WO2019006734A1 - (+)-2-莰醇在制备促鞘氨醇激酶-1和/或bdnf表达上调的药物中的应用 - Google Patents

(+)-2-莰醇在制备促鞘氨醇激酶-1和/或bdnf表达上调的药物中的应用 Download PDF

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WO2019006734A1
WO2019006734A1 PCT/CN2017/092148 CN2017092148W WO2019006734A1 WO 2019006734 A1 WO2019006734 A1 WO 2019006734A1 CN 2017092148 W CN2017092148 W CN 2017092148W WO 2019006734 A1 WO2019006734 A1 WO 2019006734A1
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brain
expression
sphingosine kinase
drug
neurotrophic factor
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PCT/CN2017/092148
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English (en)
French (fr)
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李云森
邓世平
李勇
江传亮
俞云会
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苏州沪云肿瘤研究中心股份有限公司
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Priority to JP2019537248A priority patent/JP6951449B2/ja
Priority to PCT/CN2017/092148 priority patent/WO2019006734A1/zh
Priority to CN201780085223.4A priority patent/CN110248649A/zh
Priority to EP17916830.7A priority patent/EP3578174A4/en
Publication of WO2019006734A1 publication Critical patent/WO2019006734A1/zh

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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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • 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

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  • the present application belongs to the field of chemical medicine and relates to the use of (+)-2-nonanol for the preparation of a medicament for up-regulating the expression of sphingosine kinase-1 and/or BDNF (brain-derived neurotrophic factor).
  • (+)-2-nonanol for the preparation of a medicament for up-regulating the expression of sphingosine kinase-1 and/or BDNF (brain-derived neurotrophic factor).
  • Neuronal ischemia, inflammation, immune response, trauma, neuronal degeneration and other causes can cause neuronal damage or death, resulting in serious neurological or psychiatric diseases. Therefore, neuroprotective drugs that delay the death of nerve damage or promote the growth of nerve cells are particularly important for life health.
  • Neuroprotection focuses on the structure, function, or function of protecting, restoring, healing, or regenerating cells of the nervous system (J Clin Neurosci. 2002 Jan; 9(1): 4-8).
  • the purpose of neuroprotection is to prevent or minimize damage to the nervous system, or to prevent endogenous or exogenous harmful processes that cause damage to axons, neurons, synapses and dendrites or to Reduce to a minimum.
  • Neuroprotective agents are currently in various research and experimental stages and are available in a wide variety. Including the following types: ion channel modulators, excitatory amino acid antagonists [N-methyl-D-aspartate (NMDA) antagonists, ⁇ -amino-3-hydroxy-5-methyl-4-isoxazole Propionic acid (AMPA) antagonists], nitric oxide synthase (NOS) inhibitors, free radical capture/scavengers, magnesium sulfate, GABA receptor enhancers, anti-inflammatory drugs, and cell membrane stabilizers Guidelines for the diagnosis and treatment of blood stroke 2014; Neuropharmacology, 2008, 55(3): 363-389.).
  • NMDA N-methyl-D-aspartate
  • AMPA ⁇ -amino-3-hydroxy-5-methyl-4-isoxazole Propionic acid
  • NOS nitric oxide synthase
  • free radical capture/scavengers magnesium sulfate
  • GABA receptor enhancers anti-inflammatory drugs
  • Neurotrophins are growth factors that regulate the development and maintenance of the peripheral and central nervous systems (Annu Rev) Neurosci. 1996; 19: 289-317).
  • Nerve growth factor (NGF) is a member of the neurotrophin family that was first discovered and best characterized, including other structurally related proteins, such as brain-derived neurotrophic factor (BDNF).
  • BDNF brain-derived neurotrophic factor
  • Neurotrophins act through two major signaling pathways: the phosphatidylinositol-3-kinase (PI3K)-AKT pathway and the mitogen-activated protein kinase (MAPK)-MEK pathway (both pathways involve inhibition of apoptosis) ).
  • PI3K phosphatidylinositol-3-kinase
  • MAPK mitogen-activated protein kinase
  • Neurotrophic factors are also known to act on mature neurons and in particular damaged and denatured cells (Curr Neurovasc Res. 2007 May; 4(2): 14
  • NGF neurodegenerative diseases
  • neuroinflammation and some types of cancer, multiple sclerosis, etc.
  • CNS central nervous system
  • NGF has significant immunomodulatory properties during CNS (central nervous system) inflammation to promote maintenance of CNS properties
  • CNS inflammatory diseases such as MS.
  • NGF is not an ideal drug candidate because it does not cross the blood-brain barrier, its short half-life and its side effects.
  • sphingolipids are one of the important structural components of cell membranes, and their metabolites such as ceramide, sphingosine, and sphingosine 1-phosphase (S1P) are also biologically active signaling molecules.
  • S1P sphingosine 1-phosphase
  • the life activities of the cells such as cell survival, proliferation, migration, and neovascularization, are regulated.
  • Sphingosine kinase is the rate-limiting enzyme that regulates the balance of ceramide and S1P.
  • S1P ceramide, sphingosine kinase, and S1P can participate in multiple processes in the process of cerebral ischemia, suggesting that intervention can be used as a new target for the treatment of cerebral ischemia.
  • S1P and the like are directly involved in the regulation of cell proliferation and apoptosis, which can promote various biological functions such as cell growth, proliferation and anti-inflammation.
  • S1P The cell membrane receptor is a G protein-coupled receptor, which, when combined, activates different signaling pathways and regulates cellular functions from different angles.
  • Sphingosine kinase is an important rate-limiting enzyme that maintains the balance of ceramide, sphingosine and S1P in cells, and is also an important signaling molecule that affects cell survival and proliferation.
  • S1P sphingosine 1-phosphate
  • the brain is the organ with the highest concentration of S1P (Nat Rev Immunol 2005, 5: 560-570), and the S1P receptor is widely expressed in neurons. , astrocytes and microglia (Pharmacol. Ther. 2008, 117: 77-93).
  • Asegawa et al. (Biochim Biophys Acta. 2002; 1585: 193-201) found that in rat cerebral ischemia model, S1P plays a protective role in cerebral ischemia by activating S1P1, which interacts with Akt (protein kinase B).
  • Akt protein kinase B
  • Akt plays an important role in inhibiting apoptosis.
  • S1P inhibition of apoptosis Biochim Biophys Acta. 2008, 1781: 459-466
  • S1P binds to sphingosine kinase receptor to activate Akt
  • Akt activation The release of cytochrome C induced by Bad (an apoptotic precursor protein) was disrupted, thereby inhibiting apoptosis.
  • S1P can also induce the proliferation of neuronal progenitor cells (J Neurochem.
  • S 1P can prevent apoptosis, it can be used to treat diseases caused by cerebral ischemia, etc., which can provide a new way for us to find new drugs for treating stroke.
  • Sphingosine kinase (SphKs), a key enzyme that catalyzes the production of S1P by sphingosine, is essential for the regulation of S1P levels.
  • Sphingosine kinase 1 (Sphk1) and sphingosine kinase 2 (Sphk2) are key enzymes that promote the metabolism of sphingomyelin to S1P (Stroke, 2011, 42: 1420-1428).
  • Sphk1/S1P signaling pathway regulates neurotransmitter release, neuroinflammation, and proliferation and death of neurons and microglia [J Clin Invest, 2009, 119(7): 1871- 1879]. Orhan Altay et al.
  • Sphk1/SIP also regulates the permeability of the blood-brain barrier following subarachnoid hemorrhage.
  • Frank Niessen's research (Mol Cell Biol, 2005, 25(24): 11113-11121) It was also found that on dendritic cells, the SphKs/S1P pathway is an important molecular mechanism that promotes nerve growth and inhibits apoptosis. Therefore, Sphk1 may also be an important protein that we have not previously recognized to regulate pathological damage such as cerebral ischemia. Small molecules that up-regulate Sphk1 expression are also potential drugs for treating neuronal injury diseases.
  • the purpose of the present application is to provide the use of (+)-2-nonanol for the preparation of a medicament for promoting up-regulation of sphingosine kinase-1 and BDNF (brain-derived neurotrophic factor) expression.
  • the present application is directed to the use of (+)-2-nonanol for the preparation of a medicament that promotes up-regulation of sphingosine kinase-1 and/or BDNF (brain-derived neurotrophic factor) expression.
  • (+)-2-nonanol for the preparation of a medicament that promotes up-regulation of sphingosine kinase-1 and/or BDNF (brain-derived neurotrophic factor) expression.
  • the (+)-2-nonanol described in the present application can be used for the preparation of a drug for promoting the upregulation of sphingosine kinase-1 and brain-derived neurotrophic factor, which can induce astrocyte proliferation and migration, and less Cell differentiation and survival, neurite outgrowth and nerve regeneration, and can promote the up-regulation of brain-derived neurotrophic factor, promote the survival of neurons and axon growth, and inhibit the expansion of infarct volume. Therefore, the drug of the present application is capable of In the prevention of further expansion of the infarct area, the effect of repairing damage to the direct injury site is achieved.
  • (+)-2-nonanol has a chemical formula of C10H18O and a molecular weight of 154.25, and has a structural formula as shown in Formula I:
  • the drug that promotes the expression of sphingosine kinase-1 and/or brain-derived neurotrophic factor is up-regulated Under the action of the substance, the expression of sphingosine kinase-1 is up-regulated by 2-4 fold (eg, 2-fold, 2.3-fold, 2.5-fold, 2.7-fold, 2.9-fold, 3-fold, 3.2-fold, 3.4-fold, 3.6-fold, 3.8-fold or 4 times).
  • the expression of brain-derived neurotrophic factor is up-regulated by a factor of 2-4 (eg, 2 times, 2.3 times) under the action of a drug that promotes up-regulation of sphingosine kinase-1 and/or brain-derived neurotrophic factor expression. , 2.5 times, 2.7 times, 2.9 times, 3 times, 3.2 times, 3.4 times, 3.6 times, 3.8 times or 4 times).
  • (+)-2-nonanol is used as the active ingredient of the drug which promotes up-regulation of sphingosine kinase-1 and/or brain-derived neurotrophic factor expression, and does not include other active ingredients.
  • the drug simultaneously promotes up-regulation of sphingosine kinase-1 and/or brain-derived neurotrophic factor expression. Because the simultaneous expression of both of them can prevent the further enlargement of the cerebral infarct area and repair the damaged part, in order to completely solve the brain damage, the long-term therapeutic effect is significantly improved.
  • the medicament further comprises a pharmaceutically acceptable pharmaceutical carrier; for pharmaceutically acceptable carriers, the application is not particularly limited and is selected according to techniques well known in the art.
  • the drug further includes an excipient.
  • excipient the application is not particularly limited, and those skilled in the art can select according to actual needs.
  • the pharmaceutical dosage form is a capsule, a tablet, a granule, a powder, an injection or a dropping, preferably an injection.
  • the drug for promoting the up-regulation of sphingosine kinase-1 and/or brain-derived neurotrophic factor described in the present application can be used for the treatment of brain nerve damage diseases such as stroke and Alzheimer's disease.
  • (+)-2-nonanol can be used to prepare a drug that promotes upregulation of sphingosine kinase-1 and/or brain-derived neurotrophic factor, which induces astrocyte proliferation and migration.
  • oligodendrocyte differentiation and survival, neurite outgrowth and nerve regeneration and can promote the up-regulation of brain-derived neurotrophic factor, promote the survival of neurons and axon growth, inhibit the expansion of infarct volume, and achieve prevention of stems
  • the further expansion of the plug area simultaneously achieves the effect of repairing the damage to the direct injury site, so as to completely solve the brain damage, so that the long-term treatment effect is significantly improved.
  • Figure 1 shows the expression of sphingosine kinase 1 in the administration group and the control group after administration of (+)-2-nonanol in a rat model of focal cerebral ischemia-reperfusion;
  • Figure 2 shows the expression of brain-derived neurotrophic factor BDNF in the drug-administered group and the control group after (+)-2-merol in the rat model of focal cerebral ischemia-reperfusion;
  • Figure 3 is a graph showing changes in the rate of left hind limb loss in different experimental groups
  • Figure 4 is a graph showing changes in the rate of right forelimb failure in mice of different experimental groups
  • Figure 5 is a graph showing changes in the asymmetry index of mice in different experimental groups
  • Figure 6 is a graph showing changes in body weight of mice in different experimental groups
  • Figure 7 is a graph showing the results of measuring the dendritic length in the ischemic peripheral region of mice in different experimental groups
  • Figure 8 is a graph showing the results of measuring the number of dendritic branches in the ischemic peripheral region of mice in different experimental groups
  • Figure 9 is a diagram showing the morphology changes of dendritic branches in the ischemic peripheral region of mice in different experimental groups.
  • Figure 10 is a graph showing the results of measuring dendritic spine density in the ischemic peripheral region of mice in different experimental groups
  • Middle cerebral artery occlusion (Middle cerebral artery) was prepared by internal carotid artery suture method.
  • the model of cerebral ischemia-reperfusion was administered once in the tail vein 2 hours after ischemia-reperfusion.
  • (+)-2-nonanol was administered in one dose group, that is, 2 mg/kg.
  • the brain tissue around the infarct area was taken to the size of soybean, and sent to Beijing Boao Jingdian Biotechnology Co., Ltd., using Affymetrix GeneChip Rat Genome 2302.0Array Affymetrix rat (Latin: Rattus norvegicus) genome 2302.0
  • the chip was subjected to genome-wide expression profiling.
  • (+)-2-nonanol administration group was relative to sham operation group:
  • Sphk1 Sphingosine kinase-1 (Sphk1) expression was up-regulated by 2.64 fold (as shown in Figure 1). Sphk1 phosphorylates sphingosine to produce S1P, which acts directly on brain cells, induces astrocyte proliferation and migration, oligodendrocyte differentiation and survival, neurite outgrowth and nerve regeneration. Two hours after rat MACO modeling, Sphk1 was up-regulated by 2.64-fold relative to the model group after treatment with (+)-2-nonanol (see Figure 1), revealing (+)-2- Sterols may have a role in promoting neurite outgrowth and nerve cell regeneration.
  • BDNF Brain-derived neurotrophic factor
  • (+)-2-sterol was set in three dose groups, 3.0, 1.5, 0.75 mg / kg, respectively, with edaravone as a positive control, The dose was 9 mg/kg, administered once in the tail vein 2 hours after cortical ischemia, and then once every 24 hours for a total of 14 doses.
  • the forelimb loss rate was measured by grid test on the 14th, 28th and 42th day after injury.
  • the motion of the affected side and contralateral forelimb was measured by the cylinder test on the 14th, 28th and 42th day after injury. Asymmetry index to determine its impact on motor function. After the behavior was measured, 5 animals were randomly selected from each group. Live brains, Golgi staining, determination of neuron survival and dendritic richness in the penumbra.
  • (+)-2-nonanol of the present application promotes up-regulation of sphingosine kinase-1 and/or BDNF (brain-derived neurotrophic factor) expression, and its long-term therapeutic effect is good.
  • BDNF brain-derived neurotrophic factor

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Abstract

本文公布了(+)-2-莰醇在制备促进鞘氨醇激酶-1和/或BDNF(脑源性神经营养因子)表达上调的药物中的应用，在本文中，(+)-2-莰醇可以用于制备促进鞘氨醇激酶-1和/或脑源性神经营养因子表达上调的药物，该药物可以诱发星形胶质细胞扩散和迁移、少突细胞分化和生存、神经突生长和神经再生，并且可以促进脑源性神经营养因子的表达上调，促进神经元的存活和轴突的生长，抑制梗死体积扩大，实现在防止梗塞面积的进一步扩大同时对直接损伤部位达到修复损伤的功效，以彻底解决脑损伤，使得其远期治疗效果显著提升。

Description

(+)-2-莰醇在制备促鞘氨醇激酶-1和/或BDNF表达上调的药物中的应用 技术领域
本申请属于化学医药领域，涉及(+)-2-莰醇在制备促鞘氨醇激酶-1和/或BDNF(脑源性神经营养因子)表达上调的药物中的应用。
背景技术
神经元局部缺血、炎症、免疫应答、创伤、神经元变性等原因可以导致神经元受损或死亡，结果引起严重的神经或精神性疾病。所以能延缓神经损伤死亡或促进神经细胞生长的神经保护类治疗药物对生命健康尤为重要。
神经保护集中于保护、恢复、治愈或再生神经系统细胞的结构或功能(J Clin Neurosci.2002Jan；9(1)：4-8)。神经保护的目的在于预防对神经系统的最初损害或将损害减小到最低限度，或预防对轴突、神经元、突触和树突导致损害的内源性或外源性有害过程或将其减少到最低限度。
神经保护剂，目前正处在不同的研究、试验阶段，其种类繁多。包括如下类型：离子通道调控剂、兴奋性氨基酸拮抗剂[N-甲基-D-天冬氨酸(NMDA)拮抗剂、α-氨基-3-羟基-5-甲基-4-异噁唑丙酸(AMPA)拮抗剂]、一氧化氮合酶(NOS)抑制剂、自由基俘获剂/清除剂、硫酸镁、GABA受体增强剂、抗炎药和细胞膜稳定剂等(《中国急性缺血性脑卒中诊治指南2014》；Neuropharmacology，2008，55(3)：363-389.)。
但这些研究药物限制二次生化损害和细胞死亡的能力令人失望(Arch Neurol.2007Jun；64(6)：794-800)，目前，尚没有临床上有循证依据的上市神经保护药物(《中国急性缺血性脑卒中诊治指南2014》)。
神经营养蛋白是调节外周和中枢神经系统发育和维持的生长因子(Annu Rev  Neurosci.1996；19：289-317)。神经生长因子(NGF)是首先被发现和得到最佳表征的神经营养蛋白家族成员，包括其他结构相关的蛋白质，例如脑源性神经营养因子(BDNF)。神经营养蛋白通过两种主要信号传导途径起作用：磷脂酰肌醇-3-激酶(PI3K)-AKT途径和促分裂原活化蛋白激酶(MAPK)-MEK途径(两种途径都涉及细胞凋亡抑制)。已知神经营养因子还对成熟神经元且特别是受损和变性细胞起作用(Curr Neurovasc Res.2007May；4(2)：143-51)。
NGF作为用于若干种疾病的治疗剂的潜能已经被几位研究人员证实。这样的疾病包括卒中、神经变性疾病、神经炎症和一些类型的癌症、多发性硬化等(Curr Alzheimer Res.2007Dec；4(5)：503-6；Curr Alzheimer Res.2008Feb；5(1)：38-44)。NGF在CNS(中枢神经系统)炎症过程中具有显著的免疫调节特性以促成CNS特性的维持(Prog Brain Res.2004；146：403-14)。NGF除在神经元和寡突细胞中的神经保护特性外，还诱导自身免疫脱髓鞘过程中的免疫抑制。这一发现使得它成为治疗CNS炎性疾病如MS的极为良好的候选物。然而，因不能通过血脑屏障、其半衰期短及其副作用，所以NGF不是理想的药物候选物。
多年来研究人员一直在寻找具有NGF激动剂活性或能使NGF表达上调、更好的药代动力学特性和较少的副作用的小分子药物。
此外，神经鞘脂类是细胞膜的重要结构成分之一，其代谢产物如神经酰胺、鞘氨醇、1-磷酸鞘氨醇(Sphingosine 1-phosphase，S1P)亦是具有生物活性的信号分子，可作为第一和(或)第二信使来调控细胞的生命活动，如细胞的存活、增殖、迁移、及新生血管形成等。鞘氨醇激酶是调节神经酰胺和S1P平衡的限速酶。近年有研究表明，神经酰胺、鞘氨醇激酶、S1P可参与脑缺血过程中多个环节，由此提示干预此途径可作为脑缺血治疗的新靶点。S1P等直接参与细胞增殖与凋亡的调控，其可促进细胞的生长、增殖和抗炎症等多种生物学功能。S1P 的细胞膜受体为G蛋白偶联受体，二者结合后激活不同信号传导途径，从不同角度调节细胞功能。鞘氨醇激酶是维持细胞内神经酰胺、鞘氨醇、S1P平衡的重要限速酶，也是影响细胞存活及增殖的重要信号分子。
S1P(1-磷酸鞘氨醇)作为具有生物活性的神经鞘脂代谢产物，大脑是含S1P浓度最高的器官(Nat Rev Immunol 2005，5：560-570)，S1P受体广泛表达于的神经元、星形胶质细胞和小胶质细胞(Pharmacol.Ther.2008，117：77-93)。Asegawa等(Biochim Biophys Acta.2002；1585：193-201)研究发现，在大鼠脑缺血模型中，S1P通过活化S1P1对脑缺血起到保护性的作用，该作用与Akt(蛋白激酶B)的激活有关，Akt在抑制细胞凋亡中发挥着重要作用。在S1P抑制细胞凋亡的相关研究中(Biochim BiophysActa.2008，1781：459-466)，认为Akt抑制细胞凋亡的机制是：S1P与鞘氨醇激酶受体偶联激活Akt，Akt的活化阻断了Bad(一种凋亡前体蛋白)诱导的细胞色素C的释放，从而抑制了凋亡。并且S1P还可诱导神经元祖细胞的增殖(J Neurochem.2007，103：509-517)，增强皮质神经元和内皮细胞对缺血缺氧的耐受能力，对抗缺血缺氧引起的脑细胞死亡。由于S 1P能阻止凋亡，可以用来治疗脑缺血等引起的疾病，可为我们寻找治疗卒中新药等提供一个新途径。
鞘氨醇激酶(SphKs)，是催化鞘氨醇生成S1P的关键酶，它对S1P水平的调节是必不可少的。鞘氨醇激酶1(Sphk1)和鞘氨醇激酶2(Sphk2)是促进神经鞘磷脂代谢成为S1P的关键酶(Stroke，2011，42：1420-1428)。越来越多的研究表明Sphk1/S1P信号传导途径能够调节神经递质的释放、神经炎症，以及神经元和小胶质细胞的增殖和死亡[J Clin Invest，2009，119(7)：1871-1879]。Orhan Altay等人(FASEB J，2011，25(2)：600-612)还发现Sphk1/SIP还能调节蛛网膜下腔出血后的血脑屏障的通透性。FrankNiessen的研究(Mol Cell Biol，2005，25(24)： 11113-11121)也发现，在树突状细胞上，SphKs/S1P通路是促进神经生长、抑制凋亡的重要分子机制。因此，Sphk1也可能是我们以前未认识到的、能够调控脑缺血等病理损伤的一个重要蛋白，能上调Sphk1表达的小分子也是治疗神经细胞损伤疾病的潜在药物。
因此，在本领域中，期望开发一种新的治疗神经细胞损伤疾病的药物。
发明内容
针对现有技术的不足，本申请的目的在于提供(+)-2-莰醇在制备促进鞘氨醇激酶-1和BDNF(脑源性神经营养因子)表达上调的药物中的应用。
为达到此发明目的，本申请采用以下技术方案：
一方面，本申请在于提供(+)-2-莰醇在制备促进鞘氨醇激酶-1和/或BDNF(脑源性神经营养因子)表达上调的药物中的应用。
本申请所述的(+)-2-莰醇可以用于促进鞘氨醇激酶-1和脑源性神经营养因子表达上调的药物制备，该药物可以诱发星形胶质细胞扩散和迁移、少突细胞分化和生存、神经突生长和神经再生，并且可以促进脑源性神经营养因子的表达上调，促进神经元的存活和轴突的生长，抑制梗死体积扩大，因此，本申请的药物是能够在防止梗塞面积的进一步扩大同时对直接损伤部位达到修复损伤的功效。
在本申请中，所述(+)-2-莰醇的化学式为C10H18O，分子量为154.25，具有如式I所示结构式如：
Figure PCTCN2017092148-appb-000001
优选地，在所述促进鞘氨醇激酶-1和/或脑源性神经营养因子表达上调的药 物的作用下，鞘氨醇激酶-1的表达上调2-4倍(例如2倍、2.3倍、2.5倍、2.7倍、2.9倍、3倍、3.2倍、3.4倍、3.6倍、3.8倍或4倍)。
优选地，在所述促进鞘氨醇激酶-1和/或脑源性神经营养因子表达上调的药物的作用下，脑源性神经营养因子的表达上调2-4倍(例如2倍、2.3倍、2.5倍、2.7倍、2.9倍、3倍、3.2倍、3.4倍、3.6倍、3.8倍或4倍)。
在本申请中，以(+)-2-莰醇作为所述促进鞘氨醇激酶-1和/或脑源性神经营养因子表达上调的药物的活性成分，而不包括其他活性成分。
优选地，所述药物同时促进鞘氨醇激酶-1和/或脑源性神经营养因子表达上调。因为二者的同时表达上调可以防止脑梗死面积的进一步扩大并修复损伤的部位，以彻底解决脑损伤，使得其远期治疗效果显著提升。
优选地，所述药物还包括药学上可用的药物载体；对于可药用载体，本申请不做特殊限定，根据本领域公知技术进行选择。
优选地，所述药物还包括赋形剂，对于赋形剂，本申请不做特殊限定，本领域技术人员可以根据实际需要进行选择。
优选地，所述药物的剂型为胶囊剂、片剂、颗粒剂、散剂、注射剂或滴丸，优选注射剂。
本申请所述的促进鞘氨醇激酶-1和/或脑源性神经营养因子表达上调的药物可用于脑卒中、阿尔兹海默症等脑神经损伤疾病的治疗。
相对于现有技术，本申请具有以下有益效果：
在本申请中，(+)-2-莰醇可以用于制备促进鞘氨醇激酶-1和/或脑源性神经营养因子表达上调的药物，该药物可以诱发星形胶质细胞扩散和迁移、少突细胞分化和生存、神经突生长和神经再生，并且可以促进脑源性神经营养因子的表达上调，促进神经元的存活和轴突的生长，抑制梗死体积扩大，实现在防止梗 塞面积的进一步扩大同时对直接损伤部位达到修复损伤的功效，以彻底解决脑损伤，使得其远期治疗效果显著提升。
附图说明
图1为对大鼠局灶性脑缺血再灌注模型给予(+)-2-莰醇后，给药组与对照组的鞘氨醇激酶1的表达情况；
图2为对大鼠局灶性脑缺血再灌注模型给予(+)-2-莰醇后，给药组与对照组的脑源性神经营养因子BDNF的表达情况；
图3为不同实验组小鼠左前肢失足率的变化曲线图；
图4为不同实验组小鼠的右前肢失足率的变化曲线图；
图5为不同实验组小鼠的不对称指数的变化曲线图；
图6为不同实验组小鼠的体重的变化曲线图；
图7为不同实验组小鼠的缺血周围区树突长度的测定结果图；
图8为不同实验组小鼠的缺血周围区树突分枝数的测定结果图；
图9为不同实验组小鼠的缺血周围区树突分枝形态变化图；
图10为不同实验组小鼠的缺血周围区树突棘密度的测定结果图；
其中，*P＜0.05，与模型组比较。
具体实施方式
下面通过具体实施方式来进一步说明本申请的技术方案。本领域技术人员应该明了，所述实施例仅仅是帮助理解本申请，不应视为对本申请的具体限制。
实施例1
大鼠局灶性脑缺血再灌注模型
采用颈内动脉线栓法制备大鼠大脑中动脉阻塞(Middle cerebral artery， MCAO)脑缺血再灌注模型，于缺血再灌注后2小时尾静脉注射给药1次。(+)-2-莰醇设1个给药剂量组，即2mg/kg。脑缺血再灌注48小时后取梗死区周围脑组织约黄豆大小，送样至北京博奥晶典生物技术有限公司，选用Affymetrix GeneChip Rat Genome 2302.0Array Affymetrix大鼠(拉丁文：Rattus norvegicus)基因组2302.0芯片，对其进行全基因组表达谱分析。
结果显示：(+)-2-莰醇给药组相对于假手术组之间：其中
(1)鞘氨醇激酶-1(Sphk1)表达上调2.64倍(如图1所示)。Sphk1能够磷酸化鞘氨醇生成S1P，S1P直接作用于脑细胞，诱发星形胶质细胞扩散和迁移、少突细胞分化和生存、神经突生长和神经再生。我们在大鼠MACO造模后2小时，应用(+)-2-莰醇治疗后发现给药组的Sphk1相对于模型组上调2.64倍(如图1所示)，揭示(+)-2-莰醇可能有促进神经突生长和神经细胞再生的作用。
(2)脑源性神经营养因子(BDNF)表达上调2.67倍(如图2所示)。BDNF上调能促进神经元的存活和轴突的生长，抑制梗死体积扩大。BDNF神经保护作用可能与新的基因转录，蛋白质合成以及蛋白激酶的调节有关。
实施例2
(+)-2-莰醇在小鼠运动皮层局灶性缺血模型上的远期药效学试验
采用光照致小鼠大脑运动皮层局灶性缺血模型，(+)-2-莰醇设置3个剂量组，分别为3.0、1.5、0.75mg/kg，以依达拉奉为阳性对照药，剂量为9mg/kg，于皮层缺血后2小时尾静脉注射给药1次，而后每24小时给药1次，共给药14次。采用网格试验分别于损伤后第14天、28天和42天测定其前肢失足率；采用圆筒试验分别于损伤后第14天、28天和42天测定其患侧和对侧前肢的运动不对称指数，来判断其对运动功能的影响。行为测定后，每组随机选取5只动物， 活杀取脑，高尔基染色，测定半影区神经元存活及树突丰富度。
结果显示：光照缺血损伤后连续多次给予(+)-2-莰醇治疗时，能显著改善光照损伤小鼠的运动功能，表现为小鼠左前肢(损伤侧)失足率及两侧前肢不对称指数的显著下降(如图3-图6所示)，同时对缺血周围区树突长度(如图7)和树突分枝数(如图8、图9所示)及树突棘的密度(如图10所示)都有显著的改善作用。
因此，本申请的(+)-2-莰醇促进鞘氨醇激酶-1和/或BDNF(脑源性神经营养因子)表达上调，其远期治疗效果良好。
申请人声明，本申请通过上述实施例来说明本申请的(+)-2-莰醇在制备促进鞘氨醇激酶-1和BDNF表达上调的药物中的应用，但本申请并不局限于上述实施例，即不意味着本申请必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了，对本申请的任何改进，对本申请所选用原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本申请的保护范围和公开范围之内。

Claims (12)

  1. (+)-2-莰醇在制备促进鞘氨醇激酶-1和/或脑源性神经营养因子表达上调的药物中的应用，其中，所述(+)-2-莰醇具有式I所示结构：
    Figure PCTCN2017092148-appb-100001
  2. 根据权利要求1所述的应用，其特征在于，在所述促进鞘氨醇激酶-1和/或脑源性神经营养因子表达上调的药物的作用下，鞘氨醇激酶-1的表达上调2-4倍。
  3. 根据权利要求1或2所述的应用，其特征在于，在所述促进鞘氨醇激酶-1和/或脑源性神经营养因子表达上调的药物的作用下，脑源性神经营养因子的表达上调2-4倍。
  4. 根据权利要求1-3中任一项所述的应用，其特征在于，所述药物同时促进鞘氨醇激酶-1和脑源性神经营养因子表达上调。
  5. 根据权利要求1-4中任一项所述的应用，其特征在于，所述药物还包括药学上可用的药物载体。
  6. 根据权利要求1-5中任一项所述的应用，其特征在于，所述药物还包括赋形剂。
  7. 根据权利要求1-6中任一项所述的应用，其特征在于，所述药物的剂型为胶囊剂、片剂、颗粒剂、散剂、注射剂或滴丸。
  8. 根据权利要求7项所述的应用，其特征在于，所述药物的剂型为注射剂。
  9. (+)-2-莰醇在制备治疗脑神经损伤疾病或症状的药物中的用途，其中， 所述(+)-2-莰醇具有式I所示结构：
    Figure PCTCN2017092148-appb-100002
  10. 根据权利要求9所述的用途，其特征在于，所述脑神经损伤疾病或症状由局灶性脑缺血或局灶性脑缺血再灌注引起；优选地，所述脑神经损伤疾病或症状为脑卒中和/或阿尔兹海默症。
  11. 根据权利要求9或10所述的应用，其特征在于，所述药物还包括药学上可用的药物载体和/或赋形剂。
  12. 根据权利要求9-11中任一项所述的应用，其特征在于，所述药物的剂型为胶囊剂、片剂、颗粒剂、散剂、注射剂或滴丸，优选为注射剂。
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Cited By (3)

* Cited by examiner, † Cited by third party
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CN115518057A (zh) * 2021-10-18 2022-12-27 苏州沪云新药研发股份有限公司 莰醇在制备治疗缺血性脑卒中的药物中的用途
WO2023065071A1 (zh) * 2021-10-18 2023-04-27 苏州沪云新药研发股份有限公司 莰醇在制备治疗缺血性脑卒中的药物中的用途
WO2023193347A1 (zh) * 2022-04-06 2023-10-12 沈阳药科大学 萜类化合物在调节脑膜淋巴循环促进脑内异常蛋白通过淋巴途径清除中的应用

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* Cited by examiner, † Cited by third party
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CN118045071B (zh) * 2024-04-15 2024-06-07 苏州沪云新药研发股份有限公司 一种治疗缺血性脑卒中疾病的联合用药物及其应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105012292A (zh) * 2014-04-17 2015-11-04 米文君 一种药物组合物及其用途
CN105232528A (zh) * 2014-07-10 2016-01-13 米文君 一种药物组合物及其用途
CN105879036A (zh) * 2016-04-14 2016-08-24 成都大学 一种冰片和载药纳米粒的组合物在治疗脑部疾病中的应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102180832B (zh) * 2011-03-18 2012-09-12 苏州沪云肿瘤研究中心有限公司 脑缺血保护用化合物及制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105012292A (zh) * 2014-04-17 2015-11-04 米文君 一种药物组合物及其用途
CN105232528A (zh) * 2014-07-10 2016-01-13 米文君 一种药物组合物及其用途
CN105879036A (zh) * 2016-04-14 2016-08-24 成都大学 一种冰片和载药纳米粒的组合物在治疗脑部疾病中的应用

Non-Patent Citations (17)

* Cited by examiner, † Cited by third party
Title
ANNU REV NEUROSCI., vol. 19, 1996, pages 289 - 317
ARCH NEUROL., vol. 64, no. 6, June 2007 (2007-06-01), pages 794 - 800
ASEGAWA ET AL., BIOCHIM BIOPHYS ACTA, vol. 1585, 2002, pages 193 - 201
BIOCHIM BIOPHYS ACTA, vol. 1781, 2008, pages 459 - 466
CURR ALZHEIMER RES., vol. 4, no. 5, December 2007 (2007-12-01), pages 503 - 6
CURR ALZHEIMER RES., vol. 5, no. 1, February 2008 (2008-02-01), pages 38 - 44
CURR NEUROVASC RES., vol. 4, no. 2, May 2007 (2007-05-01), pages 143 - 51
J CLIN INVEST, vol. 119, no. 7, 2009, pages 1871 - 1879
J NEUROCHEM., vol. 103, 2007, pages 509 - 517
MOL CELL BIOL, vol. 25, no. 24, 2005, pages 11113 - 11121
NAT REV IMMUNOL, vol. 5, 2005, pages 560 - 570
NEUROPHARMACOLOGY, vol. 55, no. 3, 2008, pages 363 - 389
ORHAN ALTAY ET AL., FASEB J, vol. 25, no. 2, 2011, pages 600 - 612
PHARMACOL. THER., vol. 117, 2008, pages 77 - 93
PROG BRAIN RES., vol. 146, 2004, pages 403 - 14
See also references of EP3578174A4
STROKE, vol. 42, 2011, pages 1420 - 1428

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115518057A (zh) * 2021-10-18 2022-12-27 苏州沪云新药研发股份有限公司 莰醇在制备治疗缺血性脑卒中的药物中的用途
WO2023065071A1 (zh) * 2021-10-18 2023-04-27 苏州沪云新药研发股份有限公司 莰醇在制备治疗缺血性脑卒中的药物中的用途
WO2023066162A1 (zh) * 2021-10-18 2023-04-27 苏州沪云新药研发股份有限公司 莰醇在制备治疗缺血性脑卒中的药物中的用途
WO2023193347A1 (zh) * 2022-04-06 2023-10-12 沈阳药科大学 萜类化合物在调节脑膜淋巴循环促进脑内异常蛋白通过淋巴途径清除中的应用

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