CN111743894A - Application of sesquiterpene lactone compounds in preparation of medicine for treating optic neuritis - Google Patents
Application of sesquiterpene lactone compounds in preparation of medicine for treating optic neuritis Download PDFInfo
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- CN111743894A CN111743894A CN201910245076.3A CN201910245076A CN111743894A CN 111743894 A CN111743894 A CN 111743894A CN 201910245076 A CN201910245076 A CN 201910245076A CN 111743894 A CN111743894 A CN 111743894A
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- act001
- optic neuritis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
Abstract
The invention relates to the research of optic neuritis medicines, in particular to application of sesquiterpene lactone compounds in preparing medicines for treating optic neuritis. The research finds that ACT001 can effectively inhibit the inflammatory reaction of microglia, and can remarkably reduce the release of inflammatory factors including NO, TNF-alpha and IL-6. Has the effect of inhibiting BV2 cell proliferation. Has good curative effect on optic neuritis, especially optic neuromyelitis.
Description
Technical Field
The invention belongs to the field of medicines for autoimmune diseases, and particularly relates to application of sesquiterpene lactone compounds in preparation of medicines for treating optic neuritis.
Background
Neuromyelitis Optica (NMO) is a demyelinating disease that involves the optic nerve and spinal cord. The earliest report of the disease was seen in 1872 and was originally thought to be a single-course central nervous system disorder. In Asian countries, there are many reports on NMO, and only in China, there are over 30 ten thousand NMO patients. In the outpatient department of neurology and ophthalmology, classical NMO-related optic neuritis (C-NMO-ON) is mainly characterized by simultaneous or sequential onset of both eyes, rapid visual deterioration, with or without eye pain; visual function recovery is poor, often leaving behind severe visual impairment of both eyes or at least one eye. Recurrent NMO-related optic neuritis (R-NMO-ON) is frequently a single-eye disease, is easy to relapse, and visual function damage can be partially recovered but gradually weakened along with the increase of the disease frequency. A significant portion of NMO spinal cord damage occurs after visual deterioration, which can be spaced days, weeks, months or even years, eventually leading to paraplegia, sensory and sphincter dysfunction, and possibly respiratory muscle paralysis in the worst case. Since the recurrent NMO has many common characteristics with the recurrent optic neuritis in the initial clinical presentation, it is easily misdiagnosed as the latter, which delays the treatment time on the one hand, and on the other hand, the treatment means of optic neuritis aggravates the condition of NMO, causing more serious consequences.
For a long time, there has been controversy over whether NMO is an independent disease or a subtype of Multiple Sclerosis (MS), and recent studies have found that Aquaporin 4 (AQP 4) autoantibodies (AQP4-Ab) in serum are a very specific indicator in NMO diagnosis with high sensitivity (68-91%) and specificity (85-99%).
NMO is specific due to its particular pathogenesis. Further studies have shown that AQP4-Ab specifically binds to aquaporin 4(aquaporin 4, AQP4) on the astrocytic end-foot in the Central Nervous System (CNS). It is now known that the damaging effects of AQP4-Ab on astrocytes can be achieved by both complement dependent cytotoxicity and antibody dependent cytotoxicity. According to the latest report by Verkman research team, injection of AQP4-Ab into brain parenchyma caused NMO-like tissue pathology. Specific pathological changes include: astrocytic damage, oligodendrocyte depletion, myelin loss, and neuronal apoptosis. This phenomenon is in part similar to the pathological changes that occur in patients and can therefore be used to study the pathogenic mechanisms at the cellular level during the onset of NMO. The current relatively consistent view on the pathogenic mechanism of NMO is that AQP4-Ab causes astrocyte death before it causes demyelinating disease, during which a large number of inflammatory factors are released with abnormal activation of microglia, forming the inflammatory pathogenic microenvironment of NMO disease. The research surrounding AQP4 and the discovery of AQP4-Ab finally isolated NMO from multiple sclerosis.
Current treatments for NMO mainly include acute phase treatments and remission phase treatments. Acute phase therapy aims at reducing the dysfunction of the nervous system as much as possible and promoting the recovery of diseases, and at present, the acute phase therapy mainly comprises large-dose methylprednisolone impact therapy, plasma replacement, intravenous injection of immunoglobulin, cyclophosphamide and the like; remission therapy, which is primarily aimed at reducing the number and severity of relapses, is primarily the use of immunosuppressive agents, including azathioprine, mycophenolate mofetil, mitoxantrone, methotrexate, rituximab, and the like. However, the existing treatment methods are all wide in inhibition of the systemic immune system and alleviation of systemic autoimmune reaction, the systemic side effects of patients are large, the risk of serious infection is caused, and hormone tolerance is easily caused by the treatment methods, so that treatment failure is caused.
Therefore, NMO lacks a safe and effective drug seriously, clinical needs are not met, and the need for developing a new drug for treating the disease is urgent.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides application of sesquiterpene lactone compounds in preparation of medicines for treating optic neuritis through research.
In another preferred embodiment of the present invention, the optic neuritis is neuromyelitis optica.
In another preferred scheme of the invention, the sesquiterpene lactone compound and pharmaceutically acceptable auxiliary materials are prepared into a medicament.
In another preferred embodiment of the present invention, the pharmaceutical agent is a liquid agent, a gaseous agent, a solid dosage form or a semisolid agent.
In another preferred embodiment of the present invention, the pharmaceutical agent is an injection.
In another preferred embodiment of the present invention, the pharmaceutical agent is an oral agent.
In another preferred embodiment of the present invention, the oral preparation is a capsule.
In another preferred embodiment of the present invention, the oral agent is a pill.
In another preferred embodiment of the present invention, the sesquiterpene lactone compound is a michelia lactone derivative.
The sesquiterpene lactone compounds are used for preparing the medicine for treating the optic neuritis for the first time, and the prepared medicine has a good curative effect on treating the optic neuromyelitis.
Drawings
FIG. 1 illustrates ACT001 of the formula according to an embodiment of the present invention;
FIG. 2 is a graph showing the results of a BV-2 cytotoxicity test in ACT001 according to an embodiment of the present invention;
FIG. 3 is a graph of TNF- α release following the inhibition of BV-2 activation by LPS by ACT001 in accordance with an embodiment of the present invention;
FIG. 4 is a graph of IL-6 release following the inhibition of BV-2 activation by LPS by ACT001 in accordance with an embodiment of the present invention;
FIG. 5 is a graph of NO release following inhibition of BV-2 activation by LPS by ACT001 in accordance with an embodiment of the present invention;
FIG. 6 is a graph of the ACT001 model score for alleviating symptoms of Lewis rat NMO disease according to the present invention.
Detailed Description
The present invention will now be described in detail with reference to the drawings, which are given by way of illustration and explanation only and should not be construed to limit the scope of the present invention in any way. Furthermore, features from embodiments in this document and from different embodiments may be combined accordingly by a person skilled in the art from the description in this document.
Example 1
The molecular formula of the sesquiterpene lactone compound for preparing the medicine for treating neuromyelitis optica studied in the embodiment is shown in figure 1, and the sesquiterpene lactone compound is also called as ACT001, and the chemical name of the ACT001 is as follows: (3R,3aS,9R,9aS,9bS) -3- ((dimethylamino) methyl) -9-hydroxy-6, 9-dimethyl-3, 3a,4,5,7,8,9,9 a-octahydroazuno [4,5-b ] furan-2 (9bH) -one fumarate, is a michelia lactone derivative. The molecular formula is shown in figure 1. This example uses ACT001 to conduct a therapeutic study in patients with AQP4 autoimmune antibody positive neuromyelitis optica.
The pharmacological efficacy experiment is as follows:
1. we first performed in vitro tests on the active principle, and according to the results of the in vitro tests, ACT001 showed in vitro inhibition of the proliferation of BV-2 cells, with an IC50 value of 23.6. mu.M. And can remarkably reduce the release of microglia inflammatory factors (TNF-alpha, IL-6, NO) activated by LPS at 10 mu M and reduce the microglia inflammatory response.
Meanwhile, before establishing an NMO animal model, firstly, a spinal cord intrathecal catheterization operation is performed on a Lewis rat, and an outlet can be placed at the position of the first segment of the lumbar spine of the spinal cord of the rat by controlling the length (7cm) of a PE10 flexible pipe. Lewis rats after spinal intrathecal catheterization. The next day after the operation, the rats had no difference in behavior from normal rats, the rats successfully modeled were divided into three groups, and 10 μ L each of the NMO patient serum and complement system was injected into the soft tubes of the rats after intubation, and was replenished every four days. The administration scheme is that 6 animals in the model control group are administered with physiological saline by intragastric administration every day for 15 days continuously; the injection methylprednisolone amber solution is administrated to 8 animals in the hormone group by intragastric gavage every day, the dose is 30mg/kg, and the continuous 15 days are carried out; ACT001 group 6 animals were gavaged daily with a dose of 60mg/kg ACT001 solution for 15 consecutive days. The animal status was observed daily and behavioral scores were recorded based on animal symptoms. The results show that the animals in ACT001 group were well tolerated, and disease symptoms were significantly alleviated compared to the normal saline control group, and that the effect of alleviation in ACT001 group was similar compared to the hormone-treated group, with a substantially flat overall score.
Firstly, an in vitro MTT method and a CCK8 method are applied to evaluate the influence of the ACT001 on the proliferative activity of the microglia BV2, and the result shows that the ACT001 has the effect of inhibiting the proliferation of the BV2 cells in vitro, particularly shows that the IC of the ACT001 on the BV2 cells50The value was 23.6. + -. 2.34. mu.M, as shown in Table 1 and FIG. 2.
TABLE 1 in vitro Activity inhibition of ACT001 on BV2 cells
2. ACT001 inhibiting BV2 cell activity in vitro
BV2 cells were digested, counted, and plated in 24-well plates with 1 ml/well, 20000 cells, 5% CO2, and cultured overnight in 37 ℃ incubator. 1 mug/mL LPS was added to all wells for 1h, then different concentrations of ACT001 were added, and five experimental groups were set up, respectively: a control group; ACT 001-2.5. mu.M group; ③ ACT001-5 μ M group; ACT001-10 μ M group; ACT001-20 μ M group, ACT for 8h, after the drug effect is finished, collect the supernatant, centrifuge at 12000rpm for 20min, and perform ELISA according to the kit instruction steps.
FIG. 2 is a graph showing the effect of ACT001 on the proliferative activity of BV2, and it can be seen from FIG. 2 that the ACT001 group decreased IL-6 expression in BV-2 cells compared with the control group, and the inhibition was increased with the increase of the acting dose of ACT001, and the dose was dose-dependent, and the P-values of ACT 00110. mu.M and ACT 20. mu.M were both less than 0.001, i.e. significantly decreased, and the trend was consistent with the three replicates.
3. Effect of ACT001 on IL-6 expression
BV2 cells were digested and countedInoculating 24-well plate, 1ml of 40000 cells per well, 5% CO2And culturing in an incubator at 37 ℃ overnight, adding 1 mu g/ml LPS into all the wells, reacting for 1h, adding ACT001 with different concentrations, setting five experimental groups, namely ① control group, ② ACT001-2.5 mu M group, ③ ACT001-5 mu M group, ④ ACT001-10 mu M group and ⑤ ACT001-20 mu M group, reacting for 24h, collecting supernatant after the drug action is finished, centrifuging at 12000rpm for 20min, and performing ELISA according to the kit instruction steps.
Fig. 3 shows the effect of ACT001 on IL-6 expression (. about.p <0.05,. about.p <0.01,. about.p <0.001), and it can be seen from fig. 3 that the ACT001 group decreased the expression of TNF α in BV-2 cells compared to the control group, and the inhibition was increased with increasing dose of ACT001, which was dose-dependent, and the P value of ACT001 dose group was less than 0.001, i.e., very significantly decreased, and the trend was consistent with the three-fold trend.
4. Effect of ACT001 on TNF α expression
BV2 cells were digested, counted, and plated in 24-well plates with 1 ml/well, 40000 cells, 5% CO2And culturing in an incubator at 37 ℃ overnight, adding 1 mu g/mL LPS into all the wells, reacting for 1h, adding ACT001 with different concentrations, setting five experimental groups, namely ① control group, ② ACT001-2.5 mu M group, ③ ACT001-5 mu M group, ④ ACT001-10 mu M group and ⑤ ACT001-20 mu M group, reacting for 24h, collecting supernatant after the drug action is finished, centrifuging at 12000rpm for 20min, and performing ELISA according to the kit instruction steps.
Fig. 4 shows the effect of ACT001 on TNF α expression (. P <0.05,. P <0.01,. P <0.001), and it can be seen from fig. 4 that the ACT 0012.5, 5 and 10 μ M dose groups all reduced NO expression in BV-2 cells compared to the control group, and the inhibition was enhanced with increasing dose of ACT001, and was dose-dependent, wherein the ACT 00110 μ M dose group was significantly reduced compared to the control group.
5. Fig. 5 is a graph of the effect of ACT001 on NO expression (. P <0.05,. P <0.01,. P <0.001), and it is known from fig. 5 that ACT001 significantly reduced the pathological release of microglia NO at a concentration of 5 μ M.
6. Effect of ACT001 on NMO patient in vitro testing and animal models
10 mu L of each of serum and a complement system of an NMO patient are injected into a rat soft tube successfully subjected to spinal cord sheath indwelling catheter operation, and the serum and the complement system are supplemented once every four days to establish an NMO animal model. Model animals were randomized into three groups: the physiological saline group, the hormone (methylprednisolone sodium succinate for injection) group and the ACT001 group have the following administration schemes:
that is, the dosage of group B is about 5mg/kg of ACT001 administered to human body after ACT001 and pharmaceutically acceptable excipients are formulated into a medicament, and the dosage of group C is about 10mg/kg of ACT001 administered to human body after ACT001 and pharmaceutically acceptable excipients are formulated into a medicament.
Behavioral scoring was performed based on animal symptoms.
The scoring criteria were as follows:
0 minute: no clinical symptoms;
1 minute: reduced tail tension or mild gait clumsiness;
and 2, dividing: no tension or moderate gait abnormality in the tail; the two hind limbs are weak and can recover after being turned over passively;
and 3, dividing: paralysis of both hind limbs. The patient can not recover after passively turning over, but can move after stimulation;
and 4, dividing: paralysis of both hind limbs. Paralysis of the forelimbs or loss of muscle strength with urinary and fecal incontinence;
and 5, dividing: moribund status or death.
Symptoms were calculated as ± 0.5 between the two criteria.
The experimental results show that during the administration period, animals in the ACT001 group tolerated well, disease symptoms were significantly alleviated compared to the normal saline control group, the alleviating effect was similar in the ACT001 group compared to the hormone treated group, and the behavioral scores were substantially leveled. The results of the experiment are shown in table 2 and fig. 6:
TABLE 2 behavioral scores for groups of animals
Note: p <0.05, P <0.01, P <0.001, compared to saline
Figure 6 is animal model behavioral scores. It can be seen from table 2 and fig. 6 that ACT001 can significantly reduce the behavioral scores of NMO animal models, improve symptoms in NMO disease models, and have no weaker effect than hormones.
TABLE 3 in vivo pharmacodynamic test
As can be seen from the above results, ACT001 has a significant advantage in the treatment of NMO. By carrying out an ACT001 in vitro activity test, the IC50 value of the ACT001 to BV-2 microglia is 23.6 mu M, and the release of inflammatory factors including NO, TNF-alpha and IL-6 can be obviously reduced, thereby inhibiting the microglial inflammatory reaction triggered by LPS stimulation.
In an animal model of neuromyelitis optica, experimental results show that ACT001 can significantly relieve clinical symptoms of the animal model of neuromyelitis optica, and the behavioral score of a saline group is 3.17 +/-0.26, while that of the ACT001 group is 2.00 +/-0.32 after 15 days of continuous administration, so that ACT001 is basically leveled with the behavioral score of a hormone group of 2.31 +/-0.26. The ACT001 can replace hormone to become a brand new treatment mode for NMO diseases clinically.
We prefer ACT001, and we have shown that derivatives of sphaelactone and salts thereof have the effect of treating neuromyelitis optica in addition to ACT001, according to the above experiments.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (7)
1. The application of sesquiterpene lactone compounds with the following molecular formula in preparing the medicine for treating the optic neuritis comprises the following steps:
2. the use of sesquiterpene lactones according to claim 1 in the manufacture of a medicament for the treatment of optic neuritis, wherein said optic neuritis is neuromyelitis optica.
3. The use of sesquiterpene lactones according to claim 1 in the manufacture of a medicament for the treatment of optic neuritis, wherein sesquiterpene lactones are formulated with pharmaceutically acceptable excipients.
4. The use of sesquiterpene lactones according to claim 1 in the manufacture of a medicament for the treatment of optic neuritis, wherein said medicament is in the form of a liquid, a gas, a solid, or a semi-solid.
5. The use of sesquiterpene lactones according to claim 4 in the manufacture of a medicament for the treatment of optic neuritis, wherein said medicament is an injection.
6. The use of sesquiterpene lactones according to claim 4 in the manufacture of a medicament for the treatment of optic neuritis, wherein said medicament is an oral formulation.
7. Use of sesquiterpene lactones according to any one of claims 1-6 in the manufacture of a medicament for the treatment of optic neuritis, characterized in that the sesquiterpene lactones are michelia lactone derivatives.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2022041123A1 (en) * | 2020-08-28 | 2022-03-03 | 洛阳尚德药缘科技有限公司 | Application of sesquiterpene lactone in preparing drug for treating optic neuritis |
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| AU2011205095A1 (en) * | 2004-02-03 | 2011-08-25 | The Regents Of The University Of California | Chlorite in the treatment of neurodegenerative disease |
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| AU2011205095A1 (en) * | 2004-02-03 | 2011-08-25 | The Regents Of The University Of California | Chlorite in the treatment of neurodegenerative disease |
| CN103550787A (en) * | 2013-11-11 | 2014-02-05 | 苏州大学 | MicroRNA (ribonucleic acid) antagonist and application thereof |
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| WO2022041123A1 (en) * | 2020-08-28 | 2022-03-03 | 洛阳尚德药缘科技有限公司 | Application of sesquiterpene lactone in preparing drug for treating optic neuritis |
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