CN113230258A - Application of folic acid in treating neonatal meningitis - Google Patents
Application of folic acid in treating neonatal meningitis Download PDFInfo
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- CN113230258A CN113230258A CN202110609684.5A CN202110609684A CN113230258A CN 113230258 A CN113230258 A CN 113230258A CN 202110609684 A CN202110609684 A CN 202110609684A CN 113230258 A CN113230258 A CN 113230258A
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- folic acid
- inflammatory
- meningitis
- neonatal meningitis
- neonatal
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Abstract
The invention provides application of folic acid in treating neonatal meningitis, belonging to the technical field of biological medicines. The invention proves that folic acid can obviously inhibit inflammatory reaction in newborn brain caused by lipopolysaccharide for the first time, and the inhibition of the inflammatory reaction is mainly related to activation of classical inflammatory signal pathways such as NF kappa B signal pathway, MAPK signal pathway and the like and epigenetic modification change. The folic acid plays different anti-inflammatory effects in two types of glial cells, and provides a new idea for the research of the drug action target of neonatal meningitis and the clinical treatment of neonatal intracerebral inflammatory diseases in future, so the folic acid has important clinical application value.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of folic acid in treatment of neonatal meningitis.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
Neonatal meningitis is a disease that seriously threatens the life safety of the newborn, and causes considerable economic burden worldwide. Despite advances in current drug therapy and advanced intensive care, neonatal bacterial meningitis still has a mortality rate of more than 10% and causes neurological sequelae in 20-50% of cases (Giridharan et al, 2017; Mary P.Glode, 1977). It is therefore of great importance to find safer and more effective therapeutic agents. Folic acid is currently widely accepted as a drug for preventing neural tube malformations in neonates (Lachenauer, Stabler, Field, & Stover, 2020; Sudiwala et al, 2019). Studies have found that in the brain of neonatal meningitis patients, there is an increase in the neuroinflammatory response and marked microglial and astrocyte activation (Hinkerohe et al, 2010; Izadpanah, Freyer, Weber, & Braun, 2014). Microglia and astrocytes, which are important cell types involved in the inflammatory response of the central nervous system, can release inflammatory factors IL-1 beta, TNF alpha and iNOS, and participate in the development process of inflammation in the brain. Lipopolysaccharide is an effective immune activator, and LPS (lipopolysaccharide) is injected into the abdominal cavity to cause the generation of inflammatory reaction of central nervous system of mice and simulate the pathological process of neonatal meningitis (Boje, Jawortwicz, & Raybon, 2003; BOJE, 1996). The LPS exposure in the mouse juvenile period can obviously cause the mouse intracerebral inflammatory reaction and the reactive activation of microglia and astrocytes.
Folic acid, a water-soluble vitamin, plays an important role in preventing neural tube malformations and various physiological functions in newborns (Blencowe, Coosens, model, & Lawn, 2010). In addition, folic acid, as a methyl donor of one-carbon metabolism, plays an important role in cell proliferation, cell differentiation, gene transcription regulation, and the like by affecting methylation of histones, DNA, RNA, lipids, and the like (Blencowe et al, 2010; Leung, De Castro, Savery, Copp, & Greene, 2013). NF-. kappa.B, ERK, JNK and P38 are the classical proinflammatory transcriptional activators and are important regulators of the inflammatory response of the central nervous system (Kim & Choi, 2015; Rahimifard et al, 2017). However, the role of folate in the pathogenic mechanism of NF-. kappa.B and MAPK dependent pro-inflammatory activation in astrocytes in the mouse brain in the neonatal meningitis model is not clear.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides the application of folic acid in treating neonatal meningitis. The invention proves that folic acid can obviously inhibit inflammatory reaction in newborn brain caused by lipopolysaccharide for the first time, and the inhibition of the inflammatory reaction is mainly related to activation of classical inflammatory signal pathways such as NF kappa B signal pathway, MAPK signal pathway and the like and epigenetic modification change. The folic acid plays different anti-inflammatory effects in two types of glial cells, and provides a new idea for the research of the drug action target of neonatal meningitis and the clinical treatment of neonatal intracerebral inflammatory diseases in future, so the folic acid has important clinical application value.
Specifically, the invention relates to the following technical scheme:
in a first aspect of the invention, there is provided the use of folic acid in the manufacture of a medicament for the treatment of meningitis.
According to the present invention, the concept of "treatment" means any relevant measure suitable for the treatment of neonatal meningitis, either for the prophylactic treatment of such manifested diseases or manifested symptoms, or to avoid the recurrence of such diseases, e.g. after the end of a treatment period or treatment of symptoms of diseases that have already occurred.
More specifically, the meningitis is neonatal meningitis.
In the present invention, the neonatal meningitis is a neonatal meningitis induced by lipopolysaccharide.
The treatment of neonatal meningitis is at least shown in any one or more of the following purposes:
a) ameliorating inflammatory changes in brain tissue;
b) inhibit the activation of brain glial cells;
c) inhibiting inflammatory reaction of central nervous system.
In said a), ameliorating inflammatory changes in brain tissue including reduction of cellular vacuolation and/or tissue densification from inflammatory porosity;
in the b), the brain glial cells include microglia and astrocytes. Further research of the invention proves that the anti-inflammatory action mechanisms of folic acid in different glial cells are different, and concretely, folic acid can inhibit activation of MAPK signal channel and NF kappa B signal channel in inflammatory reaction of microglia caused by LPS, but only inhibit activation of NF kappa B signal channel in inflammatory reaction of astrocyte caused by LPS. It is found through experiments that folic acid influences the methylation state of different sites in different glial cell inflammatory responses. In astrocytes, folic acid inhibited the expression of H3K27me 3; and the expression of H3K9me3 is inhibited in microglia. This also suggests that the targets and mechanisms of action exerted by folate in different glial cells are different.
In said c), inhibiting the inflammatory response of the central nervous system is embodied by inhibiting the expression of pro-inflammatory factors.
Wherein the proinflammatory factors include but are not limited to TNF-alpha, iNOS, IL-1 beta.
According to the present invention, not only is the use of folic acid for the preparation of a medicament for the treatment of neonatal meningitis disclosed, but it is also disclosed that this effect can be enhanced when a combination of folic acid and at least one other pharmaceutically active ingredient is administered. Instead of or in addition to other pharmaceutically active ingredients, folic acid can also be used in combination with other non-pharmaceutically active ingredients.
In view of the above, according to a second aspect of the present invention, there is provided a pharmaceutical composition for treating neonatal meningitis, which comprises folic acid and at least one other pharmaceutically active ingredient and/or at least one other non-pharmaceutically active ingredient.
In the sense of the invention, the pharmaceutical composition of the invention represents a substance which contains folic acid with obvious therapeutic effect on neonatal meningitis.
In a third aspect of the present invention, there is provided a use of folic acid for the preparation of an inflammatory factor inhibitor:
inflammatory factors include, but are not limited to TNF- α, iNOS, IL-1 β.
The beneficial technical effects of one or more technical schemes are as follows:
the technical scheme proves that folic acid can obviously inhibit inflammatory reaction in newborn brain caused by LPS. Folic acid has a close relationship between the treatment of neonatal meningitis and the anti-inflammatory effect of the neonatal meningitis. The folic acid is mainly related to the activation of classical inflammation signal pathways such as NF kappa B signal pathway, MAPK signal pathway and the like and the change of epigenetic modification. The different anti-inflammatory effects of folic acid exerted in two types of glial cells provide a new idea for the research of the action target of the medicine for treating neonatal meningitis in future and the clinical treatment of the neonatal intracerebral inflammatory diseases, and provide a new scientific basis for the clinical application value of folic acid which can be used as the effective medicine for treating neonatal meningitis, so that the folic acid has good practical application value.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention.
FIG. 1 shows that folic acid inhibits the activation of microglia and astrocytes in the brain of a newborn mouse according to an embodiment of the present invention. Wherein, A is the GFAP and Iba-1 positive cells of the cortex and corpus callosum area of the newborn mouse detected by immunofluorescence staining. B and C are statistical analyses of the numbers of GFAP + and Iba-1+ cells in the cortex and callus regions of newborn mice. D is mRNA expression of GFAP and Iba-1 in the brain of the newborn mouse detected by qPCR. E is Western blot for detecting the protein expression of GFAP and Iba-1 in the brain of the newborn mouse. F is the statistical analysis of the protein expression of GFAP and Iba-1 in the brain of the newborn mice. G is HE staining observation neogenesisInflammation changes in mouse cortex and corpus callosum areas. (*P＜0.05,**P＜0.02；#P＜0.05；##P＜0.02,n＝3)。
FIG. 2 is a graph showing that folic acid inhibits proinflammatory factor release in neonatal mouse brain in an embodiment of the invention. Wherein, A is Western blot for detecting the expression of TNF-alpha, IL-1 beta and iNOS in the newborn mouse brain. B, detecting the expression of TNF-alpha, IL-1 beta and iNOS in the newborn mouse brain by using Western blot. C is qPCR detection of the expression of TNF-alpha, IL-1 beta and iNOS in the newborn mouse brain. (*P＜0.05；**P＜0.02；#P＜0.05；##P＜0.02,n＝3)。
FIG. 3 is a graph showing that the anti-inflammatory effects of folic acid on microglia and astrocytes in the present example were achieved by inhibiting the activation of different inflammation-related signaling pathways. Wherein, A is Western blot for detecting the activation condition of MAPK and NF kappa B signal channels in astrocytes. B, detecting the activation condition of MAPK and NF kappa B signal channels in microglia by Western blot. (*P＜0.05,**P＜0.02,***P＜0.001,****P＜0.0001；#P＜0.05；##P＜0.02,n＝3)。
FIG. 4 is a graph showing the effect of folate on different histone methylation modification sites in astrocytes and microglia in an example of the present invention. Wherein A is the influence of folic acid on the expression of H3K27me3 in astrocytes. And B is the effect of folic acid on the expression of H3K9me3 in microglia. (*P＜0.05,**P＜0.02,***P＜0.001,****P＜0.0001；#P＜0.05；##P＜0.02,###P＜0.001,####P＜0.0001,n＝3)。
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
The present invention is further illustrated by reference to specific examples, which are intended to be illustrative only and not limiting. If the experimental conditions not specified in the examples are specified, they are generally according to the conventional conditions, or according to the conditions recommended by the sales companies; materials, reagents and the like used in examples were commercially available unless otherwise specified.
In one embodiment of the invention, the use of folic acid in the manufacture of a medicament for the treatment of meningitis is provided. .
According to the present invention, the concept of "treatment" means any relevant measure suitable for the treatment of neonatal meningitis, either for the prophylactic treatment of such manifested diseases or manifested symptoms, or to avoid the recurrence of such diseases, e.g. after the end of a treatment period or treatment of symptoms of diseases that have already occurred.
In yet another embodiment of the present invention, the meningitis is neonatal meningitis.
In still another embodiment of the present invention, the neonatal meningitis is induced by lipopolysaccharide.
In yet another embodiment of the invention, the treatment of neonatal meningitis is at least manifested by any one or more of the following:
a) ameliorating inflammatory changes in brain tissue;
b) inhibit the activation of brain glial cells;
c) inhibiting inflammatory reaction of central nervous system.
In said a), ameliorating inflammatory changes in brain tissue including reduction of cellular vacuolation and/or tissue densification from inflammatory porosity;
in the b), the brain glial cells include microglia and astrocytes. Further research of the invention proves that the anti-inflammatory action mechanisms of folic acid in different glial cells are different, and concretely, folic acid can inhibit activation of MAPK signal channel and NF kappa B signal channel in inflammatory reaction of microglia caused by LPS, but only inhibit activation of NF kappa B signal channel in inflammatory reaction of astrocyte caused by LPS. It is found through experiments that folic acid influences the methylation state of different sites in different glial cell inflammatory responses. In astrocytes, folic acid inhibited the expression of H3K27me 3; and the expression of H3K9me3 is inhibited in microglia. This also suggests that the targets and mechanisms of action exerted by folate in different glial cells are different.
In said c), inhibiting the inflammatory response of the central nervous system is embodied by inhibiting the expression of pro-inflammatory factors.
Wherein the proinflammatory factors include but are not limited to TNF-alpha, iNOS, IL-1 beta.
According to the present invention, not only is the use of folic acid for the preparation of a medicament for the treatment of neonatal meningitis disclosed, but it is also disclosed that this effect can be enhanced when a combination of folic acid and at least one other pharmaceutically active ingredient is administered. Instead of or in addition to other pharmaceutically active ingredients, folic acid can also be used in combination with other non-pharmaceutically active ingredients.
In view of the above, in another embodiment of the present invention, a pharmaceutical composition for treating neonatal meningitis is provided, which comprises folic acid and at least one other pharmaceutically active ingredient and/or at least one other non-pharmaceutically active ingredient.
In the sense of the invention, the pharmaceutical composition of the invention represents a substance which contains folic acid with obvious therapeutic effect on neonatal meningitis.
In another embodiment of the present invention, the pharmaceutically inactive ingredient may be a pharmaceutically commonly used carrier, excipient, diluent, or the like. Further, the composition can be prepared into oral preparations such as powder, granule, tablet, capsule, suspension, emulsion, syrup, and spray, external preparations, suppositories, and sterile injectable solutions according to a conventional method.
Such pharmaceutically inactive ingredients, which may include carriers, excipients and diluents, are well known in the art and can be determined by one of ordinary skill in the art to meet clinical criteria.
In still another embodiment of the present invention, the carrier, excipient and diluent include, but are not limited to, lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, and the like.
In yet another embodiment of the present invention, the medicament of the present invention may be administered into the body by known means. For example, by intravenous systemic delivery or local injection into the tissue of interest. Optionally via intravenous, transdermal, intranasal, mucosal or other delivery methods. Such administration may be via a single dose or multiple doses. It will be understood by those skilled in the art that the actual dosage to be administered in the present invention may vary greatly depending on a variety of factors, such as the target cell, the type of organism or tissue thereof, the general condition of the subject to be treated, the route of administration, the mode of administration, and the like.
In still another embodiment of the present invention, the subject to which the pharmaceutical composition is administered may be human and non-human mammals, such as mice, rats, guinea pigs, rabbits, dogs, monkeys, chimpanzees, and the like.
In another embodiment of the present invention, there is provided a use of folic acid for the preparation of an inflammatory factor inhibitor:
inflammatory factors include, but are not limited to TNF- α, iNOS, IL-1 β.
The invention is further illustrated by the following examples, which are not to be construed as limiting the invention thereto. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Examples
First, experiment method
1.1 animal models
The experiment utilizes newborn Kunming mice (2-6 days after birth) purchased from experimental animal center of Shandong university, the breeding environment of the mice is 18-22 ℃, and the mice are bred in the same nest with the mother mice, so as to ensure sufficient grain and water. Based on the characteristic that an LPS (LPS) -induced neonatal meningitis model has no sex difference, female/male neonatal Kunming mice are randomly divided into three groups: normal saline group, lipopolysaccharide group, and lipopolysaccharide plus folic acid group. The lipopolysaccharide and folate mice are exposed to an environment of Lipopolysaccharide (LPS). On 3 to 5 days of birth, newborn Kunming mice are removed from their nests for about 5 minutes, weighed, and given daily intraperitoneal injections of Folic Acid (FA) at a concentration of 4mg/kg and LPS at 0.6 mg/kg.
1.2 Western blot experiment
After anesthesia and neck-broken death, brain tissue was rapidly extracted and stored at-80 ℃. Taking out mouse brain tissue from-80 deg.C, cracking with RIPA strong lysate containing protease and phosphatase inhibitor on ice for 40min, and mixing; total protein was then obtained by centrifugation at 8000rpm for 15min at 4 ℃ and the total protein concentration was determined using bicinchoninic acid (BCA) kit. Taking supernatant into an EP tube, uniformly mixing the supernatant with a protein buffer (1: 4), boiling for 5min at 100 ℃, carrying out electrophoresis (the sample loading amount is about 30000ng) by using 10-12% SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis), then carrying out wet electrotransfer to a polyvinylidene fluoride (PVDF) membrane, sealing for 2h by using 5% skimmed milk powder, carrying out overnight at 4 ℃ by using a primary antibody (1: 1000 dilution), incubating for 1h by using a secondary antibody (1: 10000 dilution) after washing, displaying a result by chemiluminescence, exposing an X-ray (kodak) for 20-30 s, obtaining a result by scanning, carrying out grayscale scanning on the result, carrying out semi-quantification, and calculating a relative value by using beta-Actin as an internal reference.
1.3 Total RNA extraction and real-time quantitative PCR reaction
After anesthesia and neck-broken death, brain tissue is extracted quickly and stored in liquid nitrogen. Adding a proper amount of mouse brain tissue into 1ml of Trizol reagent, grinding the tissue, and standing for 5min at room temperature; adding chloroform 200ul, shaking and mixing until the solution turns to milk white, and standing at room temperature for 5 min; then, the mixture was centrifuged at 12000rpm for 20min in a 4 ℃ centrifuge. Extracting supernatant, mixing with isopropanol at a ratio of 1:1, shaking, and standing at room temperature for 2 hr; centrifuging at 4 deg.C for 15min, washing with 75% anhydrous ethanol for 2 times, centrifuging at 4 deg.C for 10 min/time, idling at 4 deg.C for 2min, and removing ethanol to obtain precipitate. After washing, adding double distilled water treated by diethyl pyrocarbonate (DEPC), measuring the concentration of RNA to ensure that the loading amount is 1 mu g, adding other reagents according to the requirements of the kit, and carrying out reverse transcription according to the instructions to prepare cDNA. Diluting the prepared cDNA with the same amount of DEPC water without RNase, adding gene specific primers and SybrGreen to prepare PCR reaction solution, and placing the PCR reaction solution on a Real time PCR instrument for PCR reaction. The primer sequences used in the experiment are presented in Supplementary Table 1. By 2-△△CtThe formula determines the relative expression. Beta-actin is used as an internal reference.
1.4 tissue immunofluorescence staining
The experimental animals are anesthetized by 10% chloral hydrate, then brain tissues are taken and fixed by perfusion of 4% paraformaldehyde, and frozen sections are obtained after sugar precipitation of 30% sucrose solution for immunostaining. And (3) dyeing: washing with 1XPBST for 3 times, each for 20 min; preparing 10% goat serum by using 5XPBST, permeabilizing and sealing for 3 h; primary antibody incubation, overnight at 4 ℃; washing with 1XPBST for 3 times, each for 20 min; sealing the fluorescent secondary antibody in dark for 1 h; washing with 1XPBST for 3 times, each for 20 min; DAPI staining, PBST washing; and sealing the anti-fluorescence quencher, taking pictures under a fluorescence microscope and analyzing.
1.5 tissue HE staining
The experimental animals were anesthetized with 10% chloral hydrate, then brain tissue was perfused with 4% paraformaldehyde and fixed overnight, and after rinsing the brain tissue with PBS, 70% and 80% were used. Dehydrating with 90%, 95% and 100% gradient alcohol, and then adding anhydrous alcohol: xylene (1: 1), xylene I, xylene II, and then according to the weight ratio of xylene: paraffin (2: 1), xylene: and (3) performing gradient wax dipping treatment on paraffin (1: 1), paraffin I and paraffin II. The tissue blocks were embedded with a paraffin embedding machine, and after the embedding was completed, they were placed in a paraffin slicer to slice 5 μm thick.
HE staining: and (4) putting the slices into dimethylbenzene for dewaxing treatment, wherein the dewaxing treatment is carried out according to the proportion of 100%. 95 percent and 90 percent. Hydrating with 80%, 70%, 50%, and 30% alcohol gradient, washing with distilled water, staining with hematoxylin, washing with distilled water to turn blue, separating color with 0.5% hydrochloric acid alcohol, and washing with distilled water. The sections were dehydrated with 70%, 80%, 90% gradient alcohol, stained with eosin, then twice with 100% alcohol, transparent in xylene, finally mounted on neutral resin mounting and photographed under an optical microscope.
1.6 statistical analysis
Data are expressed by mean + -SEM with significance set at P < 0.05 and statistical methods of data take t-test, one-way analysis of variance or two-way analysis of variance and statistical analysis is performed using SPSS software.
Second, experimental results
2.1 Folic acid can inhibit the activation of microglia and astrocytes in the brain of mice caused by LPS.
To verify the anti-inflammatory effects of folate in the brain, the effect of folate on microglial and astrocyte activation was first examined. GFAP staining by immunofluorescence+And Iba-1+The positive cell number is verified, and the folic acid is found to obviously reduce mouse intracerebral GFAP caused by LPS+And an increase in the number of Iba-1+ positive cells (FIGS. 1A, 1B and 1C). The effect of folic acid on the protein and mRNA levels of GFAP and Iba-1 was also verified and it was found that folic acid was effective in inhibiting the expression of GFAP and Iba-1 by LPS at the protein and mRNA levels (FIGS. 1D, 1E and 1F). HE staining results showed that folate significantly ameliorated LPS-induced inflammatory changes in brain tissue, such as decreased vacuolation of cells and densification of tissue from inflammatory porosity (fig. 1G). These results show that folic acid can inhibit LPS from activating glia cells in mouse brain and producing inflammatory reaction, and the function of folic acid in improving neonatal meningitis may be related to its anti-inflammatory action.
2.2 Folic acid has inhibitory effect on inflammatory reaction of central nervous system of newborn mouse caused by LPS.
In order to verify the influence of folic acid on the production of inflammatory factors caused by LPS in the newborn mouse brain, a protein immunoblotting experiment is carried out, and the experimental result proves that the LPS treatment can cause the generation of obvious inflammatory reaction in the mouse brain, meanwhile, the expression of proinflammatory factors such as TNF-alpha, iNOS and IL-1 beta is obviously increased on the protein level, and the folic acid obviously inhibits the generation of the changes (fig. 2A and 2B). Folate was detected by real-time quantitative PCR and was found to inhibit the expression of pro-inflammatory factors on the mRNA level by LPS simultaneously (FIG. 2C). It follows that folic acid has an anti-inflammatory effect in the inflammatory response of the central nervous system caused by LPS.
2.3 Folic acid can inhibit not only MAPK signal channel activation but also NF kappa B signal channel activation in the inflammatory reaction of microglia caused by LPS, but only NF kappa B signal channel activation in the inflammatory reaction of astrocytes caused by LPS.
In order to verify the anti-inflammatory action mechanism of folic acid in different glial cells, protein level changes of inflammation signal pathway related molecules are observed through western blotting experiments. It was found that LPS-induced activation of the NFKB signaling pathway could be inhibited by folate, but that folate had no effect on changes in the MAPK signaling pathway in astrocytes (fig. 3A). Whereas folic acid inhibited not only the activation of the NF κ B signaling pathway by LPS but also the activation of the MAPK signaling pathway in microglia (fig. 3B). This suggests that the mechanisms by which folic acid has an anti-inflammatory effect in the central nervous system and exerts an anti-inflammatory effect in the inflammatory response of microglia and astrocytes are different.
2.4 Folic acid alters the methylation state of different histone sites in astrocytes and microglia.
To verify the relationship between anti-inflammatory and epigenetic modification of folate, the methylation status of several classical histone methylation sites was next examined. It is found through experiments that folic acid influences the methylation state of different sites in different glial cell inflammatory responses. In astrocytes, folic acid inhibited the expression of H3K27me 3; and the expression of H3K9me3 is inhibited in microglia. This also suggests that the targets and mechanisms of action exerted by folate in different glial cells are different.
In conclusion, folic acid can obviously inhibit inflammatory reaction in the brain of the newborn caused by LPS. Folic acid has a close relationship between the treatment of neonatal meningitis and the anti-inflammatory effect of the neonatal meningitis. The folic acid is mainly related to the activation of classical inflammation signal pathways such as NF kappa B signal pathway, MAPK signal pathway and the like and the change of epigenetic modification. The folic acid plays different anti-inflammatory effects in the two types of glial cells, provides a new thought for the research of the action target of the neonatal meningitis medicament in the future and the clinical treatment of the neonatal intracerebral inflammatory diseases, and provides a new scientific basis for the clinical application value of the folic acid which can be used as an effective neonatal meningitis treatment medicament.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. Application of folic acid in preparing medicine for treating meningitis is provided.
2. The use of claim 1, wherein the meningitis is neonatal meningitis.
3. The use according to claim 2, wherein the treatment of neonatal meningitis is at least manifested in any one or more of the following uses:
a) ameliorating inflammatory changes in brain tissue;
b) inhibit the activation of brain glial cells;
c) inhibiting inflammatory reaction of central nervous system.
4. The use of claim 3, wherein in a), ameliorating inflammatory changes in brain tissue comprises a reduction in vacuolization of cells and/or densification of tissue from an inflammatory rarefaction.
5. The use of claim 3, wherein in b), the brain glial cells comprise microglia and astrocytes.
6. The use of claim 3, wherein in c), the inhibition of the inflammatory response of the central nervous system is manifested by inhibition of the expression of pro-inflammatory factors.
7. The use of claim 6, wherein the proinflammatory factors comprise TNF- α, iNOS, and IL-1 β.
8. A pharmaceutical composition for treating neonatal meningitis, which comprises folic acid and at least one other pharmaceutically active ingredient and/or at least one other non-pharmaceutically active ingredient.
9. The pharmaceutical composition of claim 8, wherein the non-pharmaceutically active ingredient is a pharmaceutically acceptable carrier, excipient or diluent.
10. The application of folic acid in preparing inflammation factor inhibitor; preferably, the inflammatory factors include TNF- α, iNOS, and IL-1 β.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030229030A1 (en) * | 2002-06-11 | 2003-12-11 | Theoharides Theoharis C. | Method of treating interleukin-6-mediated inflammatory diseases |
| CN1638751A (en) * | 2002-02-26 | 2005-07-13 | 默克阿泼洛发股份公司 | Use of folates for producing a preparation suitable for preventing and treating inflammation and diseases associated with inflammation, especially for influencing the inflammation markers CRP and SAA |
| CN103417977A (en) * | 2013-07-30 | 2013-12-04 | 天津城建大学 | Efficient folate receptor alpha subtype-mediated target drug delivery system |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1638751A (en) * | 2002-02-26 | 2005-07-13 | 默克阿泼洛发股份公司 | Use of folates for producing a preparation suitable for preventing and treating inflammation and diseases associated with inflammation, especially for influencing the inflammation markers CRP and SAA |
| US20030229030A1 (en) * | 2002-06-11 | 2003-12-11 | Theoharides Theoharis C. | Method of treating interleukin-6-mediated inflammatory diseases |
| CN103417977A (en) * | 2013-07-30 | 2013-12-04 | 天津城建大学 | Efficient folate receptor alpha subtype-mediated target drug delivery system |
Non-Patent Citations (2)
| Title |
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| TATIANA BARICHELLO 等: "Folic acid prevented cognitive impairment in experimental pneumococcal meningitis", 《J NEURAL TRANSM》 * |
| 刘国伟: "叶酸在星形胶质细胞炎症反应中的作用及其机制研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
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