CN113288920B - Application of cannabidiol monomer and lactobacillus plantarum DP189 in preparation of medicine for preventing and/or treating Parkinson's disease - Google Patents
Application of cannabidiol monomer and lactobacillus plantarum DP189 in preparation of medicine for preventing and/or treating Parkinson's disease Download PDFInfo
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Abstract
The application of the combination of the cannabidiol monomer and the lactobacillus plantarum DP189 in the preparation of the medicine for preventing and/or treating the Parkinson disease belongs to the field of functional food microorganisms, wherein the concentration of the cannabidiol monomer is 2.4mg/mL; the concentration of Lactobacillus plantarum DP189 was 10 9 ～10 10 CFU/mL; cannabidiol monomer was used separately from lactobacillus plantarum DP 189. The cannabidiol monomer and the lactobacillus plantarum DP189 strain are jointly applied to improve the behavioral ability of a Parkinson disease model mouse; inhibiting apoptosis of cerebral neurons of a Parkinson disease model mouse; reducing inflammatory response, reducing the levels of inflammatory factors TNF-alpha, IL-1 beta and IL-6; preventing the oxidative stress reaction of the Parkinson disease model mouse and reducing the oxidative stress level.
Description
Technical Field
The invention belongs to the technical field of functional food microorganisms, and particularly relates to an application of a cannabidiol monomer and lactobacillus plantarum DP189 in preparation of a medicine for preventing and/or treating Parkinson's disease.
Background
Parkinson's Disease (PD) is a degenerative disease of the nervous system, about 1% of the population over 60 years old worldwide suffer from the disease, and the prevalence rate of PD in people over 65 years old in China is about 1.7%. The main pathological features of PD are loss of dopaminergic neurons of the mesocerebral substantia nigra leading to dysfunction of movement of the nigra striatal system, resulting in behavioural changes of muscle tremor, rigidity, bradykinesia and unsteady posture. The non-behavioral symptoms mainly comprise intestinal dysfunction, hyposmia, sleep disorder, cognitive impairment and the like, and can appear decades earlier than the dyskinesia, wherein the intestinal dysfunction is the most common non-motor symptom in the early stage of PD, which indicates that the PD possibly starts from the intestinal tract.
Although monoamine oxidase type B inhibitors such as levodopa (L-DOPA) and the like have been shown to have protective and ameliorating effects on damage to the nervous system, the currently discovered drugs are also only symptomatic treatments for PD against clinical symptoms. Based on the above, the search for a safe and effective drug is of great significance for the treatment of PD.
Disclosure of Invention
The invention aims to provide application of a cannabidiol monomer and lactobacillus plantarum DP189 in preparation of a medicine for preventing and/or treating Parkinson's disease.
The technical scheme adopted by the invention for solving the technical problem is as follows:
the cannabidiol monomer and the lactobacillus plantarum DP189 are combined to prepare the medicine for preventing and/or treating the Parkinson disease.
As a preferred embodiment, the concentration of cannabidiol monomer is 2.4mg/mL; the concentration of the lactobacillus plantarum DP189 is 10 9 ～10 10 CFU/mL; the cannabidiol monomer is used separately from lactobacillus plantarum DP 189.
As a preferred embodiment, said lactobacillus plantarum DP189 has been deposited in the chinese type culture collection at 2019, 3 and 25 months, with the deposit numbers: CCTCC NO: m2019199.
In a preferred embodiment, the Lactobacillus plantarum DP189 is used by suspending it in 2% Tween-80 physiological saline at a concentration of 10 9 ～10 10 CFU/mL。
In a preferred embodiment, the cannabidiol monomer is used dissolved in 2% tween-80 saline at a concentration of 2.4mg/mL.
In a preferred embodiment, the cannabidiol monomer has a purity of 99% or greater.
As a preferred embodiment, the cannabidiol monomer is prepared using the following method:
selecting fresh industrial hemp leaves, and air-drying; weighing air-dried industrial hemp flower leaves, adding 20 times of food-grade 95% ethanol, heating, refluxing and extracting for two times, filtering, combining filtrates, and recovering solvent under reduced pressure to obtain extract containing cannabidiol monomer; adding the extract into ethyl acetate according to the weight ratio of the extract to the ethyl acetate of 1; standing overnight, removing water layer, recovering ethyl acetate layer under reduced pressure to obtain cannabinol crude product containing cannabidiol monomer, separating with preparative high performance liquid chromatography, and collecting cannabidiol monomer with purity of 99% or more.
As a preferred embodiment, the function of the drug is at least one of (1) to (5):
(1) Inhibiting apoptosis of cerebral neurons of a mouse with the Parkinson's disease;
(2) Reducing the level of inflammatory factor TNF-alpha;
(3) Reducing the level of inflammatory factor IL-1 β;
(4) Reducing the level of inflammatory factor IL-6;
(5) Preventing the oxidative stress of the organism and reducing the oxidative stress level.
The invention has the beneficial effects that:
the method adopts MPTP to establish a Parkinson disease mouse model, simultaneously establishes a normal group, a model group, a positive group, a cannabidiol monomer group, a DP189 group and a cannabidiol monomer + DP189 group, respectively performs intragastric administration, continuously performs intragastric administration for 14 days, and discusses the improvement effect of the combined application of a Lactobacillus plantarum (L.plantarum) DP189 strain and a cannabidiol monomer on the Parkinson disease model mouse. Research results show that the combined application of cannabidiol monomer and lactobacillus plantarum (L.plantarum) DP189 strain can improve the ethological ability of a Parkinson disease model mouse; inhibiting apoptosis of cerebral neurons of a Parkinson disease model mouse; reducing inflammatory response, reducing the levels of inflammatory factors TNF-alpha, IL-1 beta and IL-6; preventing the oxidative stress reaction of the Parkinson disease model mouse and reducing the oxidative stress level. Therefore, the cannabidiol monomer and the lactobacillus plantarum DP189 strain provided by the invention can be used for preparing medicines and medicines for resisting Parkinson's disease in a combined application manner, and the application prospect is very wide.
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FIG. 1 shows the results of the experimental study on the behavior of the mouse model of Parkinson's disease in example 1. In FIG. 1, A is a water maze experiment latency variation diagram of a Parkinson's disease model mouse; in fig. 1, B is a graph showing the change in the number of experiments on the autonomous activity of the mouse model of parkinson's disease. In the figure, "+" indicates significant difference (P < 0.05) and "+" indicates extremely significant difference (P < 0.01) compared to the model group.
FIG. 2 is the results of the detection of cerebral neurotransmitters in the mouse model of Parkinson's disease in example 1. FIG. 2A is a graph showing the change in the 5-hydroxytryptamine (5-HT) levels in the brains of mice in the Parkinson's disease model; in FIG. 2, B is a graph showing the change of Dopamine (DA) content in the brain of a mouse model of Parkinson's disease. In the figure, "+" indicates significant difference (P < 0.05) and "+" indicates extremely significant difference (P < 0.01) compared to the model group.
Detailed Description
The cannabidiol monomer (CBD) and the lactobacillus plantarum DP189 are combined to be applied to preparing the medicine for treating the Parkinson disease.
Preferably, the concentration of cannabidiol monomer (CBD) is 2.4mg/mL; lactobacillus plantarum DP189 at a concentration of 10 9 ～10 10 CFU/mL; cannabidiol monomer (CBD) was used separately from lactobacillus plantarum DP 189.
Preferably, lactobacillus plantarum (l.plantarum) DP189 has been deposited in the chinese collection for type culture collection, CCTCC for short, in 2019 at 25.3.m. with the address: eight-path Wuhan university school (Wuhan university collection center) 299 in Wuchang area, wuhan city, hubei province has the collection number: CCTCC NO: m2019199.
In addition, other information about lactobacillus plantarum DP189 may include separation, identification, preservation, etc. all refer to chinese patent publication No. CN 110066753A (named lactobacillus plantarum DP189 and its application).
Preferably, lactobacillus plantarum(L.plantarum) DP189 was used by suspending it in 2% Tween-80 physiological saline at a concentration of 10 9 ～10 10 CFU/mL。
Preferably, cannabidiol monomer (CBD) is used, dissolved in 2% Tween-80 saline at a concentration of 2.4mg/mL.
Preferably, the cannabidiol monomer (CBD) has a purity of greater than or equal to 99%.
Preferably, the cannabidiol monomer (CBD) is prepared by the following method:
selecting fresh industrial hemp leaves, and air-drying; weighing air-dried industrial hemp flower leaves, adding 20 times of food-grade 95% ethanol, heating, refluxing and extracting for two times, filtering, combining filtrates, and recovering solvent under reduced pressure to obtain extract containing cannabidiol monomer; adding the extract into ethyl acetate according to the weight ratio of the extract to the ethyl acetate of 1; standing overnight, removing water layer, recovering ethyl acetate layer under reduced pressure to obtain cannabinol crude product containing cannabidiol monomer, separating with preparative high performance liquid chromatography, and collecting cannabidiol monomer with purity of 99% or more.
Preferably, the function of the drug is at least one of (1) to (5):
(1) Inhibiting apoptosis of cerebral neurons of mice with Parkinson's disease;
(2) Reducing the level of inflammatory factor TNF-alpha;
(3) Reducing the level of inflammatory factor IL-1 β;
(4) Reducing the level of inflammatory factor IL-6;
(5) Preventing the oxidative stress of the organism and reducing the oxidative stress level.
The ethological ability of the Parkinson disease mouse can be improved by taking Lactobacillus plantarum DP189 and cannabidiol monomers in daily time intervals, namely, not simultaneously taking the L.planterum DP189 and cannabidiol monomers to replace the medicine for treating the Parkinson disease; inhibiting apoptosis of cerebral neurons of mice with Parkinson's disease; reducing inflammatory response, reducing the levels of inflammatory factors TNF-alpha, IL-1 beta and IL-6; preventing the oxidative stress of the organism and reducing the oxidative stress level. Has better prevention and treatment effects on the Parkinson's disease, and has the advantages of safety and no toxic or side effect.
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The test materials used in the following examples were purchased from conventional biochemicals, unless otherwise specified. The quantitative tests in the following examples, all set up three replicates and the results averaged.
Experimental materials:
liquid MRS medium: the solvent is water, and contains peptone 10g/L, beef extract 10g/L, and yeast extract 5g/L, KH 2 PO 4 2g/L, sodium acetate 5g/L, sodium citrate 5g/L, mgSO 4 ·7H 2 O 0.2g/L、MnSO 4 ·4H 2 O0.05 g/L, tween-801 mL/L and glucose 20g/L; the pH was 6.6.
C57BL/6 mice (weight 18-22 g): purchased from the enchanter national ministry of animal technology, billions, catharanthus roseus.
Basic feed: purchased from the enchanter national ministry of animal technology, billions, catharanthus roseus.
Cannabidiol monomer: selecting fresh industrial hemp flowers and leaves, air-drying, weighing 500g of the air-dried industrial hemp flowers and leaves, adding 20 times of food-grade ethanol (95%), heating, refluxing and extracting twice, filtering, combining filtrates, and recovering a solvent under reduced pressure to obtain an extract containing cannabidiol; putting the extract into ethyl acetate according to the weight ratio of the extract to the ethyl acetate of 1; standing overnight, discarding the water layer, recovering ethyl acetate layer under reduced pressure to obtain cannabinol crude product containing cannabidiol, separating cannabidiol with preparative high performance liquid chromatography, and collecting cannabidiol monomer with purity of 99% or more.
Detecting the content of TNF-alpha in serum by adopting a Jiangsu enzyme-labeled mouse tumor necrosis factor (TNF-alpha) ELISA kit; detecting the content of IL-1 beta in serum by adopting a Jiangsu enzyme-labeled mouse interleukin 1 beta (IL-1 beta) ELISA kit; detecting the IL-6 content in serum by adopting a Jiangsu enzyme-labeled mouse interleukin 6 (IL-6) ELISA kit; detecting the content of DA in the substantia nigra of brain by adopting a Jiangsu enzyme-labeled mouse neurotransmitter Dopamine (DA) ELISA kit; 5-HT content in brain substantia nigra is detected by adopting Jiangsu enzyme-labeled mouse neurotransmitter 5-hydroxytryptamine (5-HT) ELISA kit.
MPTP was purchased from sigma, USA, among others.
Example 1 Effect of Lactobacillus plantarum DP189 Strain, cannabidiol monomer, combination of cannabidiol monomer and Lactobacillus plantarum DP189 Strain on Parkinson's disease model mice
1. Establishment and grouping of animal models
Healthy male C57BL/6 mice for 8 weeks were selected for the experiment and were injected intraperitoneally with MPTP (30 mg/kg) or physiological saline once a day for 7 consecutive days. Injecting apomorphine (5 mg/kg) into the abdominal cavity 7 days after MPTP treatment, recording the rotation times within 30 mm, if the mouse rotates leftwards constantly and the rotation circle is more than 7r/min, the model is successfully made, meanwhile, abnormal actions such as hair erection, tremor, front leg lifting, tail erection and the like should appear after the last MPTP treatment for 5-30 min, the symptoms are relieved after 0.5-1 h, and the mouse returns to normal after 24 h. Mice with successful models were screened and randomized into 6 groups of gavage (15 per group): normal and model groups were gavaged with 0.2mL/d saline containing 2% tween-80 per day at 9 and 16; the positive group comprises 9.00 intragastric L-DOPA solution 0.2mL/d per day, and 16.00 intragastric normal saline containing 2% Tween-80 0.2mL/d; the cannabidiol monomer group comprises 0.2mL/d of a 9; DP189 group was gavage with 0.2mL/d of 2% Tween-80 saline at 9% per day, and DP189 strain at 16% per day at 0.2mL/d; cannabidiol monomer + DP189 group 9 00 gavage cannabidiol monomer solution 0.2mL/d daily, 16 00 gavage DP189 strain 0.2mL/d. The above groups were administered continuously for 14d. The assay behavioural experiment started on day 15 and 24h later mice were sacrificed and mouse serum and brain tissue collected for testing.
2. Behavioral experiments on Parkinson's disease model mice
The results of the mouse behavioural experiments are shown in figure 1. The experiment shows that the cannabidiol monomer and the lactobacillus plantarum DP189 strain can independently shorten the water maze latency of a mouse and increase the times of the mouse autonomic activity experiment, but the single action of the cannabidiol monomer and the lactobacillus plantarum DP189 strain is weaker than the action of the cannabidiol monomer and the lactobacillus plantarum DP189 strain in combination, compared with a model group, the cannabidiol monomer + DP189 group can improve the memory capacity and the behavior capacity of a Parkinson disease model mouse, and has extremely significant difference (P < 0.01).
3. Detection of relevant indexes of mouse brain tissue in Parkinson's disease model
The main pathological feature of parkinson's disease is the death or loss of dopaminergic neurons in the substantia nigra of the brain, resulting in a reduction of dopamine content in the brain, ultimately leading to morbidity. 5-hydroxytryptamine (5-HT) is a key enzyme in the pathway for synthesizing dopamine in the body, and the content change of the 5-hydroxytryptamine seriously influences the content of dopamine in the collective body. The result of the detection of the mouse brain neurotransmitter by the ELISA kit is shown in figure 2, the cannabidiol monomer + DP189 group can improve the 5-HT content and the DA content in the mouse brain, compared with a model group, the 5-HT content is increased by 17.42 percent, the DA content is increased by 11.25 percent, the effect is obvious compared with that of single medicine application, and the obvious difference is achieved (P is less than 0.01).
4. Detection of oxidative stress index in serum of Parkinson's disease model mouse
The results of the oxidative stress kit are shown in table 1. The experiment shows that compared with the normal group, the model group mice have lower contents of SOD and GSH-Px, and the ROS content and the MDA level are greatly increased, which shows that the adoption of the MPTP-induced subacute Parkinson disease mouse model is more successful. Compared with a model group, the cannabidiol monomer can increase the content of SOD and GSH-Px in the brain of a mouse, reduce the content of ROS and the level of MDA, and has extremely significant difference (P < 0.01); the lactobacillus plantarum DP189 strain also shows better antioxidant activity and has significant difference (P < 0.05); it is noted that the antioxidant effect of cannabidiol monomer + DP189 group is stronger than that of the two single drug groups (CBD group and DP189 group), wherein the content of SOD is increased by about 41.91% compared with the model group, and the content of ROS is reduced by about 15.13% compared with the model group, which shows good antioxidant activity and has extremely significant difference (P < 0.01).
TABLE 1
Note: compared to the model group, "+" indicates significant difference (P < 0.05) and "+" indicates very significant difference (P < 0.01).
5. Detection of inflammatory factor level in serum of Parkinson's disease model mouse
The production of inflammatory factors plays an important role in the pathogenesis of the Parkinson's disease, and the increase of the level of the inflammatory factors can greatly improve the morbidity of the Parkinson's disease. The results of detecting the levels of inflammatory factors in serum of mice model of Parkinson's disease are shown in Table 2. Experiments show that the level of the inflammatory factors in the bodies of the Parkinson's disease patients is far higher than that of the bodies of the normal patients. The inflammation experiment result shows that the cannabidiol monomer + DP189 group can obviously reduce the contents of TNF-alpha, IL-6 and IL-1 beta inflammatory factors in the serum of a mouse with the Parkinson's disease, the effect of the combined medication of the cannabidiol monomer and the DP189 group is superior to that of the single medication (CBD group and DP189 group), and compared with a model group, the content of TNF-alpha is reduced by 22.25 percent, the content of IL-6 is reduced by 12.61 percent, the content of IL-1 beta is reduced by 14.40 percent, and the obvious difference is realized (P is less than 0.01).
TABLE 2
Note: compared to the model group, "+" indicates significant difference (P < 0.05) and "+" indicates very significant difference (P < 0.01).
The invention discloses an application of cannabidiol monomer and lactobacillus plantarum DP189 in preparation of a medicine for preventing and/or treating Parkinson's disease, which can be realized by appropriately improving process parameters by referring to the content. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the invention has been described in terms of preferred embodiments, it will be apparent to those skilled in the art that variations and modifications, as appropriate, may be made to the products and methods described herein to implement and use the techniques of the invention without departing from the spirit and scope of the invention.
Claims (7)
1. Cannabidiol monomer and lactobacillus plantarumLactobacillus plantarum) The application of the DP189 combination in preparing a medicament for preventing and/or treating Parkinson's disease; characterized in that the Lactobacillus plantarum (A)Lactobacillus plantarum) DP189 has been deposited at the China center for type culture Collection in 2019 at 25.3.M with the following deposit numbers: CCTCC NO: m2019199.
2. Use according to claim 1 wherein the cannabidiol monomer is present at a concentration of 2.4mg/mL; said Lactobacillus plantarum: (Lactobacillus plantarum) DP189 at a concentration of 10 9 ～10 10 CFU/mL; the cannabidiol monomer and lactobacillus plantarum (C.) (Lactobacillus plantarum) DP189 was used separately.
3. The use according to claim 1, wherein, characterized in that the Lactobacillus plantarum (A)Lactobacillus plantarum) DP189 is administered by suspending in 2% Tween-80 physiological saline at 10% 9 ～10 10 CFU/mL。
4. The use of claim 1 wherein cannabidiol monomer, when used, is dissolved in 2% tween-80 saline at a concentration of 2.4mg/mL.
5. The use of claim 1, wherein the cannabidiol monomer is at least 99% pure.
6. The use of claim 1, wherein the cannabidiol monomer is prepared by:
selecting fresh industrial hemp leaves, and air-drying; weighing air-dried industrial hemp flower leaves, adding 20 times of food-grade 95% ethanol, heating, refluxing and extracting for two times, filtering, combining filtrates, and recovering solvent under reduced pressure to obtain extract containing cannabidiol monomer; adding the extract into ethyl acetate according to the weight ratio of the extract to the ethyl acetate of 1; standing overnight, removing water layer, recovering ethyl acetate layer under reduced pressure to obtain cannabinol crude product containing cannabidiol monomer, separating with preparative high performance liquid chromatography, and collecting cannabidiol monomer with purity of 99% or more.
7. The use according to claim 1, wherein the function of the drug is at least one of (1) to (5):
(1) Inhibiting apoptosis of cerebral neurons of mice with Parkinson's disease;
(2) Reducing the level of inflammatory factor TNF-alpha;
(3) Reducing the level of inflammatory factor IL-1 β;
(4) Reducing the level of inflammatory factor IL-6;
(5) Preventing the oxidative stress of the organism and reducing the oxidative stress level.
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| CN108603162A (en) * | 2015-09-15 | 2018-09-28 | 庆熙大学校产学协力团 | Prevention, the novel lactic acid bacteria and composition for improving or treating degenerative brain disorder or cognition dysfunction |
| WO2018114783A1 (en) * | 2016-12-23 | 2018-06-28 | Bayer Pharma Aktiengesellschaft | Tetrazole containing compounds |
| CN110891430A (en) * | 2017-06-19 | 2020-03-17 | 波比奥泰克股份公司 | Composition comprising a bacterial strain belonging to the species lactobacillus salivarius for the treatment of parkinson's disease |
| WO2019157585A1 (en) * | 2018-02-13 | 2019-08-22 | Proviva Pharma Inc. | Probiotic formulations for the treatment and alleviation of metabolic and oxidative stress, inflammation and neurodegeneration |
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