WO2023072069A1 - 异野漆树苷及其衍生物用于促进神经修复的用途 - Google Patents

异野漆树苷及其衍生物用于促进神经修复的用途 Download PDF

Info

Publication number
WO2023072069A1
WO2023072069A1 PCT/CN2022/127372 CN2022127372W WO2023072069A1 WO 2023072069 A1 WO2023072069 A1 WO 2023072069A1 CN 2022127372 W CN2022127372 W CN 2022127372W WO 2023072069 A1 WO2023072069 A1 WO 2023072069A1
Authority
WO
WIPO (PCT)
Prior art keywords
isorhoifolin
nerve
brain
use according
regeneration
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/CN2022/127372
Other languages
English (en)
French (fr)
Chinese (zh)
Inventor
陈令仪
陈裕仁
廖彣玲
王翊
李育棠
吕亭萱
李家维
陈方仪
焦传金
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.)
Individual
Original Assignee
Individual
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to US18/704,869 priority Critical patent/US20240415859A1/en
Priority to JP2024547815A priority patent/JP2024539499A/ja
Priority to CN202280071472.9A priority patent/CN118215669A/zh
Priority to KR1020247017446A priority patent/KR20240090983A/ko
Priority to EP22885946.8A priority patent/EP4424695A4/en
Publication of WO2023072069A1 publication Critical patent/WO2023072069A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0085—Brain, e.g. brain implants; Spinal cord

Definitions

  • the invention provides an application of isorhoifolin (Isorhoifolin) and its derivatives for promoting nerve repair.
  • Traumatic Brain Injury affect about 70 million people worldwide each year.
  • Common treatments include physical therapy, hyperbaric oxygen therapy, cranial magnetic stimulation, and cranial direct current stimulation. These non-invasive treatments can improve depression and cognitive function after TBI, but there are still no effective drugs that can promote nerve regeneration after brain injury.
  • Traumatic brain injury is an injury caused by external force hitting the brain. There are nearly 70 million confirmed cases worldwide every year. Traumatic brain injury can damage the cranial nerves, leading to loss of movement or cognitive function of the patient. Because the central nervous system is difficult to regenerate and restore after being damaged, there is currently no effective therapy for nerve regeneration in traumatic brain injury. Patients with traumatic brain injury often have brain lesions after a period of time and will cause brain degenerative diseases in the future. Therefore, the early use of drugs that promote brain nerve regeneration after brain injury is a therapeutic solution.
  • Isorhoifolin is a currently known compound, and the research on this compound as a drug for treatment is rare. Although it is seen that the composition containing this compound is used for the treatment of venous problems or hemorrhoids, but It is not intended for use in the treatment of nerve-related diseases. Therefore, further research in the present invention found that Isorhoifolin and its derivatives can effectively promote nerve repair and regeneration, and can penetrate the blood-brain barrier, which can be used to develop potential drugs for the treatment of traumatic brain injury.
  • the human nervous system is divided into central nervous system and peripheral nervous system, both of which are composed of neurons.
  • the trigeminal nerve is the cranial nerve in the peripheral nerves and connects to the pons (central nerve). Therefore, when Isorhoifolin and its derivatives of the present invention pass through the nasal mucosa, pass through the olfactory epithelial cells, enter the channels around the sense of smell and the trigeminal nerve, and enter the brain, they can also reach the systemic nerves through the peripheral nerves at the same time. Repair effect.
  • cranial nerves that are not easy to repair are used as experimental objects. In this way, both the central and peripheral nerves in the nervous system can be repaired.
  • the "central nervous system” consists of the brain and spinal cord.
  • the "central nervous system” described in the present invention includes but is not limited to the olfactory brain, amygdala, hippocampus, neocortex, lateral ventricle, superior optic thalamus, optic thalamus, hypothalamus, base optic thalamus, pituitary gland, pine Fruit body, third ventricle, midbrain tectum, peduncle, anterior part of the brain, cerebral aqueduct, pons, cerebellar medulla, spinal cord.
  • the "peripheral nervous system” consists of the somatic nervous system and the autonomic nervous system.
  • the "peripheral nerves” mentioned in the present invention include but are not limited to sensory nerves, motor nerves, cranial nerves, spinal nerves, sympathetic nerves, parasympathetic nerves, and enteric nervous system.
  • the invention provides an application of isorhoifolin (Isorhoifolin) and its derivatives for promoting nerve repair.
  • the isorhoifolin derivative is: rutin naringin (Narirutin).
  • the chemical structure of Isorhoifolin is as shown in chemical formula (1):
  • Isorhoifolin and its derivatives can promote 10-30% regeneration of injured hippocampal neurons (injured hippocampal neurons) and promote nerve regeneration in 3D brain tissue slices when used alone, proving The compound can effectively promote the regeneration of neurons and can be used to repair nerve damage.
  • isorhoifolin Isorhoifolin
  • its derivatives can penetrate the user's blood-brain barrier (blood-brain barrier) and enter the brain, so as to promote the repair of the damaged neurons.
  • isorhoifolin Isorhoifolin and its derivatives can penetrate the blood-brain barrier (blood-brain barrier) and enter the brain, so as to promote the repair and regeneration of cranial nerves or increase the number of nerves.
  • Isorhoifolin and its derivatives can promote the regeneration of post-injury cortical neurons, post-injury hippocampal neurons and post-injury retinal neurons.
  • Isorhoifolin has relatively low toxicity to Neuro2a cells.
  • the effective dosage concentration of isorhoifolin and its derivatives is 1 nM to 864 ⁇ M.
  • Isorhoifolin and its derivatives have significant effects on nerve repair, wherein the Isorhoifolin compound and its derivatives can penetrate the blood-brain barrier (blood-brain barrier) and enter the brain through nasal cavity administration , promote the repair of the damaged neurons; promote the repair and regeneration of cranial nerves or increase the number of nerves; and promote the nerve axis regeneration of cortical neurons and hippocampal neurons after injury.
  • blood-brain barrier blood-brain barrier
  • the Isorhoifolin compound and its derivatives can penetrate the blood-brain barrier (blood-brain barrier) and enter the brain through nasal cavity administration , promote the repair of the damaged neurons; promote the repair and regeneration of cranial nerves or increase the number of nerves; and promote the nerve axis regeneration of cortical neurons and hippocampal neurons after injury.
  • Fig. 1 is a flow chart of the present invention in vitro (in vitro) nerve repair test.
  • Fig. 2 is a reference schematic diagram for calculating the gap closure rate (gap closure rate) of the present invention.
  • 3A-3C are the experimental results of hippocampal nerve repair in vitro (in vitro) with isorhoifolin of the present invention.
  • Fig. 4 is the result of the hippocampal nerve regeneration experiment in vitro (in vitro) of Isorhoifolin derivative rutin naringin (Narirutin) of the present invention.
  • Fig. 5 is the result of cortical nerve regeneration experiment in vitro (in vitro) of Isorhoifolin derivative rutin naringin (Narirutin) of the present invention.
  • Fig. 6 is the experimental flow chart of the ex vivo brain tissue section of the present invention.
  • Fig. 7 is the result of the slice experiment of isorhoifolin (ex vivo) brain tissue of the present invention.
  • Fig. 8 is the result of an experiment on brain tissue slices of Isorhoifolin derivative rutin naringin (Narirutin) in vitro (ex vivo) of the present invention.
  • Fig. 9 is the result of the cytotoxicity test of the Isorhoifolin compound of the present invention.
  • Fig. 10 is a flow chart of the experiment of the present invention to control the model of cortical impact traumatic brain injury and the results of the experiment of Isorhoifolin compounds promoting the recovery of motor coordination after brain injury in mice.
  • Fig. 11 is a flow chart of the present invention promoting the repair of retinal nerve tissue in ex vivo.
  • Fig. 12 is the experimental result of Isorhoifolin of the present invention promoting the repair of retinal nerve tissue in ex vivo.
  • Embodiment 1 Isorhoifolin (Isorhoifolin) and its derivatives in vitro (in vitro) nerve repair test
  • the experimental procedure is shown in Figure 1.
  • the fetal rats of 18-day pregnant rats were taken out, and then the brains of the fetal rats were divided into cortex and hippocampus, and then the cortex and hippocampus were separated into cortical nerve cells. (cortical neurons) and hippocampal neurons (hippocampal neurons), the hippocampal neurons are planted in a 48-well plate, this day is called Day In Vitro 0 (DIV0), and Cytosine beta-D-arabinoside will be added at DIV2 (AraC) inhibits the proliferation of glia cells.
  • DIV0 Day In Vitro 0
  • Cytosine beta-D-arabinoside will be added at DIV2 (AraC) inhibits the proliferation of glia cells.
  • the nerve cells are scratched with a micropipette tip, and different concentrations of isorhoifolin (Isorhoifolin) are added. Seventy-two hours after the addition of isorhoifolin, nerve cells were labeled with TUJ1 antibody by immunofluorescence staining to observe the situation of nerve regeneration. This experiment was taken with a Zeiss Observer Z1 microscope.
  • Isorhoifolin isorhoifolin
  • the degree of nerve axis regeneration is quantified by the gap closure rate.
  • the white dotted line is the boundary created by the scratching of the nerve cells drawn by the tip of the micropipette, and the black part in the middle is the boundary produced by the micropipette. In the area scratched by the pipette tip, the regenerated neurites will grow from both sides of the dotted line to the middle.
  • the calculation method is to draw a line between the gaps (gap) every 50 ⁇ m in the injured area to calculate the width of the gap, and take the average after drawing a total of ten lines Value: the length of the gap between injured borders (Length of gap between injured borders, Lg), after a period of time in the same injury area, a line is drawn every 50 ⁇ m to connect the nerve axis extended by regeneration, the length is calculated, and the average value is taken after ten lines are drawn : The length of the gap between regenerated neurons (Ln), the gap closure rate is calculated by (Lg-Ln)/Lg, and the scale bar is 100 ⁇ m. This experiment was shot with Zeiss Observer Z1 microscope.
  • the white dotted line is the boundary generated by scratching the nerve cells with the tip of a micropipette, and the scale bar is 100 ⁇ m.
  • This experiment was taken with a Zeiss Observer Z1 microscope. From this experiment, it can be known that Isorhoifolin can promote the proliferation of neurite in the hippocampus.
  • 3A is the graph of the experimental results of Isorhoifolin from 3.5nM to 34.6nM
  • 3B is the graph of the experimental results of Isorhoifolin from 0.009 ⁇ M to 864 ⁇ M
  • 3C is the graph of the calculation results of the gap closure rate of different concentrations of Isorhoifolin.
  • Isorhoifolin Derivative Narirutin Promotes Nerve Regeneration in the Hippocampal Gyrus after Injury
  • the experimental procedure is also shown in Figure 1.
  • the fetuses of 18-day-pregnant rats were taken out, and then the brains of the fetuses were divided into cerebral cortex and hippocampus, and then separated into cortical nerve cells and hippocampal nerve cells. Nerve cells are planted in a 48-well dish. This day is called Day In Vitro 0 (DIV0).
  • DIV0 Day In Vitro 0
  • Cytosine beta-D-arabinoside (AraC) will be added to inhibit the proliferation of neuroglial cells.
  • a micropipette tip will be used Nerve cells were scratched, and 1nM and 10nM Narirutin were added respectively, and 0.1% DMSO was used as the solvent control group.
  • Isorhoifolin derivative rutin naringin (Narirutin) promotes post-injury cortical nerve regeneration in the cortex
  • the procedure of this experiment is also shown in Figure 1.
  • the fetuses of 18-day-pregnant rats were taken out, and then the brains of the fetuses were divided into cerebral cortex and hippocampus, and then separated into cortical nerve cells and hippocampal nerve cells.
  • the cells are planted in a 48-well plate, which is called Day In Vitro 0 (DIV0) on this day.
  • Cytosine beta-D-arabinoside (AraC) will be added to inhibit the proliferation of glial cells at DIV2, and the tip of a micropipette will be used at DIV8.
  • the nerve cells were scratched, and 10nM and 100nM Narirutin were added respectively, and 0.1% DMSO was used as the solvent control group. The results in the figure have been standardized with the 0.1% DMSO group. Seventy-two hours after adding Narirutin, nerve cells were labeled with TUJ1 antibody by immunofluorescence staining to observe the nerve regeneration. This experiment was taken with a Zeiss Observer Z1 microscope, and the scale bar is 100 ⁇ m.
  • Embodiment two Isorhoifolin and its derivatives ex vivo (ex vivo) brain tissue slice experiment
  • the present invention uses 3D brain tissue slice culture to observe the effect of compounds on nerves.
  • the experimental method is to take out the fetuses of 18-day-pregnant mother mice, then take out the brains of the fetuses and embed them in low-melting agarose gel, and then use Leica microtome VT100 slices to collect brains with a thickness of 350 ⁇ m. After slicing, use a scalpel to injure (injury), and plant it in an insert in a 6-well plate.
  • This culture method allows the brain slices to be in contact with medium and air at the same time.
  • brain slice culture is compared to in vitro Culture (in vitro culture) can more truly reflect the interaction and three-dimensional structure of nerve cells and other cells of the brain.
  • TUJ1 is antibody-labeled nerve cells
  • GFAP is antibody-labeled glial cells
  • DAPI is reagent-labeled cell nuclei.
  • the white dotted line marks the site of the scalpel injury
  • the left side of the dotted line is the brain slice tissue
  • the right side of the dotted line is the newborn nerve axis.
  • the effect of Isorhoifolin on promoting nerve regeneration can be quantified by calculating the length of the white dotted line and the area of the newborn nerve shaft on the right side of the white line, and dividing the area of the newborn nerve shaft by the length of the white dotted line to calculate the neurite length.
  • the scale bar is 100 ⁇ m
  • this experiment was taken with Zeiss LSM800confocal microscope.
  • the effect of Isorhoifolin on nerve regeneration was observed in ex vivo brain slices. From the experimental results, it can be known that Isorhoifolin has the effect of promoting nerve regeneration.
  • the experimental process of Isorhoifolin derivative rutin naringin is also shown in Figure 6.
  • the brains of fetal rats were taken out, and the brains were embedded in low-melting point agarose gel, and the Leica Microtome VT100 cut the brain into slices with a thickness of 350 ⁇ m, cultured after scratching the brain slices with a scalpel, and added ddH 2 O or Narirutin every day, and after 96 hours of culture, fluorescent immunostaining was used to label nerve cells with TUJ1 antibody , GFAP antibody labeled glial cells, DAPI reagent labeled cell nuclei, the scale bar of this experiment is 100 ⁇ m. This experiment was shot with a Zeiss LSM800 confocal microscope.
  • Embodiment three Isorhoifolin cytotoxicity test
  • CellTiter-Glo cell viability assay was used to detect the toxicity of Isorhoiofolin to Neuro2a cells.
  • CellTiter-Glo cell viability assay can detect the ATP content in cells, and then observe the survival rate of cells after adding compounds.
  • Embodiment four Isorhoifolin promotes the motor coordination recovery test after brain injury in mice
  • Pre-training was carried out at -5, -3, and -1Dpi (Day post injury), that is, 5, 3, and 1 days before the brain injury, and at 0Dpi, using controlled
  • the cortical impact model (control cortical impact traumatic brain injury model) performed brain injury on mice, and administered Isorhoifolin at 14 or 140 ⁇ g/kg by nasal administration at 0, 2, 4, 6, 8, 10, and 12 Dpi, and at 1 , 3, 6, 10, 13Dpi for horizontal bar experiments.
  • Embodiment five Isorhoifolin promotes the repair of isolated (ex vivo) retinal nerve tissue
  • Retinal explants were obtained from 8-day-old C57BL/6 mice, and the eyes were removed after sacrifice. Then, the eyeball was separated from the retina with forceps and micro scissors and removed. Remove the vitreous body, and finally cut the separated retina into four pieces, trim and scratch the edge of the tissue with micro scissors, culture each piece on a 18mm round glass slide, put it into a 12-well plate, and put it in the incubator , cultured at 5% CO 2 and 35°C for five days, and each piece of retinal tissue needed to be replaced with fresh culture medium every day and 9 ⁇ M or 90 ⁇ M Isorhoifolin was added.
  • the group given Isorhoifolin had a significant post-injury recovery effect compared with the group given only water (ddH 2 O).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Psychology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Otolaryngology (AREA)
PCT/CN2022/127372 2021-10-25 2022-10-25 异野漆树苷及其衍生物用于促进神经修复的用途 Ceased WO2023072069A1 (zh)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US18/704,869 US20240415859A1 (en) 2021-10-25 2022-10-25 Use of isorhoifolin and derivative thereof in promoting nerve repair
JP2024547815A JP2024539499A (ja) 2021-10-25 2022-10-25 神経修復を促進するためのイソロイホリン及びその誘導体の用途
CN202280071472.9A CN118215669A (zh) 2021-10-25 2022-10-25 异野漆树苷及其衍生物用于促进神经修复的用途
KR1020247017446A KR20240090983A (ko) 2021-10-25 2022-10-25 신경 복원 촉진에 사용되는 이소로이폴린 및 그 유도체의 용도
EP22885946.8A EP4424695A4 (en) 2021-10-25 2022-10-25 USE OF ISORHOIFOLINE AND A DERIVATIVE THEREOF IN PROMOTING NERVE REPAIR

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202163271411P 2021-10-25 2021-10-25
US63/271,411 2021-10-25

Publications (1)

Publication Number Publication Date
WO2023072069A1 true WO2023072069A1 (zh) 2023-05-04

Family

ID=86159046

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/CN2022/127372 Ceased WO2023072069A1 (zh) 2021-10-25 2022-10-25 异野漆树苷及其衍生物用于促进神经修复的用途
PCT/CN2022/127414 Ceased WO2023072085A1 (zh) 2021-10-25 2022-10-25 异丙基-d-吡喃葡萄糖苷衍生物、制备方法及其用途

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/127414 Ceased WO2023072085A1 (zh) 2021-10-25 2022-10-25 异丙基-d-吡喃葡萄糖苷衍生物、制备方法及其用途

Country Status (7)

Country Link
US (2) US20250255893A1 (https=)
EP (2) EP4424695A4 (https=)
JP (2) JP2024541121A (https=)
KR (2) KR20240090983A (https=)
CN (2) CN118139869A (https=)
TW (2) TWI898161B (https=)
WO (2) WO2023072069A1 (https=)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101045072A (zh) * 2007-05-08 2007-10-03 胡军 山香圆叶提取物及其医药用途

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102617658B (zh) * 2012-03-09 2014-08-20 中国烟草总公司郑州烟草研究院 β-紫罗兰醇-β-D-葡糖苷的制备方法及其在烟草加香中的应用
CN102617659A (zh) * 2012-03-09 2012-08-01 中国烟草总公司郑州烟草研究院 α-紫罗兰醇葡糖苷的合成方法及其在卷烟中的加香应用
CN106167508A (zh) * 2016-07-13 2016-11-30 上海应用技术学院 一种具有紫罗兰香味的葡萄糖苷化合物及其制备方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101045072A (zh) * 2007-05-08 2007-10-03 胡军 山香圆叶提取物及其医药用途

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
KUO PING-CHUNG, LIAO YU-REN, HUNG HSIN-YI, CHUANG CHIA-WEI, HWANG TSONG-LONG, HUANG SHIOW-CHYN, SHIAO YOUNG-JI, KUO DAIH-HUANG, WU: "Anti-Inflammatory and Neuroprotective Constituents from the Peels of Citrus grandis", MOLECULES, vol. 22, no. 6, 9 June 2017 (2017-06-09), pages 967, XP093060945, DOI: 10.3390/molecules22060967 *
See also references of EP4424695A4 *
XIAO BO; LI MENG;LI XIAO; WANG LIN-HONG: "Protective Effect of Hesperidin on Retinal Nerve Cells in Diabetic Rat", WORLD LATEST MEDICINE INFORMATION, vol. 19, no. 80, 31 December 2019 (2019-12-31), pages 26 - 27, XP009545237, ISSN: 1671-3141, DOI: 10.19613/j.cnki.1671-3141.2019.80.011 *
XU YAN, YE XIAOLEI, YAN WANG: "Hesperidin Alleviates Rotenone-induced Nerve Cell Damage", CHINESE JOURNAL OF CRITICAL CARE MEDICINE, vol. 12, no. 3, 30 June 2019 (2019-06-30), pages 182 - 186, XP009545238, ISSN: 1674-6880 *
YOKOYAMA, K. SHIMADA, Y. HORI, E. SEKIYA, N. GOTO, H. SAKAKIBARA, I. NISHIJO, H. TERASAWA, K.: "Protective effects of Choto-san and hooks and stems of Uncaria sinensis against delayed neuronal death after transient forebrain ischemia in gerbil", PHYTOMEDICINE, ELSEVIER, AMSTERDAM, NL, vol. 11, no. 6, 20 September 2004 (2004-09-20), AMSTERDAM, NL , pages 478 - 489, XP004957149, ISSN: 0944-7113, DOI: 10.1016/j.phymed.2003.04.001 *
ZENG JIAJIA, HU WEILUN, LI HAO, LIU JIANGANG, ZHANG PENG, GU YANXIANG, YU YINGCHUN, WANG WENJUAN, WEI YUN: "Purification of linarin and hesperidin from Mentha haplocalyx by aqueous two‐phase flotation coupled with preparative HPLC and evaluation of the neuroprotective effect of linarin", JOURNAL OF SEPARATION SCIENCE, WILEY, DE, vol. 44, no. 12, 1 June 2021 (2021-06-01), DE , pages 2496 - 2503, XP093060942, ISSN: 1615-9306, DOI: 10.1002/jssc.202001243 *

Also Published As

Publication number Publication date
TW202317142A (zh) 2023-05-01
US20240415859A1 (en) 2024-12-19
JP2024541121A (ja) 2024-11-06
CN118215669A (zh) 2024-06-18
KR20240090982A (ko) 2024-06-21
TWI898161B (zh) 2025-09-21
WO2023072085A1 (zh) 2023-05-04
EP4424694A1 (en) 2024-09-04
EP4424695A1 (en) 2024-09-04
EP4424694A4 (en) 2026-03-11
JP2024539499A (ja) 2024-10-28
EP4424695A4 (en) 2025-10-22
TW202320806A (zh) 2023-06-01
CN118139869A (zh) 2024-06-04
US20250255893A1 (en) 2025-08-14
KR20240090983A (ko) 2024-06-21

Similar Documents

Publication Publication Date Title
US20240052347A1 (en) Complex for treating optic nerve disease, and preparation method therefor and use thereof
CN106795490B (zh) 用线粒体特化细胞治疗神经退行性疾病的医药组合物
Li et al. Exosomes isolated during dopaminergic neuron differentiation suppressed neuronal inflammation in a rodent model of Parkinson’s disease
Jia et al. Electroacupuncture alleviates orofacial allodynia and anxiety-like behaviors by regulating synaptic plasticity of the CA1 hippocampal region in a mouse model of trigeminal neuralgia
Guo et al. Melatonin combined with chondroitin sulfate ABC promotes nerve regeneration after root-avulsion brachial plexus injury
Shan et al. Activation of the hippocampal CA1 astrocyte Gq and Gi G protein-coupled receptors exerts a protective effect against attention deficit hyperactivity disorder
Lepore Intraspinal cell transplantation for targeting cervical ventral horn in amyotrophic lateral sclerosis and traumatic spinal cord injury
WO2023072069A1 (zh) 异野漆树苷及其衍生物用于促进神经修复的用途
NL2025156B1 (en) Use of prostaglandin e1 in preparation of medicament for treating intracerebral hemorrhage
CN107779437B (zh) 自噬诱导剂作为微管稳定药物促进神经再生的用途
Sun et al. Hypothermia protects the integrity of corticospinal tracts and alleviates mitochondria injury after intracerebral hemorrhage in mice
JP2024539499A5 (https=)
CN107296808B (zh) 化合物埃博霉素b在制备修复角膜神经创伤的药物中的应用
Wang et al. Olfactory mucosa mesenchymal stem cell‐derived exosomes protect against neuroinflammation after subarachnoid hemorrhage by activating mitophagy
WO2019085366A1 (zh) 一种促红细胞生成素来源肽及其制备方法和用途
TWI823110B (zh) 天南星科萃取物用於促進神經修復的用途
CN110279685A (zh) L-丝氨酸在预防或治疗高原颅脑损伤中的应用
KR102477030B1 (ko) 인간 전분화능 줄기세포 유래 신경전구세포를 유효성분으로 포함하는 혈관성 치매 예방 또는 치료용 약학 조성물
Hwang et al. Stem cells ameliorate neurotrauma-induced visual disturbances and retinopathy via broad normalization of the β-catenin-related signaling pathway
CN111617234B (zh) 外源性重组蛋白Reelin在制备治疗脑出血药物中的应用
EP1180036B1 (en) Cell therapy for chronic stroke
CN102379873A (zh) 一种急性全身性猴帕金森病模型及其药物筛选方法
Hesse 11 Surgical Treatments
Fan et al. Maternal Exposure to Sevoflurane Disrupts Oligodendrocyte Myelination of the Postnatal Hippocampus and Induces Cognitive and Motor Impairments in Offspring
Tian et al. The possible protective mechanism of hyperbaric oxygen (HBO) in memory impairments induced by Aβ25–35 in rats

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22885946

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2024547815

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 202280071472.9

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: 18704869

Country of ref document: US

ENP Entry into the national phase

Ref document number: 20247017446

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2022885946

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 11202402828T

Country of ref document: SG

ENP Entry into the national phase

Ref document number: 2022885946

Country of ref document: EP

Effective date: 20240527