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WO2019131136A1 - Agent protecteur du cerveau - Google Patents

Agent protecteur du cerveau Download PDF

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Publication number
WO2019131136A1
WO2019131136A1 PCT/JP2018/045708 JP2018045708W WO2019131136A1 WO 2019131136 A1 WO2019131136 A1 WO 2019131136A1 JP 2018045708 W JP2018045708 W JP 2018045708W WO 2019131136 A1 WO2019131136 A1 WO 2019131136A1
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WO
WIPO (PCT)
Prior art keywords
group
hydrogen atom
peridinin
cerebral ischemia
protective agent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2018/045708
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English (en)
Japanese (ja)
Inventor
健一 小野寺
東　洋一郎
源顕 齊藤
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
JSR Corp
Kochi University NUC
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JSR Corp
Kochi University NUC
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Priority to JP2019562954A priority Critical patent/JP6966804B2/ja
Publication of WO2019131136A1 publication Critical patent/WO2019131136A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
    • 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
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a drug for effectively protecting brain tissue from an inflammatory reaction caused by cerebral ischemia.
  • Stroke (cerebrovascular disorder) is mainly classified into cerebral infarction, cerebral hemorrhage and subarachnoid hemorrhage.
  • cerebral infarction cerebral blood flow is insufficient due to blockage or thinning of cerebral blood vessels due to arteriosclerosis in cerebral blood vessels and thrombus made of blood vessels other than the brain being transported to the brain.
  • Hematological disorder is a disease that causes necrosis.
  • intracerebral hemorrhage bleeds in the brain due to high blood pressure, aging, etc., and a blood clot compresses brain cells.
  • Subarachnoid hemorrhage is the occurrence of hemorrhage in the subarachnoid space due to rupture of the cob in the cerebral artery.
  • necrotic brain tissue is not restored, and even if life is saved, not only motor paralysis, sensory disorders, speech disorders but also dementia symptoms often remain.
  • diseases called lifestyle-related diseases such as high blood pressure, heart disease, hyperlipidemia and diabetes are increasing, and the risk of stroke is increasing accordingly.
  • cerebrovascular disease is the third leading cause of death next to cancer and ischemic heart disease, and this is also the case in advanced Western countries. Thus, an effective means of treating stroke is needed.
  • thrombolytic agents such as tissue-type plasminogen activator have been used to lyse the thrombus that caused the cerebral infarction and resume blood flow.
  • tissue-type plasminogen activator have been used to lyse the thrombus that caused the cerebral infarction and resume blood flow.
  • disorders caused by free radicals caused by blood flow resumption are also deeply involved in the post-ischemic condition, and thrombolytic agents alone do not provide a fundamental solution for brain tissue necrosis.
  • edaravone which is a radical scavenger
  • edaravone has side effects such as hepatic dysfunction and renal dysfunction, and there are also data that abnormal changes in clinical laboratory test values, such as abnormal liver function test values, reach as much as 21.4% of the patients who receive it. No matter how lethal the treatment is for cerebral infarction, which is a fatal disease, such high side effect rate is problematic.
  • peridinin which is a natural marine carotenoid, exhibits an excellent inhibitory effect on delayed allergy, and has filed a patent application (Patent Document 1).
  • an object of the present invention is to provide a drug for effectively protecting brain tissue from an inflammatory reaction caused by cerebral ischemia.
  • the present inventors have intensively studied to solve the above problems. As a result, they have found that certain carotenoid compounds can suppress the excessive release of inflammatory cytokines after reperfusion following cerebral ischemia and can reduce the excessive inflammatory response, thereby completing the present invention.
  • the present invention is described.
  • a brain protective agent comprising a carotenoid compound represented by the following formula (I) as an active ingredient.
  • R 1 to R 3 independently represent a hydrogen atom or a C 1-18 alkanoyl group
  • R 4 to R 17 independently represent a hydrogen atom or a C 1-6 alkyl group, provided that R n and R n + 2 (n is an integer of 4 or more and 15 or less) are bonded to each other May form an ester group
  • the brain protective agent according to the present invention can protect brain tissue by suppressing excessive release of inflammatory cytokines after reperfusion following cerebral ischemia and reducing excessive inflammatory reaction that damages brain tissue. Such action mechanism is not found in conventional brain protective agents. Also, although it is an approved drug, its active ingredient is a carotenoid compound as compared with edaravone according to the present invention, as compared with edaravone, which has a short half-life due to a radical scavenger, and a severe action and a serious side effect. It can be said that there is little safety. Therefore, the brain protective agent according to the present invention is very useful as one that can reduce the sequelae after stroke.
  • FIG. 1 is a graph of in vitro experimental results showing the suppressive effect of peridinin according to the present invention on the excessive release of inflammatory cytokines by microglia caused by zinc ions.
  • FIG. 2 is a graph of in vivo experimental results showing the suppressive effect of peridinin according to the present invention on the excessive release of inflammatory cytokines in the hippocampus caused by zinc ions.
  • FIG. 3 is a photograph and a graph of in vitro experimental results showing the inhibitory effect of peridinin according to the present invention on the generation of active oxygen in microglia caused by zinc ions.
  • FIG. 1 is a graph of in vitro experimental results showing the suppressive effect of peridinin according to the present invention on the excessive release of inflammatory cytokines by microglia caused by zinc ions.
  • FIG. 2 is a graph of in vivo experimental results showing the suppressive effect of peridinin according to the present invention on the excessive release of inflammatory cytokines in the hippocampus caused by
  • FIG. 4 is a photograph and graph showing the anti-inflammatory effect of peridinin on activation of hippocampal microglia to type M1 after reperfusion following cerebral ischemia.
  • FIG. 5 is a graph showing the results of a Y-maze test to determine whether pre-administration of peridinin has a protective effect on short-term spatial recognition memory loss.
  • the brain protective agent according to the present invention contains a carotenoid compound represented by the above formula (I) (hereinafter sometimes abbreviated as “carotenoid compound (I)”) as an active ingredient.
  • carotenoid compound (I) a carotenoid compound represented by the above formula (I)
  • C 1-18 alkanoyl group which is R 1 to R 3 in the above formula (I) refers to a formyl or C 1-17 alkyl-carbonyl group, wherein “C 1-17 alkyl group” is carbon number 1 or more and 17 or less linear or branched monovalent saturated hydrocarbon groups.
  • C 1-18 alkanoyl group in addition to formyl, for example, acetyl, ethyl carbonyl, n-propyl carbonyl, isopropyl carbonyl, n-butyl carbonyl, pivaloyl, n-hexyl carbonyl, n-octyl carbonyl, n-nonyl carbonyl, 6-methyloctyl carbonyl, 7-methyloctyl carbonyl, n-decyl carbonyl, 8-methyl nonyl carbonyl, n-undecyl carbonyl, 9-methyl decyl carbonyl, n-dodecyl carbonyl, 10-methyl undecyl carbonyl, n-tri Examples include decylcarbonyl, 11-methyldodecylcarbonyl, n-tetradecylcarbonyl, n-pentadecylcarbonyl, n-hexa
  • C 1-18 alkanoyl group a C 1-8 alkanoyl group or a C 9-18 alkanoyl group is preferable, a C 1-6 alkanoyl group is more preferable, a C 1-4 alkanoyl group is more preferable, and a C 1-2 alkanoyl group is more preferable.
  • Groups are more preferred, with acetyl being particularly preferred.
  • the “C 1-6 alkyl group” which is R 4 to R 17 in the above formula (I) refers to a linear or branched monovalent saturated hydrocarbon group having 1 to 6 carbon atoms.
  • methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, n-hexyl and the like can be mentioned, preferably a C 1-4 alkyl group More preferably, it is a C 1-2 alkyl group, and most preferably methyl.
  • carotenoid compound (II) can be mentioned as carotenoid compound (I).
  • R 1 to R 3 are as defined above.
  • peridinin is a hydrogen atom in which R 1 and R 2 are hydrogen, R 3 is acetyl, R 4 , R 5 , R 7 , R 9 and R 11 to R 16 are hydrogen atoms, R 10 and R 17 Is methyl and X is a single bond.
  • Symbiodinium sp. which is a dinoflagellate.
  • Peridinin a natural carotenoid compound isolated from OTCL2A strain and the like, has the following steric structure.
  • Fucoxanthin which is a naturally occurring carotenoid compound mainly isolated from non-uniform algae such as brown algae, has the following three-dimensional structure.
  • the carotenoid compound (I) used in the present invention can be isolated and purified from algae since it is mainly a natural marine carotenoid.
  • the above peridinin is Symbiodinium sp. It can be isolated and purified from dinoflagellate such as OTCL2A strain.
  • peridinin is demonstrated as an example, other carotenoid compound (I) can also be isolated by the same method from algae.
  • the dinoflagellate producing peridinin Symbiodinium sp. are symbiotic with symbiotic relationships with marine invertebrates. As marine animals that are hosts, there can be mentioned foraminifers, radiolarians, flatworms angut, jellyfish, corals, bivalves and the like. Thus, to isolate peridinin from nature, the dinoflagellate Symbiodinium sp. Is isolated from the marine animal and cultured, and the cultured dinoflagellate may be homogenized and then extracted. It is also possible to extract peridinin directly from marine animals that contain peridinin producing dinoflagellate. In the case of using marine animals, as in the case of using dinoflagellate, marine animals containing dinoflagellate may be homogenized and then extracted.
  • the extraction solvent may be selected as appropriate.
  • alcohol solvents such as methanol and ethanol
  • ketone solvents such as acetone and methyl ethyl ketone
  • halogenated hydrocarbon solvents such as dichloromethane and chloroform
  • aromatics such as benzene and toluene Hydrocarbon solvents
  • ester solvents such as methyl acetate and ethyl acetate
  • ether solvents such as diethyl ether and tetrahydrofuran
  • amide solvents such as dimethylformamide and dimethylacetamide; among these organic solvents having a concentration of 60 v / v% or more
  • a mixed solvent of water miscible organic solvent and water can be mentioned.
  • the extraction conditions may be adjusted as appropriate.
  • the extraction can be performed at normal temperature, but may be heated to about 30 to 60 ° C. depending on the air temperature in order to enhance the extraction efficiency.
  • the dinoflagellate may be ground in the extraction solvent after the extraction solvent is added to the dinoflagellate.
  • the extraction time is not particularly limited, but can be, for example, about 1 hour or more and 10 days or less.
  • the extraction operation for example, by measuring the action of production of inflammatory cytokines in the same manner as in Examples described later or referring to physical property data of known compounds, etc., by chromatography such as thin layer chromatography, HPLC, preparative chromatography, etc.
  • the active ingredient may be specified.
  • the carotenoid compound (I) may be isolated from algae, or may be produced by derivatizing the isolated compound.
  • a carotenoid compound (I) in which any one or more of R 1 to R 3 is a C 1-18 alkanoyl group can be produced by esterifying a predetermined hydroxyl group. Such esterification can be carried out by a method known to those skilled in the art using an acid corresponding to a C 1-18 alkanoyl group, or an activated ester compound thereof or an acid chloride compound, and further, if necessary, a condensing agent.
  • R 3 of peridinin and fucoxanthin which are natural compounds among the carotenoid compounds (I) is an acetyl group.
  • the brain protective agent according to the present invention can protect the brain by suppressing excessive inflammatory reaction caused by zinc ions after reperfusion following cerebral ischemia. Therefore, it may be administered prophylactically before cerebral ischemia, but if it is difficult, it is preferable to administer it after cerebral ischemia and further simultaneously with or after reperfusion treatment. According to the experimental findings by the present inventors, the brain protective agent according to the present invention can suppress active oxygen at the time of reperfusion following cerebral ischemia and M1 type microglia which causes excessive inflammatory reaction. it can. Examples of patients to which the brain protective agent according to the present invention should be administered include humans and animals other than humans.
  • the dosage form or administration form of the brain protective agent according to the present invention is preferable.
  • an isotonic solution of plasma such as physiological saline or glucose aqueous solution whose pH has been adjusted can be used.
  • the carotenoid compound (I) is dried together with salts etc.
  • pure water, distilled water, sterilized water etc. can also be used if the solution finally becomes isotonic or nearly isotonic with plasma.
  • the concentration may also be that of a normal injection, and can be, for example, 0.05 mg / mL or more and 10 mg / mL or so.
  • the dosage of the brain protective agent of the present invention is not particularly limited, and may be appropriately adjusted according to the age, sex, weight, symptoms, severity, etc. of the patient. It can be about 0.5 mg / kg body weight or more and 100 mg / kg body weight or less.
  • the administration time per one dose can be about 10 minutes or more and about 2 hours or less.
  • the number of times of administration per day can be about 0.5 times or more and 5 times or less.
  • Example 1 Isolation of peridinin The dinoflagellate Symbiodinium sp. From the red sea mussel Tridacna crocea. The OTCL2A strain was isolated and cultured. 100.2 g of frozen cells obtained from 156 L of culture solution are homogenized in 200 mL of 70% ethanol using a homogenizer ("Ultra-Turrax T25" made by Janke & Kunkel) and allowed to stand at 4 ° C for 3 days and then centrifuged separated. The supernatant was collected, and the above operation was repeated twice on the precipitate. All supernatants were combined and concentrated in vacuo.
  • Microglia were isolated from the brain of 1-day-old neonatal mouse C57BL / 6, and a medium for cell culture ("Eagle MEM” Fetal Bovine Serum produced by Nissui Pharmaceutical (Thermo) And the cells were cultured at 37.degree. C. for 2 weeks.
  • the resulting microglia culture solution was added to a cell culture well plate at 300 ⁇ L per well (about 6.4 ⁇ 10 5 cells / well).
  • 50 ⁇ L of a 0.03-0.3 ⁇ g / mL aqueous solution of peridinin was added per well, and the mixture was incubated at 37 ° C. for 30 minutes.
  • microglia were activated to type M1 by adding 50 ⁇ L of 1 ng / mL aqueous solution of lipopolysaccharide per well and incubating at 37 ° C. for 22 hours. The culture supernatant was collected, and the concentrations of inflammatory cytokines IL-1 ⁇ , TNF ⁇ and IL-6 were measured by ELISA.
  • Example 2 A 10 to 100 ⁇ g / mL aqueous solution of peridinin or 2 ⁇ L of a 0.1 mM aqueous solution of CaEDTA, which is a chelating agent, was administered to the intracerebroventricular zone of a male C57BL / 6N mouse weighing approximately 35 g and 12 weeks old. Within 10 minutes of administration, cerebral ischemia was achieved by occlusion of the bilateral common carotid arteries for 20 minutes, followed by reperfusion. Three days after cerebral ischemia treatment, total RNA was extracted from the hippocampus of each mouse, and gene expression levels of inflammatory cytokines TNF ⁇ , IL-6 and IL-1 ⁇ were measured by real-time PCR.
  • Example 3 It was tested whether peridinin could suppress the generation of reactive oxygen species (ROS) caused by zinc in microglia.
  • the microglia were precultured for 30 minutes in a medium containing or not containing 1 ⁇ M dihydroethidium (DHE) and 300 ng / mL of peridinin, and then cultured for 2 hours in the presence of 60 ⁇ M ZnCl 2 .
  • DHE indicates the amount of superoxide anion radical and is used to detect active oxygen.
  • the microglial cells were observed under magnification with an all-in-one fluorescence microscope ("BZ-9000" manufactured by Keyence Corporation) to detect cells stained with DHE. The results are shown in FIGS. 3A and 3B. In addition, the result of FIG.
  • FIG. 3B is an average value of 4 examples.
  • “*” indicates that there is a significant difference at p ⁇ 0.05 with respect to the control
  • “#” indicates that there is a significant difference at p ⁇ 0.05 with respect to the ZnCl 2 only treatment group.
  • Example 4 In order to confirm the anti-inflammatory effect of peridinin on activation of hippocampal microglia to type M1 after reperfusion following cerebral ischemia, double immunostaining with the microglia marker Iba1 is used as a representative M1 marker The expression of certain CD16 / 32 was examined. The results are shown in FIGS. 4A and 4B. In addition, the result of FIG. 4B is an average value of six examples. In FIG. 4B, "*" indicates that there is a significant difference at p ⁇ 0.05 with respect to the solvent-treated sham-operated mouse group, and "#" and "##” indicate that there is a difference with respect to the solvent-treated cerebral ischemia-operated mouse group.
  • Example 5 To determine whether pre-administration of peridinin had a protective effect on short-term loss of spatial recognition memory, a Y-shaped maze test was performed 5 days after induction of cerebral ischemia. Specifically, gray wood was used to form a Y-shaped maze having 40 ⁇ 2 ⁇ 3 cm identical three arms at 60 ° intervals. The mouse was placed at the end of either arm and allowed to move freely for 10 minutes and the entry to each arm was recorded with a digital video camera. If the mouse invades into an arm different from the two arms that entered the previous and previous times is defined as "alternate response", and if the mouse reenters any of the two arms that invaded the previous and previous rounds, "error" Defined as The percentage of alternation reaction was calculated by the following equation.
  • FIG. 5 The results are shown in FIG. In addition, the result of FIG. 5 is an average value of six examples.
  • “*” indicates that there is a significant difference at p ⁇ 0.05 with respect to the solvent-treated sham-operated mouse group. [Number of alternation reactions / (total number of entry to arm-2)] x 100
  • a significant reduction in spontaneous alternation was observed as compared to the sham-operated mice.
  • mice pre-administered with peridinin the decrease in spontaneous alternation induced by cerebral ischemia was clearly prevented.

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Abstract

L'objet de la présente invention est de fournir un médicament permettant de protéger efficacement les tissus cérébraux vis-à-vis de réactions inflammatoires induites par une ischémie cérébrale. L'agent protecteur du cerveau selon la présente invention est caractérisé en ce qu'il comprend un composé caroténoïde spécifique utilisé comme principe actif.
PCT/JP2018/045708 2017-12-26 2018-12-12 Agent protecteur du cerveau Ceased WO2019131136A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112716932A (zh) * 2021-01-25 2021-04-30 宁波大学 岩藻黄素用于制备预防或治疗术后认知功能障碍的药物或食品中的应用

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JPH07101872A (ja) * 1993-10-04 1995-04-18 Electric Power Dev Co Ltd 抗癌剤
JP2001335480A (ja) * 2000-05-24 2001-12-04 Riken Vitamin Co Ltd 神経細胞保護剤
JP2007314436A (ja) * 2006-05-23 2007-12-06 Oriza Yuka Kk 脳内活性酸素発生抑制剤
JP2011500556A (ja) * 2007-10-10 2011-01-06 アミコゲン、インク フコキサンチン又はこれを含有する海藻類抽出物を含有する脂質代謝性疾患の予防又は治療用組成物
JP2013540110A (ja) * 2010-09-30 2013-10-31 ベイジン ギンコ グループ バイオロジカル テクノロジー カンパニー リミテッド 神経変性疾患に対して神経保護作用を有する製品の製造におけるフコキサンチンの応用
JP2015093860A (ja) * 2013-11-13 2015-05-18 国立大学法人高知大学 遅延性アレルギー抑制剤

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JPH07101872A (ja) * 1993-10-04 1995-04-18 Electric Power Dev Co Ltd 抗癌剤
JP2001335480A (ja) * 2000-05-24 2001-12-04 Riken Vitamin Co Ltd 神経細胞保護剤
JP2007314436A (ja) * 2006-05-23 2007-12-06 Oriza Yuka Kk 脳内活性酸素発生抑制剤
JP2011500556A (ja) * 2007-10-10 2011-01-06 アミコゲン、インク フコキサンチン又はこれを含有する海藻類抽出物を含有する脂質代謝性疾患の予防又は治療用組成物
JP2013540110A (ja) * 2010-09-30 2013-10-31 ベイジン ギンコ グループ バイオロジカル テクノロジー カンパニー リミテッド 神経変性疾患に対して神経保護作用を有する製品の製造におけるフコキサンチンの応用
JP2015093860A (ja) * 2013-11-13 2015-05-18 国立大学法人高知大学 遅延性アレルギー抑制剤

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Title
ONODERA, KENICHI ET AL.: "Peridinin from the Marine Symbiotic Dinoflagellate, Symbiodinium sp., Regulates Eosinophilia in Mice", MARINE DRUGS, vol. 12, no. 4, 27 March 2014 (2014-03-27), pages 1773 - 1787, XP55622373, ISSN: 1660-3397, DOI: 10.3390/md12041773 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112716932A (zh) * 2021-01-25 2021-04-30 宁波大学 岩藻黄素用于制备预防或治疗术后认知功能障碍的药物或食品中的应用

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