[go: up one dir, main page]

WO2013091334A1 - 雷帕霉素在制备治疗精神分裂症药物中的应用 - Google Patents

雷帕霉素在制备治疗精神分裂症药物中的应用 Download PDF

Info

Publication number
WO2013091334A1
WO2013091334A1 PCT/CN2012/074508 CN2012074508W WO2013091334A1 WO 2013091334 A1 WO2013091334 A1 WO 2013091334A1 CN 2012074508 W CN2012074508 W CN 2012074508W WO 2013091334 A1 WO2013091334 A1 WO 2013091334A1
Authority
WO
WIPO (PCT)
Prior art keywords
rapamycin
schizophrenia
mice
effect
spontaneous activity
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/CN2012/074508
Other languages
English (en)
French (fr)
Inventor
李艳琴
丁虹
林觉
郑春明
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.)
Wuhan University WHU
Original Assignee
Wuhan University WHU
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 Wuhan University WHU filed Critical Wuhan University WHU
Publication of WO2013091334A1 publication Critical patent/WO2013091334A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • the present invention relates to the use of rapamycin for the preparation of a medicament for the treatment of schizophrenia, and belongs to the field of medical technology.
  • Schizophrenia is a serious mental disorder in mental illness with a prevalence of about 1%. Symptoms are divided into positive symptoms such as psychomotor excitability, hallucinations, delusions, etc. Negative symptoms such as lack of spontaneous, apathy, flexion disorders, etc., usually accompanied by cognitive disorders, the main pathological mechanism and central dopamine (D2 Hyperfunction is associated with poor prefrontal function.
  • the main anti-schizophrenia drugs include: The first generation includes traditional antipsychotics represented by chlorpromazine and haloperidol; the second generation includes risperidone, olanzapine, quetiapine, and aripipramine. Atypical antipsychotics represented by azole, ziprasidone and amisulpride.
  • DA dopamine
  • 5-HT serotonin
  • Drugs block the dopamine D2 receptors in the midbrain-cerebral cortex and midbrain-marginal system, but they also cause extrapyramidal effects because they also affect the DA function of the substantia nigra-striatum and nodule-funnel system. Reaction (EPS), as well as endocrine, metabolic changes and other adverse reactions.
  • EPS Reaction
  • the drug acts on other nerve conduction systems, such as blocking the alpha receptor of the adrenergic system, the M1 receptor of the choline system, and the HI receptor of the histamine system, such as cardiovascular, autonomic nervous system , as well as adverse reactions such as calming, lethargy, weight gain, and obesity.
  • the second-generation anti-schizophrenia drugs In addition to acting on the DA system, the second-generation anti-schizophrenia drugs also act on the 5-HT system, which has less effect on other nerve conduction systems and can reduce adverse reactions. It is effective for negative symptoms.
  • these current antipsychotics are for people with schizophrenia The treatment is only symptomatic, and far from treatment. Therefore, when patients with schizophrenia are relieved by treatment, they must continue the long-term maintenance treatment of the drug for several years or even life to prevent recurrence. Therefore, the current treatment of schizophrenia still lacks a thorough therapeutically effective drug.
  • Psychiatry, 2011, 198, 173 - 175 that genetic factors and some early environmental factors interfere with the normal development of the nervous system, leading to cell structural disorders during brain development, and no psychiatric symptoms in childhood, as they enter puberty or In early adulthood, under the circumstance of external environmental factors, the psychological integration function is abnormal and schizophrenia symptoms appear. Therefore, inhibiting abnormal neuronal plasticity during neurodevelopment is the key to schizophrenia treatment. There are no related therapeutic drugs.
  • the mammalian ram target (Ramamycin mTOR) is a serine/threonine kinase. Protein synthesis controlled by the mTOR signaling pathway is involved in neural plasticity formation (Dash PK, et al. J Neurosci, 2006, 26 (31): 8048-56. Parsons RG, et al. J
  • Rapamycin is a natural inhibitor of mTOR (Gingras AC, et al. Curr Top Microbiol
  • the present invention provides the use of rapamycin for the preparation of a medicament for treating schizophrenia, and the anti-schizophrenia medicament prepared by using the above product has good curative effect.
  • the technical solution provided by the invention is: The application of rapamycin in the preparation of a medicament for treating schizophrenia.
  • experimental mice were administered rapamycin 1, 2. 5, 5 mg/kg by intraperitoneal injection, and a mouse model of schizophrenia was prepared by using the electric shock stimulation method and MK-801 excitation.
  • rapamycin 1, 2, 5, 5 mg / kg One hour after the intraperitoneal injection of rapamycin 1, 2, 5, 5 mg / kg, the effects of rapamycin on the irritation and spontaneous activity of mice were observed by electric shock and intraperitoneal injection of MK-801.
  • the untreated mice were still irritated with an electric shock, and the behavioral score was 100%.
  • rapamycin After the administration of rapamycin, the effect of suppressing the irritation reaction was dose-dependent, that is, the low dose was ineffective, and the medium and high doses were Significant inhibition effect. Moreover, pre-administration of rapamycin treatment can prevent high-risk spontaneous activity caused by MK-801. It indicates that rapamycin can improve the symptoms of schizophrenia.
  • the rapamycin (English name Rapamycin, Sirolimus, RAPA; Chinese also known as: sirolimus) according to the present invention is a macrolide antibiotic, and the molecular formula of rapamycin is C51H79N013, and the molecular weight is 914. .17 is a white solid crystal, melting point 183 ⁇ 185 ° C lipophilic, soluble in organic solvents such as methanol, ethanol, acetone and chloroform, very slightly soluble in water, almost insoluble in ether.
  • the molecular structure of rapamycin is:
  • the present invention also provides a medicament for treating schizophrenia, which comprises an effective amount of rapamycin and an auxiliary material, which can be synthesized according to the conventional techniques commonly used in the pharmaceutical industry.
  • the present invention has the beneficial effects of:
  • the rapamycin of the present invention has a good effect, and the prepared drug is expected to fundamentally treat schizophrenia and prevent recurrence after stopping the drug.
  • Figure 1 shows the effect of rapamycin on spontaneous activity in normal mice.
  • Figure 2 is the effect of rapamycin on the spontaneous activity of MK-801 mice, * compared with the normal control group (P ⁇ 0.05); Rapamyciri. detailed description
  • Example 1 Effect of rapamycin on irritation response induced by plantar electroporation in mice
  • Rapamycin is a novel immunosuppressive agent with good curative effect, low toxicity and no nephrotoxicity.
  • rapamycin was selected as a drug against schizophrenia, and a small electric shock schizophrenia was established.
  • Drugs and reagents rapamycin are commercially available analytical reagents.
  • the mouse vocabulary was purchased from the Experimental Animal Center of Wuhan University.
  • mice were randomly divided into 4 dose groups of rapamycin 0, 1, 2.5 and 5 mg/kg. The administration was performed by intraperitoneal injection, and the behavioral index was detected 1 hour after the administration.
  • mice were screened before the experiment. A pair of mice were placed in an electric stimulation device, the lid was closed, the power was turned on, and the AC output knob was adjusted from 0 mV to 100 mV until the mice were An irritating response occurs, and the recorded voltage value is the voltage threshold at which the mouse is irritated. If the stimulus does not appear above lmin, it will be discarded. Then, each group of mice was administered with a corresponding dose of rapamycin for 1 hour, and again, whether or not an irritation reaction occurred.
  • mice were screened before the experiment. A pair of mice were placed in an electric stimulation device, the lid was closed, the power was turned on, and the AC output knob was adjusted from OmV to 100 mV until the mice were irritated. The recorded voltage value is the voltage threshold at which the mouse is irritated. If you have not stimulated for more than 1min, it will be discarded. Then, each group of mice was given 1 hour after the corresponding dose of rapamycin, and the irritation reaction was detected again at the threshold voltage of the foot shock. The behavioral score, ie the number of mice with irritable reaction after administration, was obtained. The ratio of the number of mice in which the irritating response occurred before administration. Experimental result 1. The effect of rapamycin on irritation response in mice
  • the untreated mice showed an irritation reaction before and after the electric shock of the foot, and the behavioral score was
  • Example 2 Effect of rapamycin on MK-801-induced high-risk spontaneous activity in mouse schizophrenia. This example selects rapamycin as a drug for high-risk activity against schizophrenia, and builds MK-801 schizophrenia. In a mouse model, we investigated the effect of rapamycin on the high-risk spontaneous activity in mice, and aimed to select a drug with high efficacy and low toxicity for high-risk spontaneous activity against schizophrenia. Materials and Methods
  • Rapamycin sigma-R0395; MK-801: sigma-M107; DMS0 and other reagents are commercially available analytical reagents.
  • the mouse vocabulary was purchased from the Experimental Animal Center of Wuhan University.
  • mice were randomly divided into normal control + rapamycin 0, 1, 2.5, and 5 mg/kg groups and MK-801 model + rapamycin 0, 1, 2.5, and 5 mg/kg groups. . Dosing is administered intraperitoneally. Behavioral indicators were tested 1 hour after dosing.
  • mice Each group of mice was given the corresponding dose of rapamycin for 1 hour, MK-801 model group was given 0.5 mg/kg of MK-801, the normal control group was given the corresponding vehicle, and the spontaneous control was detected after the administration. Activity for 1 hour.
  • mice Each group of mice was given a corresponding dose of rapamycin in the spontaneous activity test box to record the number of shuttle lattices. One hour later, the vehicle was injected intraperitoneally with MK-801 and spontaneous activity was recorded for 1 hour.
  • the spontaneous activity of the mouse uses the DigBehv spontaneous activity video analysis system (manufactured by Shanghai Jiliang Software Technology Co., Ltd.), which is composed of 4 spontaneous activity observation boxes and video synthesizers with a size of 25 cmX 25 cmX 40 cm (length X width X height). , video pattern sampling card and analysis software.
  • the system can track video of mouse activities, automatically record mouse activity trajectories, and calculate activity paths.
  • the indicators for spontaneous activity evaluation are: The total distance of activity of the mouse within a certain period of time (such as 60 min), that is, the total distance becomes longer and the spontaneous activity increases.
  • mice Each group of mice was given the corresponding dose of rapamycin in the spontaneous activity test box to record the number of shuttle lattices.
  • the spontaneous activity of the mouse adopts the DigBehv spontaneous activity video analysis system (manufactured by Shanghai Jiliang Software Technology Co., Ltd.), which is a spontaneous activity observation box and video synthesizer with 4 specifications of 25 cmX 25 cmX 40 cm (length X width X height). , video pattern sampling card and analysis software.
  • the system can video track mouse activities, automatically record mouse activity trajectories, and calculate activity paths.
  • the indicators for spontaneous activity evaluation are: The total distance of activity of the mouse within a certain period of time (such as 60 min), that is, the total distance becomes longer and the spontaneous activity increases.
  • rapamycin After administration of rapamycin in the MK-801 model group, it has a significant inhibitory effect on the spontaneous activity from MK-801 to the hair, that is, it is ineffective at low doses of 1 mg/g, medium and high doses (2.5 mg/g, 5. Omg/g) showed a significant inhibitory effect, and the results are shown in Figure 2. The difference was significant.
  • rapamycin can improve schizophrenia Highly spontaneous spontaneous activity response.
  • Rapamycin can effectively improve the symptoms of schizophrenia induced by plantar electric shock in mice, and its effect is dose-dependent and has remarkable curative effect.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了雷帕霉素在制备治疗精神分裂症药物中的应用。本发明雷帕霉素为治疗精神分裂症的易激怒、活动高涨的症状提供了一种有效的药物。

Description

雷帕霉素在制备治疗精神分裂症药物中的应用 技术领域 本发明涉及雷帕霉素在制备治疗精神分裂药物中的应用， 属于医药技术领 域。 背景技术 精神分裂症是精神疾病中的一种严重的精神障碍， 患病率大约在 1%。 其症 状分为正性症状如精神运动性兴奋、 幻觉、 妄想等； 负性症状如缺乏自发性、 情 感淡漠、 屈曲性障碍等， 通常伴有认知障碍， 其主要病理机制与中枢多巴胺 (D2) 功能亢进和前额叶功能低下有关。 如今， 抗精神病药物已有长足的发展， 其确 切的疗效，无可否认地大大改善了精神分裂症患者的预后，但仍不能改变其为一 种严重致残性疾病的事实。世界卫生组织 (WHO) 1998年公布的全球疾病负担 (GBD) 调查研究， 以伤残调整生命年 (DALY)作为评价疾病负担的指标， 结果提示， 精神 分裂症位于致残性疾病的前十位。
抗精神分裂症的药物主要有： 第一代包括以氯丙嗪和氟哌啶醇为代表的传统 抗精神病药物； 第二代包括以利培酮、 奥氮平、 喹硫平、 阿立哌唑、 齐拉西酮和 氨磺必利等为代表的非典型抗精神病药物。有关抗精神病药物的作用机制研究较 多， 其药效机制极为复杂， 通常以神经递质和受体学说来阐释， 至今研究最多的 为多巴胺 (DA)与 5-羟色胺 (5-HT)系统。 药物阻断中脑 -大脑皮质和中脑-边缘系 统的多巴胺 D2受体发挥药理作用，但由于也影响到黑质 -纹状体和结节-漏斗系统 的 DA功能，故而会引起锥体外系反应 （EPS)， 以及内分泌、代谢改变等不良反应。 此外， 当药物作用于其他神经传导系统时， 如阻断肾上腺素系统的 α受体， 胆碱 系统的 Ml受体， 组胺系统的 HI受体时， 就会产生诸如心血管、 自主神经系统， 以 及镇静、 嗜睡、 体重增加、 肥胖等不良反应。 第二代抗精神分裂症药物除了作用 于 DA系统外， 还同时作用于 5-HT系统， 对其他神经传导系统的作用较小， 可减少 不良反应。对阴性症状有效。然而， 目前的这些抗精神病药物对精神分裂症患者 的治疗仅是对症治疗， 而远非对因治疗。 因此， 当精神分裂症患者经治疗获得缓 解后， 尚须继续药物几年甚至终身的长期维持治疗以防复发。 因此， 目前精神分 裂症治疗尚缺乏彻底治疗有效药。
目前， 精神分裂症神经发育学说 （Owen MJ et al. The British Journal of
Psychiatry, 2011, 198, 173 - 175 ) 认为遗传因素及一些早期环境因素干扰了神 经系统的正常发育， 导致大脑发育过程中出现了细胞结构紊乱， 幼年期尚不出现 精神症状， 随着进入青春期或成年早期， 在外界环境因素的不良剌激下， 导致心 理整合功能异常而出现精神分裂症症状。因此，抑制神经发育过程中异常神经可 塑性是精神分裂症对因治疗的关键所在， 目前还未见有相关的治疗药物。
哺乳动物雷帕霉素靶蛋白 (mammal ian target of Rapamycin mTOR) 是一 种丝氨酸 /苏氨酸激酶。 mTOR信号转导通路控制的蛋白合成参与了神经可塑性形 成（ Dash PK, et al. J Neurosci, 2006, 26 (31) : 8048—56. Parsons RG, et al. J
Neurosci, 2006, 26 (50) : 12977-83)。 雷帕霉素 （西罗莫司、 Sirol imus ,
Rapamycin ) 是 mTOR 的天然抑制剂 (Gingras AC, et al. Curr Top Microbiol
Immunol, 2004, 279 (169-97 ； Hay N, et al. Genes Dev, 2004,
18 (16) : 1926-1945. Inoki K, et al. Nat Genet, 2005, 37 (1) : 19- 24)， 属新型 大环内酯的抗排斥药物， 是目前世界上最新的强效免疫抑制剂， 临床上用于器官 移植的抗排斥反应。 它的免疫抑制活性比现行临床广泛使用的环孢素强数十倍， 雷帕霉素毒性低、 用量小（2mg/天 /人）， 且与环孢素有协同免疫抑制作用， 临床 上与环孢素联合使用。 与环孢素和 FK506 (他克莫司）相比， 雷帕霉素是肾毒性 最低的免疫抑制剂，且无神经毒性。但雷帕霉素用于制备治疗精神分裂症的作用， 尚未见报道。 发明内容
针对上述背景技术存在的问题，本发明提供雷帕霉素在制备治疗精神分裂症 药物中的应用， 使用上述产物制备的抗神分裂症药物具有较好的疗效。
本发明提供的技术方案是： 雷帕霉素在制备治疗精神分裂症药物中的应用。 本发明经腹腔注射给予实验小鼠雷帕霉素 1、 2. 5、 5mg/kg， 采用足部电击 激怒法和 MK-801 激发制备精神分裂症小鼠模型。 雷帕霉素腹腔注射 1、 2. 5、 5mg/kg后 1小时， 采用电击法和腹腔注射 MK-801分别观察雷帕霉素对小鼠的激 怒反应和自发活动的影响。 结果可见，未给药的小鼠，给予电击仍然出现激怒反应，行为学评分为 100%; 给予雷帕霉素处理后， 抑制激怒反应的效应出现剂量依赖性， 即低剂量无效， 中 高剂量呈明显抑制效应。 而且， 预给予雷帕霉素处理后可阻止由 MK-801所致的 高发性自发活动。 表明雷帕霉素可改善精神分裂症状。
本发明中所述的雷帕霉素 （英文名称为 Rapamycin , Sirolimus , RAPA; 中 文还称为： 西罗莫司）属大环内酯类抗生素， 雷帕霉素的分子式为 C51H79N013, 分子量为 914. 17， 为白色固体结晶， 熔点为 183〜 185°C 亲脂性， 可溶解于甲 醇、 乙醇、 丙酮和氯仿等有机溶剂， 极微溶于水， 几乎不溶于乙醚。
雷帕霉素的分子结构式为：
Figure imgf000004_0001
本发明还提供了治疗精神分裂症的药物，其中含有有效剂量的雷帕霉素和辅 料， 按现有医药工业常用技术合成即可。
本发明具有的有益效果在于： 本发明雷帕霉素效果好，制成的药物有望从根 本上治疗精神分裂症及防止停药后的复发。 附图说明
图 1为雷帕霉素对正常小鼠自发活动的影响。
图 2为雷帕霉素对 MK-801模型小鼠高发性自发活动的作用， *与正常对照组 木目比 P〈0. 05;
Figure imgf000004_0002
Rapamyciri。 具体实施方式
下面以实施例对本发明做进一步的说明，但是不对本发明的保护范围构成任 何限制。
实施例 1 : 雷帕霉素对足底电击致小鼠激怒反应的作用
雷帕霉素是一种新型免疫抑制剂， 具有疗效好， 低毒， 无肾毒性的特点， 本 实施例选择雷帕霉素作为抗精神分裂症的药物，通过建立足底电击精神分裂症小 鼠模型， 探讨雷帕霉素对小鼠激怒反应的改善作用， 旨在选择一种疗效确切、毒 性小的抗精神分裂症易激惹症状的药物。 材料与方法
药品及试剂 雷帕霉素： sigma-R0395 ; DMS0等试剂均为市售分析纯试剂。 动物 SPF级 C57雄性小鼠， 体重 20-25g 。 武汉大学动物实验中心提供， 动物合格证号为 NO.00014833， 生产许可证号： SCXK (鄂） 2003-2004。 鼠词料， 购于武汉大学实验动物中心。
实验方法
动物分组与处理： 小鼠随机分为雷帕霉素 0、 1、 2.5和 5mg/kg 4个剂量组。 给药均采用腹腔注射， 与给药后 1小时进行行为学指标检测。
动物造模： 各组小鼠在实验前进行筛选， 将一对小鼠放入电剌激装置中， 盖 上盖子， 把电源打开， 从 0 mV至 lOOmV调节交流电输出旋钮， 直至这对小鼠 出现激怒反应， 记录电压值即为小鼠出现激怒反应的电压阈值。 若剌激 lmin以 上仍未出现者弃用。然后， 各组小鼠分别给予相应剂量的雷帕霉素后 1小时， 再 次检测其是否出现激怒反应。
检测指标：
各组小鼠在实验前进行筛选， 将一对小鼠放入电剌激装置中， 盖上盖子， 把 电源打开， 从 O mV至 lOOmV调节交流电输出旋钮， 直至这对小鼠出现激怒反 应， 记录电压值即为小鼠出现激怒反应的电压阈值。 若剌激 lmin以上仍未出现 者弃用。然后， 各组小鼠分别给予相应剂量的雷帕霉素后 1小时， 再次检测在阈 电压足底电击时是否出现激怒反应，得出行为学评分即给药后激怒反应出现的小 鼠数与给药前激怒反应出现的小鼠数之比。 实验结果 1. 雷帕霉素对小鼠激怒反应的作用
结果可见， 未给药的小鼠， 在足底电击前后均出现激怒反应， 行为学评分为
100%； 给予雷帕霉素处理后， 抑制激怒反应的效应出现剂量依赖性， 即低剂量 lmg/g时无效， 行为学评分为 100%， 中高剂量（2. 5mg/g、 5. Omg/g) 时呈明显抑 制效应， 其行为学评分分别是 12. 5%和 0， 结果见表 1。 给药组与对照组相比差 异具有显著性， 说明雷帕霉素可改善精神分裂症的激怒反应。 表 1. 雷帕霉素对小鼠激怒反应的作用 剂量 激怒反应 （有或无） 行为学评分 组别 n
mg/kg 给药前 （n) 给药后 （n) (%) 正常对照组 0 8 8 8 100
1. 0 8 8 8 100 雷帕霉素组 2. 5 8 8 1 12.5**
5. 0 8 8 0 0**
*与正常对照组相比 P〈0. 05; **P〈0. 01。 实施例 2: 雷帕霉素对 MK-801致小鼠精神分裂症高发性自发活动的作用 本实施例选择雷帕霉素作为抗精神分裂症高发性活动的药物， 通过建 MK-801精神分裂症小鼠模型， 探讨雷帕霉素对小鼠高发性自发活动的改善作用， 旨在选择一种疗效确切、 毒性小的抗精神分裂症高发性自发活动的药物。 材料与方法
药品及试剂 雷帕霉素： sigma-R0395; MK-801 : sigma-M107; DMS0等试 剂均为市售分析纯试剂。
动物 SPF级 C57雄性小鼠， 体重 20-25g 。 武汉大学动物实验中心提供， 动物合格证号为 NO.00014833， 生产许可证号： SCXK (鄂） 2003-2004。 鼠词料， 购于武汉大学实验动物中心。
实验方法
动物分组与处理： 小鼠随机分为正常对照 +雷帕霉素 0、 1、 2.5和 5mg/kg组 和 MK-801模型 +雷帕霉素 0、 1、 2.5和 5mg/kg 组共八组。给药均采用腹腔注射， 与给药后 1小时进行行为学指标检测。
动物造模： 各组小鼠给予相应剂量的雷帕霉素 1小时后， MK-801模型组给 予 0. 5mg/kg的 MK-801 , 正常对照组给予相应的溶媒， 给药后检测其自发活动 1 小时。
检测指标：
( 1 ) 雷帕霉素对正常小鼠自发活动的影响：
各组小鼠给予相应剂量的雷帕霉素放入自发活动检测箱记录其穿梭格子的 次数 1小时后， 腹腔注射 MK-801的溶媒并继续记录自发活动 1小时。 小鼠自发 活动采用 DigBehv自发活动视频分析系统 (上海吉量软件科技有限公司生产），是 由 4个规格为 25 cmX 25 cmX 40 cm (长 X宽 X高）的自发活动观察箱、 视频合成 器、视频图样采样卡和分析软件等组成。本系统能对小鼠活动进行视频跟踪， 自 动记录小鼠活动轨迹， 计算活动路程。 自发活动评价的指标是： 小鼠一定时间段 内（如 60 min)的活动总路程， 即总路程变长显示自发活动增加。
(2) 雷帕霉素对 MK-801模型小鼠高发性自发活动的作用：
各组小鼠给予相应剂量的雷帕霉素放入自发活动检测箱记录其穿梭格子的 次数 1小时后，腹腔注射 0. 5mg/kg的 MK-801并继续记录自发活动 1小时。小鼠 自发活动采用 DigBehv自发活动视频分析系统（上海吉量软件科技有限公司生 产）， 是由 4个规格为 25 cmX 25 cmX 40 cm (长 X宽 X高）的自发活动观察箱、 视频合成器、视频图样采样卡和分析软件等组成。本系统能对小鼠活动进行视频 跟踪， 自动记录小鼠活动轨迹， 计算活动路程。 自发活动评价的指标是： 小鼠一 定时间段内（如 60 min)的活动总路程， 即总路程变长显示自发活动增加。 实验结果
1. 雷帕霉素对正常小鼠自发活动的影响
结果可见， 正常对照组给予相应剂量雷帕霉素对小鼠的自发活动没有影响 (见附图 1 )，
2. 雷帕霉素对 MK-801模型小鼠高发性自发活动的作用
MK-801模型组给予雷帕霉素后， 对由 MK-801至发的高发性自发活动具有明 显的抑制效果， 即低剂量 lmg/g时无效， 中高剂量（2. 5mg/g、 5. Omg/g) 时呈明 显抑制效应， 结果见图 2， 差异具有显著性。 说明雷帕霉素可改善精神分裂症 的高发性自发活动反应。
实验结论
雷帕霉素能有效改善足底电击致小鼠精神分裂症易激惹症状，其作用具有剂 量依赖性， 疗效显著。

Claims

1、 雷帕霉素在制备治疗精神分裂症药物中的应用， 雷帕霉素结构式 如下：
Figure imgf000009_0001
2、 治疗精神分裂症的药物， 其 含有雷帕霉素。
PCT/CN2012/074508 2011-12-22 2012-04-23 雷帕霉素在制备治疗精神分裂症药物中的应用 Ceased WO2013091334A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201110435058.5 2011-12-22
CN2011104350585A CN102488687A (zh) 2011-12-22 2011-12-22 雷帕霉素在制备治疗精神分裂症中的应用

Publications (1)

Publication Number Publication Date
WO2013091334A1 true WO2013091334A1 (zh) 2013-06-27

Family

ID=46180594

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2012/074508 Ceased WO2013091334A1 (zh) 2011-12-22 2012-04-23 雷帕霉素在制备治疗精神分裂症药物中的应用

Country Status (2)

Country Link
CN (1) CN102488687A (zh)
WO (1) WO2013091334A1 (zh)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014520811A (ja) 2011-06-29 2014-08-25 ザ トラスティース オブ コロンビア ユニバーシティ イン ザ シティ オブ ニューヨーク 統合失調症の易罹病性及び認知機能障害と関連付けられるニューロン結合の阻害剤
WO2014145857A1 (en) * 2013-03-15 2014-09-18 The Trustees Of Columbia University In The City Of New York TARGETING THE mTOR PATHWAY IN NEUROLOGICAL DISEASE
CN112877419A (zh) * 2021-01-20 2021-06-01 武汉大学 预测精神分裂症发生风险的dna甲基化标记物及筛选方法和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1187127A (zh) * 1995-06-07 1998-07-08 吉尔福特药品有限公司 旋转异构酶活性抑制剂
WO2010083044A1 (en) * 2009-01-16 2010-07-22 Massachusetts Institute Of Technology Diagnosis and treatment of autism spectrum disorders

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1187127A (zh) * 1995-06-07 1998-07-08 吉尔福特药品有限公司 旋转异构酶活性抑制剂
WO2010083044A1 (en) * 2009-01-16 2010-07-22 Massachusetts Institute Of Technology Diagnosis and treatment of autism spectrum disorders

Also Published As

Publication number Publication date
CN102488687A (zh) 2012-06-13

Similar Documents

Publication Publication Date Title
US20220202798A1 (en) Use of pridopidine for the treatment of fragile x syndrome
Wu et al. Activation of serotonin 5-HT2C receptor suppresses behavioral sensitization and naloxone-precipitated withdrawal symptoms in heroin-treated mice
TW201841637A (zh) 使用ccr3-抑制劑治療老化相關損傷之方法及組合物
AU2016226006A1 (en) Method of treatment with tradipitant
Qiu et al. Anxiolytic-like effects of paeoniflorin in an animal model of post traumatic stress disorder
US20210106573A1 (en) Methods of use of cyclic amide derivatives to treat sigma receptor mediated disorders
WO2014090990A1 (en) Leukotriene pathway antagonists for the treatment of dementia, cognitive deficits in parkinson's disease and/or learning and memory deficiencies in parkinson's disease
CN118401241A (zh) 用于治疗慢性肾脏病的醛固酮合成酶抑制剂
JP7269875B2 (ja) ピラゾロキノリン誘導体を含有するレビー小体病治療剤
WO2013091334A1 (zh) 雷帕霉素在制备治疗精神分裂症药物中的应用
AU2019338236B2 (en) A GABAA receptor ligand
TWI612961B (zh) 類鐸受體４拮抗劑及於自體免疫肝臟疾病之用途
Bai et al. A comparison of the effects of digoxin, ouabain and milrinone on naloxone-precipitated withdrawal syndrome in mice
EP3727587A1 (en) Compositions and methods for williams syndrome (ws) therapy
TW202027752A (zh) 使用ccr-3抑制劑治療老化相關損傷之方法及組合物
RU2840025C2 (ru) Способы применения производных циклического амида для лечения опосредуемых сигма-рецепторами расстройств
Class et al. Patent application title: USE OF PRIDOPIDINE FOR THE TREATMENT OF FRAGILE X SYNDROME Inventors: Michael Hayden (Herzliya, IL) Mahmoud Abdulhossein Pouladi (Singapore, SG) Assignees: PRILENIA NEUROTHERAPEUTICS LTD. NATIONAL UNIVERSITY OF SINGAPORE Agency For Science, Technology and Research
CN114761008B (zh) 用于在患有痴呆的患者中治疗行为和心理症状的方法
Allahtavakoli et al. Effect of morphine withdrawal syndrome on cerebral ischemia outcome in rats
HK40071167A (zh) 用於在患有痴呆的患者中治疗行为和心理症状的方法
CN116672341A (zh) 雷帕霉素在治疗渐冻症和额颞叶痴呆中的应用
HK40016661B (zh) 用於治疗脆性x综合征的普利多匹定
HK40016661A (zh) 用於治疗脆性x综合征的普利多匹定

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: 12859571

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12859571

Country of ref document: EP

Kind code of ref document: A1