阅读说明：本技术 化合物Aspergillusidone G在制备神经保护药物中的应用 (Application of compound Aspergillus G in preparation of neuroprotective drugs ) 是由 张翼 杨文聪 聂影影 杨志友 刘亚月 宋采 洪鹏志 于 2019-08-29 设计创作，主要内容包括：本发明公开了化合物Aspergillusidone G在制备神经保护药物中的应用。本发明证实了缩酚酸环醚类化合物Aspergillusidone G可以显著提高大脑皮层神经细胞的存活率,对MPP<Sup>+</Sup>诱导的大脑皮层神经细胞损伤具有极显著的逆转作用；另外,化合物Aspergillusidone G对患者无毒副作用。因此,化合物Aspergillusidone G在制备神经保护药物、制备减轻/逆转MPP+诱导的神经细胞损伤的药物和制备预防/治疗神经退行性疾病的药物中具有重要意义和广泛的推广应用价值。(The invention discloses application of a compound Aspergillus nidone G in preparation of a neuroprotective drug. The invention proves that the depside cycloether compound Aspergillus G can obviously improve the survival rate of cerebral cortex nerve cells and is used for MPP + The induced damage to the nerve cells of the cerebral cortex has extremely obvious reversal effect; in addition, compound aspergillus nidone G has no toxic side effects to patients. Therefore, the compound Aspergillus G has important significance and wide popularization and application values in preparing neuroprotective drugs, drugs for relieving/reversing MPP + induced nerve cell injury and drugs for preventing/treating neurodegenerative diseases.)

1. Application of compound Aspergillus G in preparing neuroprotective drugs.

2. Application of compound Aspergillus G in preparation of relieving/reversing MPP⁺Use in a medicament for inducing neuronal cell damage.

3. Application of compound Aspergillus G in preparation of medicines for preventing/treating neurodegenerative diseases.

4. The use of claim 3, wherein the neurodegenerative disease is Parkinson's syndrome.

5. Alleviate/reverse MPP⁺Medicament for the induction of neuronal cell damage, characterized in that it comprises an effective amount of the compound aspergillus nidone G.

6. A neuroprotective agent comprising an effective amount of the compound aspergillus ussidone G.

7. A medicament for preventing/treating neurodegenerative diseases, which comprises an effective amount of the compound aspergillus nidone G.

Technical Field

The invention belongs to the technical field of biochemical medicine. More particularly, it relates to the application of compound Aspergillus nidone G in the preparation of neuroprotective medicine.

Background

Parkinsonism (PD) is a neurodegenerative disease, a chronic, progressive neurological disease that results in a disorder of memory, mobility and consciousness due to neuronal loss in the brain and spinal cord. As the population ages and the environment deteriorates, the threat of neurodegenerative diseases to human beings is more and more serious; among them, the most influential are Alzheimer's Disease (AD) and PD.

PD seriously threatens the physical and mental health of the old, and the current research result shows that the main pathological features of the PD are the degeneration of dopaminergic neurons in the substantia nigra pars compacta and the generation of endoplasmic lewy bodies. Neurodegeneration and lewy bodies may also be found in the locus ceruleus, basal ganglia, hypothalamus, cerebral cortex, cranial neuromotor nuclei, and central and peripheral parts of the autonomic nervous system of PD patients. 1-methyl-4-phenylpyridinium (MPP)⁺) Has neurotoxic effect and can induce PD production.

At present, traditional medicines for treating PD are mainly based on increasing dopamine transmitter in brain, including compound levodopa, dopamine receptor agonist, monoamine oxidase B inhibitor, and catechol-O-methyltransferase inhibitor. Levodopa is beneficial to almost all PD patients, but most patients suffer from adverse events such as dyskinesia (involuntary movement) and motor response fluctuation after 5-10 years of treatment. It can be seen that the traditional medicine for treating PD has limited effect, can only improve PD symptoms and cannot prevent the progress of the disease, and also can cause a plurality of adverse reactions. Therefore, screening of the natural neuroprotective agent with low toxicity, good activity and high yield has important practical significance for preventing and treating neurodegenerative diseases.

The depside cyclic ether compounds are natural micromolecular compounds produced by fungi, and the prior patent CN108640841A discloses the application of the depside cyclic ether compounds in preparing antifungal agents and antibacterial agents. However, there is no report on neuroprotection of depside cyclic ether compounds.

Disclosure of Invention

The invention aims to overcome the defects and defects of large toxic and side effects and high price of the existing medicines for treating neurodegenerative diseases and provides application of a compound Aspergillus nidone G in preparation of neuroprotective medicines.

The first purpose of the invention is to provide the application of the compound Aspergillus nidone G in the preparation of neuroprotective drugs.

The second purpose of the invention is to provide the compound Aspergillus G in the preparation of relieving/reversing MPP⁺Use in a medicament for inducing neuronal cell damage.

The third purpose of the invention is to provide the application of the compound Aspergillus nidone G in the preparation of medicines for preventing/treating neurodegenerative diseases.

It is a fourth object of the present invention to provide a method for mitigating/reversing MPP⁺A medicament for inducing nerve cell damage.

The fifth purpose of the invention is to provide a neuroprotective drug.

The sixth object of the present invention is to provide a medicament for preventing/treating neurodegenerative diseases.

The above purpose of the invention is realized by the following technical scheme:

application of compound Aspergillus G in preparing neuroprotective drugs.

Compound (I)Application of Aspergillus niger G in preparation of relieving/reversing MPP⁺Use in a medicament for inducing neuronal cell damage.

Application of compound Aspergillus G in preparation of medicines for preventing/treating neurodegenerative diseases.

Preferably, the neurodegenerative disease is parkinson's syndrome.

The compound Aspergillus G is 6- (1-methyl-trans-propenyl) -4- (2, 4-dihydroxy-6-methylbenzoyloxy) -2-hydroxy-3-methylbenzoic acid, and the structural formula is shown as the formula (I):

in addition, the invention also provides a medicament for reducing/reversing MPP < + > induced nerve cell damage, which comprises an effective amount of the compound Aspergillus G.

The invention also provides a neuroprotective medicament comprising an effective amount of the compound Aspergillus niger G.

The invention also provides a medicament for preventing/treating neurodegenerative diseases, which comprises an effective amount of the compound Aspergillus niger G.

The compound Aspergillus niger G of the invention is prepared by fermenting, crude extracting, separating and purifying Aspergillus unguiculatus 6-20-6 which is a strain induced by Aspergillus talus.

Preferably, the preparation method of the compound Aspergillus nidone G comprises the following steps:

s1, fermentation: inoculating Aspergillus unguiculatus mutant strain Aspergillus 6-20-6 of marine fungus into a fungus liquid culture medium, standing, fermenting, and collecting mycelium and fermentation liquid respectively;

s2, crude extraction: extracting the fermentation liquor obtained in the step S1 with ethyl acetate, concentrating, ultrasonically extracting mycelia with an organic solvent, concentrating, and mixing the obtained concentrates to obtain a crude extract;

s3, separation and purification: and (4) performing gel column chromatography on the crude extract obtained in the step S2, detecting by silica gel thin-layer chromatography, and performing reversed-phase preparative liquid chromatography and thin-layer preparative separation and purification on an elution component containing a target substance to obtain the compound Aspergillus nidone G.

Wherein the Aspergillus unguiculatus mutant strain Aspergillus unguiculatus 6-20-6 has been deposited at the Guangdong province microbial culture collection center in 2018, 03 and 20 days, and the deposit numbers are as follows: GDMCC 60337; and (4) storage address: zhou 100 Dazhou 59, building 5, Guangzhou institute of microorganisms.

Preferably, the formula of the fungus liquid culture medium in step S1 is: 400-600 mL of fresh potato juice, 15-25 g of sea salt, 15-25 g of sucrose, 3-8 g of peptone, 400-600 mL of distilled water and pH 6-8.

More preferably, the formula of the fungus liquid culture medium in the step S1 is: 500mL of fresh potato juice, 20g of sea salt, 20g of sucrose, 5.5g of peptone and 500mL of distilled water, and pH is 7.

Preferably, the fermentation time of the step S1 is 18-25 d.

More preferably, the fermentation time of step S1 is 21 d.

Preferably, the number of times of the extraction in the step S2 is 2-4 times.

More preferably, the number of extractions of step S2 is 3.

Preferably, the organic solvent in step S2 is any one or more of chloroform, acetone, ethyl acetate, ethanol, or methanol.

More preferably, the organic solvent in step S2 is a mixed solvent of acetone and methanol.

Preferably, the number of times of the ultrasound in step S2 is 2 to 4.

More preferably, the number of times of the ultrasound in step S2 is 3.

Preferably, the gel column chromatography conditions in step S3 are: the mobile phase of the gel column chromatography is methanol, the flow rate is 0.5-1 mL/min, and the gel column chromatography is collected in one tube within 10-15 min.

Preferably, the conditions for the reverse phase preparative liquid chromatography purification of step S3 are: the mobile phase is a mixture of 1: 3-3: 2, filling 10-15G of reverse phase silica gel into the column sleeve at the flow rate of 4-8 mL/min, and collecting a main peak with the retention time of 15-25 min to obtain the depside cycloether compound Aspergillus.

The invention has the following beneficial effects:

the invention provides application of a compound Aspergillus nidone G in preparation of a neuroprotective drug. The invention proves that the depside cycloether compound Aspergillus G can obviously improve the survival rate of cerebral cortex nerve cells and is used for MPP⁺The induced damage to the nerve cells of the cerebral cortex has extremely obvious reversal effect; in addition, the compound Aspergillus nidone G has no toxic or side effect on patients. Therefore, the compound Aspergillus G has important significance and wide popularization and application values in preparing neuroprotective drugs, drugs for relieving/reversing MPP + induced nerve cell injury and drugs for preventing/treating neurodegenerative diseases.

Drawings

FIG. 1 is a NMR chart of an aspergillidone G, a cyclic ether of depside.

FIG. 2 is a NMR chart of the cyclic ether of depsides Aspergillus G.

FIG. 3 is a graph showing the results of measurement of neuroprotective activity of the depside cyclic ether compound Aspergillus usadone G; wherein, 1 represents adding 1 μ M depside ring ether compound Aspergillus G; "10" represents the addition of the 10. mu.M concentration of the Cyclic ether of depsides compound Aspergillus G.

Detailed Description

The present invention is further illustrated by the following specific examples, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.

Unless otherwise indicated, reagents and materials used in the following examples are commercially available.