2.5 μL of 1 mg / mL CCPA solution, and then injected with 2.5 μL of 1 mg / mL bromocriptine solution. There were 5 rats in each group. After the injection, the rats were fully awake, exposed to hyperbaric oxygen, and the convulsion latency was recorded. The experimental results are as follows: Figure 2 .

[0073] Figure 2 The results showed that compared with the solvent control group, the use of 2.5 μg CCPA or 2.5 μg bromocriptine alone had no significant effect on seizures, and could not delay, counteract or trigger oxygen seizures. However, the combination of 2.5 μg CCPA and 2.5 μg bromocriptine could significantly delay oxygen seizures.

[0074] Example 3 Effects of 5 μg CCPA and 5 μg bromocriptine alone and in combination on oxygen convulsions in rats

[0075] According to the method shown in Example 1, rats in the control group were injected with 10 μL of 60% DMSO artificial cerebrospinal fluid through the lateral ventricle; rats in the CCPA experimental group were injected with 5 μL of 1 mg / mL CCPA solution; rats in the bromocriptine experimental group were injected with 5 μL of 1 mg / mL bromocriptine solution; the 5 μg CCPA+5 μg bromocriptine experimental group was first injected with 5 μL of 1 mg / mL CCPA solution, and then injected with 5 μL of 1 mg / mL bromocriptine solution. There were 5 rats in each group. After the injection, the rats were fully awake, exposed to hyperbaric oxygen, and the convulsion latency was recorded. The experimental results are as follows: Figure 3 .

[0076] Figure 3 The results showed that compared with the solvent control group, the use of 5μg CCPA or 5μg bromocriptine alone had no significant effect on convulsions, and could not delay, counteract or induce oxygen convulsions. However, the combination of 5μg CCPA and 5μg bromocriptine could significantly counteract oxygen convulsions, and no convulsions occurred in the experimental rats during the 60-minute hyperbaric oxygen exposure.

[0077] Example 4 Effects of 20 μg CCPA and 10 μg bromocriptine alone and in combination on oxygen convulsions in rats

[0078] According to the method shown in Example 1, rats in the control group were injected with 10 μL of 60% DMSO artificial cerebrospinal fluid through the lateral ventricle; rats in the CCPA experimental group were injected with 5 μL of 4 mg / mL CCPA solution; rats in the bromocriptine experimental group were injected with 5 μL of 2 mg / mL bromocriptine solution; the 20 μg CCPA + 10 μg bromocriptine experimental group was first injected with 5 μL of 4 mg / mL CCPA solution, and then injected with 5 μL of 2 mg / mL bromocriptine solution. There were 5 rats in each group. After the injection, the rats were fully awake, exposed to hyperbaric oxygen, and the convulsion latency was recorded. The experimental results are as follows: Figure 4 .

[0079] Figure 4 The results showed that compared with the solvent control group, 20 μg CCPA alone could significantly delay the onset of oxygen convulsions. 10 μg bromocriptine alone had no significant effect on convulsions and could not delay, counteract or induce oxygen convulsions. When 20 μg CCPA was used in combination with 10 μg bromocriptine, it could significantly counteract oxygen convulsions.

[0080] The preferred embodiments of the present invention have been specifically described above, but the present invention is not limited to the embodiments. Those skilled in the art may make various equivalent modifications or substitutions without violating the spirit of the present invention. These equivalent modifications or substitutions are all within the scope defined by the claims of this application.

Claims

1. Use of adenosine A1 receptor agonist and dopamine D2 receptor agonist in combination in the preparation of drugs or foods for preventing central nervous system oxygen poisoning.

2. The use of the adenosine A1 receptor agonist and the dopamine D2 receptor agonist in combination with each other according to claim 1 in the preparation of a drug or food for preventing oxygen poisoning of the central nervous system, characterized in that: The adenosine A1 receptor agonist is CCPA, and the dopamine D2 receptor agonist is bromocriptine.

3. The use of the adenosine A1 receptor agonist and the dopamine D2 receptor agonist in combination in the preparation of a drug or food for preventing central nervous system oxygen poisoning according to claim 1, characterized in that: The medicine or food for preventing central nervous system oxygen poisoning is used for preventing oxygen convulsion caused by central nervous system oxygen poisoning.

4. The use of the adenosine A1 receptor agonist and the dopamine D2 receptor agonist in combination in the preparation of a drug or food for preventing central nervous system oxygen poisoning according to claim 1, characterized in that: The medicine is a pharmaceutical composition with CCPA and bromocriptine as active ingredients, or a pharmaceutical composition containing CCPA and bromocriptine.

5. The use of the adenosine A1 receptor agonist and the dopamine D2 receptor agonist in combination in the preparation of a drug or food for preventing oxygen poisoning of the central nervous system according to claim 4, characterized in that: The dosages of CCPA and bromocriptine in the pharmaceutical composition are CCPA 2.5-20 μg and bromocriptine 2.5-10 μg, respectively.

6. Use of the adenosine A1 receptor agonist and the dopamine D2 receptor agonist according to any one of claims 1 to 5 in the preparation of a drug or food for preventing oxygen poisoning of the central nervous system, characterized in that: The medicine also includes commonly used pharmaceutical excipients, which are one or more of diluents, excipients, adhesives, fillers, disintegrants, flavoring agents, and sweeteners.

7. Use of the adenosine A1 receptor agonist and the dopamine D2 receptor agonist according to any one of claims 1 to 5 in the preparation of a drug or food for preventing oxygen poisoning of the central nervous system, characterized in that: The dosage form of the medicine is oral or injection.

8. The use of adenosine A1 receptor agonist and dopamine D2 receptor agonist in combination in the preparation of a drug or food for preventing central nervous system oxygen poisoning according to claim 1, characterized in that: The food is prepared by adding CCPA and bromocriptine into daily food.

9. A drug for preventing oxygen poisoning of the central nervous system, characterized in that: The medicine is a pharmaceutical composition with CCPA and bromocriptine as active ingredients, or a pharmaceutical composition containing CCPA and bromocriptine.

10. A food for preventing oxygen poisoning of the central nervous system, characterized in that: The food is prepared by adding CCPA and bromocriptine into daily food.

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