CN1261158C - 生长激素在制备用于诱导神经保护作用的药剂中的应用 - Google Patents
生长激素在制备用于诱导神经保护作用的药剂中的应用 Download PDFInfo
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Abstract
本发明涉及使用神经保护物质和药物,神经保护物质是由激活神经系统生长激素受体诱导产生的。主要使用药物包括生长激素、生长激素类似物或功能等效配体。那些药物也可包括一种或多种辅助的神经保护剂。
Description
本发明涉及神经保护,特别是涉及神经保护(neuroprotection)方面的生长激素、生长激素类似物或功能等效配体的一种新的治疗学上的应用。
与本发明相关的背景技术
已经报道过生长激素受体/结合蛋白(GHR/BP)存在于未成年小鼠(Lobie等1993)和成年小鼠(Burton等1992)的大脑中,尤其在未成年小鼠的中枢神经系统中,其分布显然更为广泛。生长激素受体和结合蛋白的表现度的个体发育显然类似于发育中的中枢神经系统的IGF-1和IGF-2受体的表现度,主要产生于胎儿和新生儿体内,以后便逐渐下降(Bartlett等1991,Bondy和Lee1993,Garofalod等1989)。对于转基因鼠的研究表明,无论是IGF-1消除或是生长激素缺乏,试验小鼠都表现出髓鞘生成减退和大脑变小。(Beck等1995,Noguchi(1991),因此表明了生长激素和IGF-1在大脑发育、生长和髓鞘生长中的作用。最近一项对生长激素缺乏儿童的研究,显示了下丘脑障碍影响生长激素的分泌,与在直观的运动心理测试中评分的显著相关性,表明一种反常的促进生长中枢与减弱的识别表现间的关系。(Andronikof-sanglade等1997)。
迄今为止,还没有对生长激素的神经保护(neuroprotective)功能的论证。(此处“neuroprotective”意为在中枢神经系统中显示出的神经预防性的和/或神经保护性的能力)。而美国专利4,791,099中描述了运用生长激素和雄性激素结合治疗神经系统疾病的情况,但是没有单独地进行生长激素给药的描述。当然,在美国专利4,791,099中,也没有生长激素合成代谢方面的学说,以提供给病人关于雄性激素的恢复的作用和更有接受力的治疗效果,没有提到神经预防性和神经保护性。
是本专利申请人发现生长激素本身具有神经保护性能。该发现是惊人的,尽管在生长激素与IGF-1之间存在促生长关系,且已证明了IGF-1在体内外都具有神经保护性的作用(Knusel等1990,Guan等1993)。这是因为IGF-1是通过IGF-1受体发挥作用,而生长激素不是那样。因此,生长激素在丘脑中具有神经保护性,有报道在丘脑中有生长激素受体免疫活性的分配,(Lobie等1993,《发展的脑研究》(Developmental Brain Research 74:225)),而在纹状体中则不是这样,与此相反,IGF-1在纹状体中具有神经保护性能,IGF-1受体在纹状体中已被报道其存在,(Hill等1986《神经系统科学》(neuroscience)17:1127;Lesinak等1988,《内分泌学》(Endocrinology)123:2089),这与丘脑的情况不同。进一步由于本发明申请人已经发现生长激素中枢给药对大脑是具有神经保护性的,而又不影响并存的IGF-1水平的增长。
正是这些惊人的发现构成本发明的基础。
发明简述
首先,本发明提供了一种在病人的大脑中诱导产生神经保护作用的方法,包括向所述病人大脑进行生长激素、其类似物或相同功效配体的给药的步骤。
在此,“类似物”是指一种活性剂的断片或衍生物,该类似物至少与所述活性剂具有实质性等效的生物活性。
“功能等效配体”是指能与大脑中的神经系统受体结合,并使之激活的药剂,如同生长激素能与神经系统受体结合并使之激活。
进一步,本发明提供了一种诱导病人大脑中的神经保护作用效应的方法,包括在所述病人的大脑中增加生长激素和相同功效的配体的有效浓度。
优选的是,所述生长激素/类似物/配体的有效浓度通过直接给药使之增加。
或者,生长激素或配体的有效浓度是通过给予一种药剂而增加,该药剂刺激生长激素或配体的产生,或者减少或阻止对生长激素或配体活性的抑制作用。
优选的是,这种神经保护作用是一种神经修复作用。
或者,这种神经保护作用是一种神经预防作用。
更进一步的优选实施例中,本发明提供了一种修复病人神经元的方法,所述病人在先的神经元损害结果是注定导致神经元死亡的;该方法包括增加所述病人大脑中的生长激素、类似物或相同功效的配体有效量的步骤。
这里所用的“神经元损害”具有广泛的可能性,包括由创伤(损伤)、突变性疾病和机能紊乱、运动性疾病和障碍、脱髓鞘疾病和病症、神经综合症、眼部疾病和睡眠障碍引起的神经损害。
本发明申请人已经发现生长激素的神经保护作用是通过神经系统生长激素受体来介导的。“神经系统生长激素受体”是指大脑中发现的任何生长激素与之结合并激活的受体,或是指任何生长激素能与之结合并激活的受体。这些受体包括生长激素受体(GHR)和催乳激素受体(PRL-R)。
因此,进一步讲,这项发明提供了一种诱导病人大脑的神经保护功能的方法,包括引起所述病人大脑中神经系统生长激素受体的活性提高的步骤。
优选的是,这种活性的提高是通过用一种药剂对上述病人大脑直接给药,提高所述神经系统生长激素受体的活性。
优选的是,上述药剂直接和神经激素受体结合。这种药剂可以是生长激素、一种生长激素类似物或是一种等效功能的配体,如催乳激素、一种催乳激素的类似物、胎盘催乳激素或胎盘催乳激素的类以物。
另一种选择,这种药剂是能导致另一种药剂有效浓度提高,后者可与神经系统生长激素受体结合(即这种药剂的间接投药作用)。优选的是,这种药剂选自生长激素释放蛋白(GRP)、生长激素释放激素(GHRH)、同等功效的促泌素和生长激素抑制素释放的抑制因子(SRIF)。
这种方法的实用之处是有神经保护作用。
另外,所述方法诱导产生一种神经修复的作用。
更进一步,本发明提供了一种治疗由于神经方面的损伤会导致神经元死亡,修复病人神经元的方法,该方法包括提高所述病人大脑中神经系统生长激素受体活性的步骤。
申请人也打算采用一种结合治疗方法,用生长激素或生长激素类似物/配体给药来修复第一类病人神经细胞,以及辅助神经保护剂用来给药保护第二类病人的神经细胞。因此,本发明进一步提供了一种治疗病人用以保护神经元的方法,所述方法包括在与另一种神经保护剂结合的同时进行生长激素、生长激素类似物或某种同等功效的配体给药。
优选的是,所述的辅助神经保护剂选自IGF-1、GPE、苯丙酸诺龙、NGF、TGF-β、生长激素结合蛋白、IGF结合蛋白和bFGF。
这种方法实用之处在于诱导神经修复的效果来复活神经元,否则由于神经伤害会导致(神经元)死亡。
在一个实施例中,这类伤害是亨廷顿氏(Huntington)疾病或阿尔海默氏(Alzheimer)疾病,并且所述的生长激素/类似物/配体和一种或多种GPE、IGF-1和苯丙酸诺龙结合进行给药。
在另一个实施例中,这种伤害是皮质基质的变性或斯蒂尔-里查德森-奥茨斯基综合症(Steel-Richardson-Olszewski),并且所述的生长激素/类似物/配体与IGF-1结合进行给药。
在另一个实施例中,这种伤害是戴韦克氏病(Devic)或皮克氏病(Pick),并且所述的生长激素/类似物/配体和GPE、IGF-1二者或二者之一结合进行给药。
再一个实施例中,这种伤害是糖尿病性神经病,并且所述的生长激素/类似物/配体和苯丙酸诺龙、IGF-1二者或二者之一结合进行给药。
更进一步,本发明提供了一种治疗由于神经方面的损伤会导致神经元死亡,修复病人神经元的药物,该药物包括结合使用生长激素、一种生长激素类似物或一种功能等效配体,以及一种或多种辅助类神经保护剂,除IGF-1外,优选的是一种或多种GPE、苯丙酸诺龙、NGF、TGF-β、一种生长激素结合蛋白、一种IGF结合蛋白以及bFGF。
优选的是,所述药物进一步包括IGF-1。
此外,本发明提供了生长激素或一种生长激素类似物或功能等效配体,用于一种神经保护药物的制备。
优选的是,所述的药物是一种用于治疗由于神经方面的损伤会导致神经元死亡,修复病人神经元的药物。
附图简要描述
对工艺熟悉的人对本发明的各种调整和变化亦非常熟悉,但这些并不背离本发明的范围和宗旨。即便本发明是与其适宜的特殊实施例一起阐述的,应该明了的是,权利要求的发明不应该被不适当地限制在这些特殊实施例里。确实,对那些对工艺熟悉的人来说,对所描述的实施本发明模式的各种调整已经非常熟悉。这些调整都在随后所附的权利要求范围内。另外通过所附图表可以更好地理解本发明。
图1适度的HI(缺氧伤害)之后,GH(生长激素)对ICV鼠在血清及CSF IGF-1的水平的治疗效果。
图2适度的HI之后,以神经元记分表示对ICV鼠治疗效果;以及
图3适度的HI之后,以神经元存活显示GH对ICV鼠的治疗效果。
发明详述
如上所述,本发明涉及到神经保护。包括神经预防和神经修复两个方面,但更侧重于神经修复。
申请者已经发现能够使用两种方法影响神经预防,特别是神经修复,第一种方法主要通过侧重生长激素及其类似物和功能等效配体。申请者已经发现在病人的大脑内提高生长激素、生长激素类似物或功能等效配体的有效浓度,可以诱发产生神经保护的效果,特别是神经修复的效果。
这种方法中使用的生长激素可以是任何哺乳动物的生长激素,例如人生长激素、鼠生长激素、猪生长激素。优选的用于人类疾患的生长激素最好是人生长激素。
本发明所用的生长激素可以是充分提纯的、天然的、重组技术生产的,或是化学合成的形式。例如,这种生长激素可以用已知方法直接从血液中(如血清或血浆)中分离出来。例如,参见Phillips(1980)新英格兰药学杂志(New Eng J.Med)302:371-380;Svoboda等(1980)《生物化学》(Biochemistry)19:790-797;Cornell和Boughdady(1982)《生物化学制剂》(Prep.Biochem.)12:57;Cornell和Boughdady(1984)《生物化学制剂》14:123;欧洲专利EP123,228号;以及美国专利4,769,361号。另外,运用那些肽类专业人员已经掌握的几种技术中任何一种,可以化学合成生长激素。例如,Li等(1983)《美国国家化学学会会刊》(Proc.Natl.Acad.SciUSA)80:2216-2220,Stewart和Young(1984)《固相缩氨酸合成》(Solid Phase Peptide Synthesis)(美国伊利诺斯州罗克福德皮尔斯化学公司),以及Barany和Merrifilield(1980)《生物化学上肽的分析与合成》(The peptides:Analysis,Synthesis,Biology),Gross和Meienhofer在纽约学院快报(Academic Press,Mew York)1980卷2,3-254页《关于固相肽合成技术》;Bodansky(1984)《肽合成原理》(Principles of Peptide Synthesis)(柏林springer-Verlag);Gross和Meienhofer编辑(1980)《生物化学上肽的分析与合成》纽约学院快报卷1关于经典液相合成。生长激素也可通过同时存在的其它多肽合成方法进行化学制备。例如,参见Houghten(1985)《美国国家化学学会会刊》82:5131-5135和美国专利4,631,211号。
用重组DNA技术的基因工程可以成为制造生长激素的最有效的方法。我们知道人体DNA序列编码了这些蛋白质,并且以表现度值传入宿主细胞。在E.Coli、酵母、昆虫和哺乳动物细胞中利用重组基因技术制造蛋白质。隐藏的多肽可以通过增加标志序列到DNA序列以编码神经学疗法。另外,DNA序列可以被调整用来制造各种片段、类似物或衍生物。这些DNA重组技术在专业领域是普遍运用的。
最方便的方法是,使用生长激素本身或某种生长激素前体药物(一种在体内被分裂以释放药物的方式)来直接给药,提高生长激素的有效浓度。但是,本申请人并不排除通过生长激素显效药或促泌素给药来提高生长激素浓度(直接作用增加大脑产生生长激素的物质,例如生长激素释放肽(GHRP),如GHRP-1,GHRP-2,GHRP-6,Hexarelin,G-7039,G-7502,L-692,429,L-692,585,L-163,191,[Deghenghi等1994,《生命科学》(Life Sci.)54:1321;Bowers 1993,《儿科内分泌学学报》(J.Paed Endocrinol.)6:21;Smith等(1993)《科学》260:1640;McDowell等1995,Proc.Natl.Acad.Sci.USA 92:11165;Patchett等1995,《美国国家化学学会会刊》(Proc.Natl.Acad.Sci.USA)92:7001;Clark和Robinson(1996)《细胞因子和生长因子回顾》(Cytokine Growth Factor Reviews)7(1):65]或生长激素释放激素(GHRH)[Frohman等(1992)《前沿神经内分泌学》(FrontNeuroendocrinol.)13:344;Clark和Robinson(1996)《细胞因子和生长因子回顾》7(1):65]或生长激素抑制剂拮抗剂(与生长激素结合,或者以其他方式阻止或减少体内生长激素的产生)。后者是通过干扰某种抑制机理来对生长激素的有效浓度发生间接的作用,包括物质如生长激素抑制因子(生长激素释放抑制因子(SRIF)[Gillees(1997)《药理科学趋势》(Trends in Pharmacol.Sci.)18(3):87]。
另一种给药形式可采用一种具有复制功能,用以编码生长激素的媒介物。此类媒介物(可以是一种修正过的细胞系或病毒,可在病人体内进行生长激素表达),具有有较长时间内在病人体内提高生长激素浓度的能力。[Maxwell等(1998)Neurosurgery 43(5):1157]此类媒介物可以构成大脑植入物的一部分。
除了生长激素本身以外,值得考虑利用生长激素类似物或其功能等效配体。
这里所说“类似物”是指某种蛋白质或肽,是一种经过修改的生长激素变体(如经过插入、删除或替代一种或多种氨基酸,糖基化作用,磷酸化作用或增加一种或多种外来成分),但是保持至少实质上的功能等效。
某种蛋白质是另一种蛋白质的一种特定功能等效蛋白质,则要满足该等效蛋白质与原蛋白质具有免疫交叉反应,并至少实质上与原蛋白质具有等效功能。所述等效物可以是,例如,某种蛋白质片段,如C端或A端被删除,一种蛋白质与另一种蛋白质或载体融合,或某种片段与另一种氨基酸融合。例如,可能是利用常规技术在序列中采用等效氨基酸进行替代,常见等效的氨基酸组是:
(a)Ala,Ser,Thr,Pro,Gly;
(b)Asn,Asp,Glu,Gln;
(c)His,Arg,Lys;
(d)Met,Leu,Ile,Val;和
(e)Phe,Tyt,Trp
功能等效蛋白质一般有至少70%,优选的是至少80%,更理想的是90%到95%或更多,并且最理想的是98%或更多氨基酸序列与参照分子的氨基酸序列一致。“参照分子”是指对照比较的序列,既可能是完整的序列,也可能是特定序列的片段。“序列一致性”是指所述氨基酸序列变体的一种特定的、相邻的节段被排列,并与参照分子氨基酸序列比较时,在变体和参照分子中可以发现相同的氨基酸残基。
为了优化两个序列调整的目的,所述变体的氨基酸序列的邻接节段可以附加氨基酸残基或删除氨基酸残基。用于和参照分子氨基酸序列比较的邻接的节段会包含至少20个邻接的核苷酸,并且可以是30,40,50或100或更多的核苷酸。为了提高序列一致性的修正,包括对变体中氨基酸序列的间隙进行不利间隙修正(assigninggap penalties)。序列调整方法对于本技术领域专业人士来说是熟知的。
应用数学方法可以完成两个序列间百分比一致性的测定。一个用序列比较数学算法的非限定例子是Myers和Miller算法(1998)CABIOS 4:11-17。这个算法被编入ALIGN程序2.0版,是GCG序列调整软件包的一部分。当应用所述ALIGN程序用来比较氨基酸序列时,可用一个PAM120重量残数表,间隙长度障碍12(a gaplength penalty)和一个间隙长度障碍4。另一个更好的程序是成对调整程序(Pairwise Alignment Program)(序列探测者),是用缺省参数。另一个数学算法用来比较两个序列的非限定例子是Karlin和Altschul(1990)《美国国家化学学会会刊》(Proc.Natl.Acad.Sci.USA)87:2264,在Karlin和Altschul(1993)《美国国家化学学会会刊》(Proc.Natl.Acad.Sci.USA)90:5873-5877进行了修正。这样的算法被编进Altschul等人的NBLAST和XBLAST程序(1990)J.Mol.Biol.215:403。与本发明中生长激素核酸分子类似的核苷酸序列可以通过执行NBLAST程序,用BLAST核酸序列获得,计数=100,码长=12。BLAS蛋白质搜索可以用XBLAST程序进行,计数=50,码长=3,从而获得与本发明生长激素蛋白质分子类似的氨基酸序列。为了比较的目的而获得由间隙的排列,可以利用有间隙的BLAST,在Altschul等人1997《核酸研究》25:3389中有表述。或者,PSI-Blast可用来进行重复搜索,以检测分子间远族关系。见Altschul等人(1997)前述。当利用BLAST,有间隙的BLAST,以及PSI-BLAST程序时,可以使用对应程序缺省参数(例如XBLAST和NBLAST)。参见http:/www.ncbi.nlm.nih.gow。
功能等效的生长激素类似物可以参照该类似物结合并激活适当受体的能力,容易地进行筛分。在这种情况下,所述受体是神经系统生长激素受体。
如上面指出的,术语“神经系统生长激素受体”是应作广义理解,包括在神经细胞群上所有生长激素可与之结合或激活的受体。两种这样的受体是生长激素受体(GHR)和催乳激素受体(PRL-R)。特别指出,术语“神经系统生长激素受体”包括人类GHR和人类PRL-R。
人类生长激素受体(GHR)是一种620氨基酸单链蛋白质,包括一个糖基化的246氨基酸细胞外配体结合区域,一单独的24氨基酸透膜区和一350氨基酸的细胞质区[Postel-Vinal和Kelly(1996)《拜利乐瑞斯临床内分泌和代谢》(Baillieres Clinical Endicrinologyand Metabolism)10:323]。所述GHR单体与一种生长激素(GH)在结合位置1上结合,然后要求第二GHR在位置2与同样的GH结合,在此之后,受体发生双聚反应和转导作用。单独的转导作用包括细胞质激酶的激活,从而导致大量细胞质多肽的糖基化。
人类催乳激素的受体(PRL-R)是一590氨基酸单链多肽,带一经糖基化的210氨基酸外细胞配体结合区,一单独的24氨基酸透膜区,以及一358氨基酸的细胞内区域。该PRL-R单体结合一单独的催乳激素(PRL)。然后要求第二PRL-R与同样的PRL结合,在此之后,受体发生双聚反应和转导作用。单独的转导作用包括细胞质激酶的激活,从而导致机理上与GHR非常相似的大量细胞质多肽的糖基化。
PRL-R的第二短结构已被表征出来(Kelly等(1991)EndocrineReviews 12:235)。此类受体与较长受体在细胞外和透膜区相同,但是有小得多的细胞质区域,仅有57个氨基酸。
这就引出了发明者第二种神经保护,特别是神经修复方法。,这种方法集中在如上面定义的神经系统生长激素受体,并且通过使用结合并激活那些受体的药剂,起到神经保护作用。
若能获得生长激素和其类似物则是最好的。实际上,使用生长激素及其类似物是本发明优选的一面。但是,并不限于使用生长激素及其类似物,可延伸于任何在结合与激活(刺激)神经系统生长激素受体方面具有等效功能的配体。也就是说所述配体具有影响细胞内信息传输的功效。
这些配体例如是催乳激素及其类似物,及胎盘催乳素及其类似物。这些也能结合并激活神经系统生长激素受体(Lowman等(1991),J.Biol.Chem.266:10982)。
通过使用某种神经系统生长激素受体的至少是配体结合区的筛分方案,可以识别其他有刺激作用的配体。例如,这个筛分方案可以利用非洲蟾蜍的母卵细胞中的神经系统生长激素受体表达的信息,应用标准的DNA重组方法和测定方法(即刺激配体引起受体传达的信号的转到作用)。并且,经典的“研磨和粘合”变体结合试验也可利用。这里,整个大脑或特定脑区被均匀化,并且,与神经系统生长激素受体特定结合的化合物被赋予特征。这项技术允许化合物的特定性和亲和(功效)进一步特征化(Frielle等(1989)Clin.Chem.35(5):721-725)。
本发明方法有治疗功效。“治疗功效”是指受到伤害后,比起未进行治疗药剂给药情况,神经元有任何生存能力改善、增生和生长。“神经元生存能力改善”是指通过治疗药剂给药,降低至少1%-10%的神经损失,优选的是10%-50%,更优选的是大约10%-90%,并且最优选的是大于90%,是指超出未给药情况。
确定神经伤害程度的方法,以及确定用治疗药剂给药后神经的生存能力是否提高的方法,对于本技术领域专业人员来说是应知的。这类方法包括但不限定于组织学的方法、分子标记分析法和功能/行为分析法。例如,在发生缺血性损伤后,ω3(外周型苯二氮结合位置的密度会显著增加(Benazodes,J.等(1990)《脑研究》(BrainRes.)522:275-289)。一致测定ω3位置的方法,并且,可以用这种方法来测定大脑缺血性损伤的程度。参见下例,Gotti,B.等(1990)《脑研究》522:290-307和此处的引述。另外生长结合蛋白-43(GAP-43)可用作中枢神经系统受到损伤后新的轴索生长情况的标记。例如Stroemer等(1995)《中风》(Stroke)26:2135-2144,Vaudano等(1995)J.《神经科学》15:3594-3611。这种治疗效果也可通过病人的运动技能、认知机能、感官的感知能力、语言能力的提高,和/或引起癫痫发作倾向的减少来衡量。这种功能/行为的测试用,来评估知觉运动的功能和反射的功能在以下例举的文献中有记载,如Bederson等(1986)《中风》17:472-476,DeRyck等(1992《脑研究》573:44-60,Markgraf等(1992)《脑研究》575:238-246,Alexis等(1995)《中风》(Stroke)26:2338-2346。也可用斯堪的纳维亚人中风量表(Scandinavian Stroke Scale(SSS))或百撒尔索引(Barthel Index)来衡量神经存活情况的改善。
为实现预期的医疗上的应用,这种活性化合物(生长激素,类似物或配体)将按配方制成药剂。配方具体细节将取决于最终所意图获得的神经保护效果。当所述神经保护效果是一种神经修复效果时,其配方主要取决于需挽回的伤害和给药途径,但是通常包括结合活性物质的合适的载体、赋形剂或稀释剂。对本领域专业人士来说,如何对常用给药方式选用载体、赋形剂或稀释剂是应知的。
为了发挥神经保护剂的作用,可选用多种给药途径。例如包括腰部穿刺,脑内(ICV)或心室内给药,包括利用神经外科手术植入一个室内管,带有一个腹部泵,储存管和药物。另外,可通过嗅觉神经通路进行中枢神经直接给药,例如可参考美国专利5,624,898。
剂量比也要根据配方具体条件。不过,举例来说,注射剂的配方中,生长激素剂量范围高于0.01ug/100g。
我们可以认为,前面的各种叙述,将就以下的实验进行介绍,两者都是示范性和说明性的,而不应该被解释成对权利要求范围的限制,并且意味着为本发明的权利要求提供进一步的解释。
实验
材料和方法
动物准备
以下实验所用指标是经奥克兰大学动物伦理委员会认可的。将体重在40-50克之间,断奶21天的Wistar鼠放于12小时昼夜交替的环境,并且在整个研究过程中,他们可自由接近食物和水。鼠依性别和体重搭配,随机分配到治疗组和对照组中。根据前面描述(Sirimanne等J Neuroscience Methods,55:7-14,1994),用改进型Levine鼠准备进行诱导损伤。简而言之,将该鼠麻醉并放在含2%氟烷/氧气混合其体中,通过中腹颈暴露的切口,将右颈动脉结扎。手术后该鼠被放在精确控制的,温度45℃,相对湿度85±5%的环境中。然后将它们置于缺氧状态15分钟(8%氧气/氮气)。
治疗
在缺氧处理结束两小时后,治疗组鼠(n=12)注入重组的鼠生长激素20μg,10μl,对照组仅注入赋形剂,为防止动物着凉,注射过程在高热灯照下进行。所有溶液和针头均应保证在无菌条件下准备和贮存。
用0.15ml静脉麻醉剂SaffanTM(新西兰Pitman-Moore公司)再次对该鼠进行轻度麻醉。使用最初由Jirikowski描述(J NeuroscienceMethods,42:115-118,1992)的改进技术,将金属帽置于鼠头上,以确保注射针正确定位,引导对右后外侧脑室进行注射。在校正过的微注射泵控制下,以单剂量速率1.0ul/分钟,对鼠进行重组鼠生长激素(2mg/ml于8.77mg/ml NaCl,2.5mg/ml苯酚,2.0mg/ml多山梨醇酯20,和10mM柠檬酸钠pH6.0),或单独的赋形剂。为防止回流,注射针应多放置3分钟。
CSF取样
缺氧处理3天后,进行脑脊髓液(CSF)取样。将鼠用Saffan麻醉剂麻醉,并放于2%氟烷环境。然后将鼠放于定向框架,使头前屈,将肌肉钝解剖置于解剖池magna,以露出硬膜。在双目放大镜下,用一支精密30号针取出脑脊髓液。通过腹膜进行戊巴比妥钠过量给药使鼠致死,直接从心脏取血样。
显微解剖学
经贲门灌注盐水,然后是新制的修正Bouin溶液(0.1M PBS,4%多聚甲醛(重量/体积),0.08%戊二酸(体积/体积),15%苦味酸(体积/体积)饱和溶液),进行原位固定后,收集脑组织,进行显微结剖学处理。取出脑,称重然后置于修正Bouin溶液室温过夜。次日将脑放于70%。乙醇中3-4天。每日乙醇换新。将脑包埋于石蜡处理(通过分级乙醇脱水,用氯仿脱脂,用石蜡浸润,封存于石蜡)。从组织上切下8um切片,并放于预涂聚-L-赖氨酸的载玻片上。用酸性品红/劳氏紫着色。
神经元计数步骤
在每个大脑中,神经结果用两个层次进行评价,在纹状体中(前囟点+0.8mm),和在海马状突起的灰质前角背侧(前囟点-3.3mm)。用两种技术进行神经元结果评估:
1)在皮质和海马状突起计分:
用遮光测试仪对额顶的皮质和海马状突起评定,对神经元计分使用一种标准的5点神经元损伤计分(Willams等Pediatric Research,27:561-565,1990):4=无损伤,3=0-10%细胞损失,2=11-50%细胞损失,1=51-90%细胞损失,0=>90%细胞损失。
皮质在纹状体中(前囟点+8.0mm)和海马状突起的灰质前角背侧(前囟点-3.3mm)进行评分,并被分为5个区。对海马状突起分别在CA1/2,CA3和齿状脑回计分。然后对神经元计分结合每一结构与治疗组进行比较。
2)在纹状体和丘脑的计分:
在放大200倍的光学显微镜下,用一个目镜测微计对每个纹状体和丘脑的四个区域计分。在显微镜下200μm2/格,对每区域用4格计数。受损伤区的健康神经元被计数,以及每脑对侧,根据以下方法计算存活率百分数:每区RHS计数/LHS计数×100。对每一结构存活计数,然后比较治疗组与对照组。
对血浆和脑脊髓液(CSF)中的IGF-1的放射性免疫测定
用IGF结合蛋白(IGFBP)阻断放射性免疫测定(RIA)测定血浆中的IGF-1和脑脊髓液(CSF),首次披露于Blum和Breier(Growth Regulation,4:11-19,[1994])。多克隆抗体(#878/4)孵育于对IGF-1具有高亲和力和专一性,对IGF-II(0.01%)低交叉反应的新西兰白兔。该测定使用非提取过程,用酸性缓冲也稀释样品,用过量IGF-II复培养。稀释到pH2.8,过量的IGF-II提供功能阻断结合蛋白干扰。
血浆在酸性缓冲液(20mM磷酸钠pH=2.8,0.1Mm NaCl,0.1%BSA,0.02%NaN3,0.1%聚乙二醇辛基苯基醚)稀释,和CSF样品被稀释于(1∶11)在0.5M磷酸钠,0.1%BSA,0.1%聚乙二醇辛基苯基醚,0.1%NaN3,1Mm PMSF,pH1.25以使IGFs从IGFBPs中脱掉。初级抗体,带过量IGF-II于25ng/管,稀释于一种缓冲溶液,恢复中性pH(100mM磷酸钠[pH7.8],40Mm NaCl,0.02%,NaN3,0.2%BSA,0.1%聚乙二醇辛基苯基醚),并达到起始工作稀释值1∶50000)。0.1ml的稀释样品,对照品或标准品(rh-IGF-1,由旧金山的基因技术公司提供)用0.1ml抗体-IGF-II溶液和0.1ml 125I-IGF-l达每管计数15-20000进行孵育。4℃下孵育48小时后,加入1ml次级抗体复合物,室温下管内继续孵育1小时。接着,在3800转/30分钟,4℃条件下,进行离心处理,试管用沉淀法分取,沉淀小丸用伽玛计数计(gamma counter)计数。
rh-IGF-I的碘化使用一种修正的氯氨-T法,由Hunter和Greenwood提出[《生物化学杂志》(Biochemical Journal),91:43-56,1964]。此测定系统是根据第三国际胰岛素样生长因素研讨会推荐进行的[Bang等《内分泌学》(Endocrinology),136:816-81,(1995)],包括CSF标准曲线的平行位移,冷IGF-1的收回。在CSF中收回的未标记的IGF-1是89.6%(n=2)。ED-50是0.1ng/管,测试内和测试间的变化系数分别是5%和9%。
统计
数据分析采用成对t-测试或者非参数方程,Wilcoxon分级测试。用SigmastatTM 2.0版进行计算(加利福尼亚圣来佛Jandel科学协会)。所有结果以平均值±偏差表示。
结果
结果见图1-3。
用生长激素治疗和仅用赋形剂治疗的动物,死后比较脑重没有任何区别(1.432±0.032vs1.455±0.028g)。
用生长激素治疗能引发减少由于HI伤害(159±7.3vs 135±11.7ng/ml,p=0.068)引起的血清中IGF-l降低趋势。CSF IGF-1水平远远低于血浆之中的水平。生长激素治疗(3.82±0.35 vs 3.86±0.27ng/ml)后CSF IGF-1水平没有变化。参见图1。
用生长激素治疗后,皮质神经元计分明显提高。在纹状体水平和海马状突起水平所有5个皮质区联合计分是(3.54±0.074 vs 2.98±0.124,p<0.001)。参见图2。
用生长激素治疗后,海马状突起神经元计分明显提高。在CA1/2,CA3和齿状脑回联合计分为(3.03±0.176 vs 1.818±0.259,p=0.005)。参见图2。
用生长激素治疗后,背外侧丘脑神经元存活数明显提高。四个区域联合计分,与脑对侧计数比较是(104±2.18 vs 87.4±4.67%,p=0.006),参见图3。
用生长激素治疗后,背外侧纹状体神经元存活数无明显提高。四个区域联合计分,与脑对侧计数比较是(83.8±4.7 vs 75.3±6.1%,p=0.178),参见图3。
结论
用生长激素中枢给药作为神经元修复剂是有效的。神经元修复效果的出现,不伴随CSF-IGF-1的提高,说明神经保护效果是独立于IGF-1的。
生长激素作为一种神经元修复剂在一定脑区域是有效的,该区域有内源性生长激素受体表现(皮质、海马状突起和丘脑),而在如纹状体区则没有。这表明生长激素的神经保护效果,主要通过生长激素受体或催乳激素受体运作。
工业应用
本发明提供一种新的神经保护途径。特别是提供新的神经元修复方法。该发明可用于治疗和预防。特别是应用于遭受以下神经损伤病人的治疗,包括由创伤、突变性疾病和机能紊乱、运动性疾病和障碍、脱髓鞘疾病和病症、神经综合症、眼部疾病和睡眠障碍引起的神经损害。
创伤
击伤、脑外伤、窒息、脊柱受伤和CO中毒。
突变性疾病和机能紊乱
家族或非家族的阿尔海默氏病、多重梗塞痴呆、非阿尔海默氏型前叶痴呆、皮克病、亨廷顿氏舞蹈病、韦希尼-霍夫曼病、韦尼克脑病、共济失调毛细血管扩张症、皮质基底退化、蒙古种病(Down’ssyndrome)、莱特综合症(Rett syndrome)、胎儿宫内生长迟缓(IUGR)、阿尔佩病(Alper disease)、斯蒂尔-里查德森-奥茨斯基综合症(Steele-Richardson-Olszewski)、颞叶癫痫、癫痫持续状态和不明因的智力迟钝。
运动性疾病和障碍
脊髓小脑性运动失调、进行性肌阵挛失调综合症、Leigh氏症、多重系统萎缩症、脑瘫痪、Friedeich氏遗传性运动失调、完全遗传性突发性半身不遂、脊髓肌肉萎缩、糖尿病神经病、遗传感觉神经病I型,ALS(肌肉萎缩型脊索侧索硬化)、慢性先天性运动机能失调型神经病、Tangier氏病。
脱髓鞘疾病和病症
炎症包括:急性传染性脑脊髓炎、眼神经炎、横脊髓炎、Devic氏病,白质营养障碍病、复合硬化症;非炎症包括:渐进性多病灶脑白质病,中央桥脑脱髓鞘病变。
神经性综合症
胎儿酒精综合症、自闭症和肌震挛运动失调。
眼疾病
青光眼
睡眠障碍
发作性睡病
进一步,本发明探讨的生长激素、生长激素受体可单独用来治疗以上疾病,也可结合起来应用。后者涉及给药,特别是,生长激素或其类似物/配体,结合使用辅助神经保护剂。所述的辅助神经保护剂通常是,或至少部分地,对不同于受生长激素或其类似物/配体保护的神经元细胞具有保护性。
辅助神经保护剂可非限定地选自有生长因子组成的组。“生长因子”是指一种记号细胞外多肽的分子,能刺激细胞生长和细胞分裂繁殖。优选的是那些对广泛细胞类型有反应的生长因子。例如神经营养型生长因子,非限定性地包括,成纤维细胞生长因子族成员,如基础成纤维细胞生长因子(bFGF)(Abraham等(1986)《科学》233:545-48),酸性成纤维细胞生长因子(aFGF)(Jaye等(1986)《科学》233:541-45),hst/Kfgf基因产品,FGF-3[Dickson等(1987)《自然》(nature)326-833],FGF-4[Zhan等(1988)《分子细胞生物学》(Mol.Cell.Biol.)8:3487-3495],FGF-6[deLapeyriere等91990《致癌基因》(Oncogene)5:823-831],角质化细胞生长因子(KGF)(Finch等(1989)《科学》(Science)245:752-755)和雄性激素诱发生长因子(AIGF)[Tanaka等(1992)《美国国家化学学会会刊》(Proc.Natl.Acad.Sci USA)89:8928-8923]。附力的FGF族成员包括,例如,int-2,成纤维细胞生长因子异体同型因子-1(FHF-1)(美国专利No.5,872,226),FHF-2(美国专利No.5,876,697),FHF-3和FHF-4[Smallwood等(1996)《美国国家化学学会会刊》93:9850-9857],Karatinocyte生长因子2[Emoto等(1997)《生物化学杂志》(J.Biol Chem)272:23191-23194],神经胶质激活因子(Miyamoto等(1993)《分子细胞生物学》13-4251-4259),FGF-18(Hu等(1998)《分子细胞生物学》18:6063-6074),并且FGF-16(Miyake等(1998)《生物化学生物物理学研究通讯》(Biochem.Biophys.Res.Commun)243:148-152。
附加的辅助神经保护剂包括纤毛神经营养因子(CNTF),神经生长因子(NFG)(Seiler,M.(1984)《脑研究》300:33-39;Hagg T,等(1988)《神经病学指数》(Exp Neurol)101:303-312;Kromer L F(1987)《科学》235:214-216;以及Hagg T等(1988)《神经病学指数》101:303-312:Kromer L F(1987)《科学》235-214-216;和Hagg T等(1990)《神经科学杂志》(J.Neurosci)10(9)3087-3092),脑衍生神经营养因子(BDNF)[(Kiprianova,1等(1999)《神经科学研究杂志》(J.Neurosci.Res),56:21-27),神经营养因子3(NT3),神经营养因子4(NT4),转换生长因子-β1(TGF-β1)(Henrick-Noack,P等(1996)《中风》27:1609-14),骨形体发育蛋白(BMP-2)[Hattori,A等(1999)《神经化学杂志》(J.Neurochem)72:2264-71],神经胶质-细胞系衍生神经营养因子(GDNF)[Miyazaki,H等(1999)《神经科学通信》(Neurosci Letter)264:9-12],白血病抑制因子(LIF)(Blesch,A等(1999)《神经科学杂志》19:3356-66),制瘤素M,白细胞间素和胰岛素样生成因子1和2。
其它形式辅助神经保护剂包括,例如,氯美噻唑(Zendra)(Marshal,J W等(1999)《神经病学指数》156:121-9);4-羟基二喹啉酸(KYAN)[Salvati,P等(1999)《神经精神生药理学、生物学、精神病学进展》(Prog.Neuropsychopharmacol Biol Psychiatry)23:74l-52],Semax(Miasoedova,N.F.等(1999)Zh Nevrol PsikhiatrImss Korsakova 99:15-19),FK506(免疫抑制剂)[Gold,B G等(1999)《药理学实验疗法杂志》(J.Pharmacol.Exp.Ther.)289:1202-10],L-苏型-1-苯-2-癸醇-3-吗啉-1-丙醇[Inokuchi,J.等(1998)《生物化学聚合物效应》(Act Biochim Pol)45:479-92]雄性促肾上腺皮质激素-(4-9)类似物(ORG 2766)和地唑西平(dizolcipine)(MK-801)[Herz,RC等(1998)《欧洲药理学杂志》(Eur.J.Pharmacol)346:159-65],脑白细胞素-6[Loddick,SA等(1998),《结合胞二邻胆碱血液流动转移》(J.Cereb Blood Flow Metab)18:176-9],西啉给啉(selegiline)(Semkova,I等(1996)《欧洲药理学杂志》315:19-30),MK-801(Barth,A等(1996),《神经学报告》(Neuro Report)7:1461-4;谷氨酸拮抗剂如,NPS1506,GV1505260,MK801(Baumgartner,WA等(1999)《安·托洛克外科术》(Ann Thorac Surg)67:1871-3),GV150526(Dyker,AG等(1999)《中风》30:986-92);AMPA拮抗剂,如NBQX(Baumgartner,WA(1999)等《安·托洛克外科术》(Ann Thora Surg)67:1871-3,PD152247(PNQX)(Schielke,GP等(1999)《中风》30:1472-7),SPD 502(Nielsen,EO等(1999)《药理学实验疗法杂志》289:1492-501),LY303070和LY300164(May,PC等(1999)《神经科学通信》262:219-221)。
《生物化学生物物理学研究通讯》生物活性变异体。IGF-1是一种70氨基酸神经保护性多肽激素。广泛分布于中枢神经系统,并显示出胰岛素样和分生生长生物活性[Baskin,DG等(1988)《神经科学趋势》(Trends in Neuroscience)11:107-111]。在体外研究表明,IGF-1神经保护的作用在中枢神经系统中扩展到多种类型的神经元(Knusel等(1990)《神经科学杂志》10:558-570,Svezic和Schubert(1990)《生物化学生物物理学研究通讯》172:54-60,McMorris和Dubois(1988),《神经科学研究杂志》(J.Neurosci Res)21:199-209。另外,用多种动物模型的体内研究表明,在中枢神经系统刚刚受损后,外源性给予IGF-1,诱导出神经保护作用(Guan等(1993)《结合胞二邻胆碱血液流动转移》(J.Cereb Blood FlowMetab)13:609-616,以及Johnston等(1996)《临床调查杂志》(J.Clin.Invest.)97:300-308,美国专利号5,861,373,美国专利号5,093,317,美国专利号5,776,897,均在这里引述为参考文献。
优选的辅助神经保护剂包括IGF-1、GPE、苯丙酸诺龙、NGF、TGF-β生长激素结合蛋白、IGF结合蛋白(特别是IGFBP-3)和bFGF。
包括生长激素和一种或多种IGF-1、GPE、苯丙酸诺龙的特定结合,用来治疗亨廷顿舞蹈病或阿尔海默氏病;生长激素和IGF-1,用来治疗皮质基质的变性或斯蒂尔-里查德森-奥茨斯基综合症;生长激素和GPE、IGF-1二者或二者之一,用来治疗戴韦克(Devic)氏病或皮克病;生长激素和苯丙酸诺龙、IGF-1二者或二者之一,用于治疗糖尿病性神经病。
结合治疗方法是令人满意的,各组分活性剂可按配方共同给药,包括以单一药剂形式。因此,本发明提供这类神经保护药剂,包括生长激素或其类似物,与一种或多种,辅助类神经保护剂,除IGF-1外,特别是一种或多种GPE、苯丙酸诺龙、NGF、TGF-β以及bFGF。其中最好进一步包括IGF-1。
这类药可用任何常规方式制备,并且可进一步包括标准药物采用的载体、赋形剂或稀释剂。
本领域专业人士可以理解以上描述仅提供示例。
参考文献
Andronikof-Sanglade,A.,Fjellestad-Paulsen,A.,Ricard-Malivoir,S.,和Evain-Brion,D.(1997)所著《对异常生长激素分泌矮小儿童视觉运动心理特定变异的测试》(Specific abnormalities in a visualmotor psychological test in short children with abnormal growthhormone secretion),《儿科学报》(Acta Paediatrica)86[2],154-159.
Bartlltt,W.P,Li,X.S.,Williams,M.,和Benkovic,S.(1991)所著《在鼠出生后中枢神经系统的类胰岛素生长因子-1 mRNA定位》(Localisation of insuliin-like growth factor-1 mRNA in murine centralnervous system during postnatal development),见《发展的生物化学》(Developmental Biology)147,239-250.
Beck,K.D.,Powellbraxton,L,Widmer,H.R.,Valverde,J.和Hefti,F(1995)所著《IGF-1因子损害导致脑变小、中枢神经系统髓鞘形成低下、海马回颗粒及纹状体细小白蛋白包含神经元损失》(IGF-1gene disruption results in reduced brain size,CNS hypomyelination,and loss of hippocampal granule and striatal parvalbumin-containingneurons)见《神经元》(Neuron)14,717-730.
Bondy,C.和Lee,W.H.(1993)《在脑成长过程中类胰岛素生长因子(IGF)结合蛋白质-5和IGF-1基因表达相关性》(Correlationbetween insulin-like growth factor(IGF)binding protein-5 and IGF-1gene expression during brain development)。见《神经科学杂志》(Journal of Neuroscience)13,5092-5104.
Burton,K.A.,Kabigting,E.B.,Clifton,D.K.和Steiner,R.A.(1992).《在成年雄鼠脑部及其海马回生长激素抑制因子神经细胞生长激素受体信使核酸损害》(Growth hormone receptor messengerribonucleic acid distribution in the adult male rat brain and itscolocalisation in hypothalamic somatostatin neurons),见《内分泌学》(Endro crinology)131,958-963.
Garofalo,R.S.和Rosen,O.M.(1989)著《在中枢神经系统发育过程中胰岛素和类胰岛素生长因子1(IGF-1)受体:两个免疫学上独立的IGF-1β亚单位的表现》(Insulin and insulin-like growth factor1(IGF-1)receptors during central nervous system development:expression of two immunologically distinct IGF-1 receptor betasubunits),见《分子和细胞生物学》(Molecular & cellular Biology)(9,2816-2817)。
Lobie,P.E.、Garcia Aragon,J.、Lincoln,D.T.、Barnard,R.、Wilcox,J.N.和Waters,M.J.(1993)著《生长激素受体在中枢神经系统的基因表达的定位和个体发育》(Localisation and ontogeny of growthhormone receptor gene expression in the central nervous system),见《发展的脑研究》(Developmental Brain Research)74[2],225-233.
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Gillies,G.(1997)著《生长激素抑制素:神经内分泌情况》(Somatostatin:the neuroendocrine story)见《药理学科学趋势》(Trends in Pharmacological science)18(3),87-95.
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Claims (3)
1.生长激素在制备用于在皮质、海马状突起和丘脑中诱导神经保护作用的药剂中的应用,其中所述神经保护作用是指修复由于缺氧会注定导致死亡的神经元。
2.根据权利要求1所述的应用,其中所述的缺氧是亨廷顿氏疾病,阿尔海默氏疾病,皮质基质的变性,斯蒂尔-里查德森-奥茨斯基综合症或糖尿病性神经病导致的。
3.一种神经保护药物组合物,包括一种治疗上的有效量的生长激素,并包括一种或多种选自由催乳激素、胎盘催乳激素、GPE、苯丙酸诺龙、NGF、TGF-β,生长激素结合蛋白、IGF结合蛋白组成的组的药剂。
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CNB998106135A Expired - Fee Related CN1261158C (zh) | 1998-09-03 | 1999-09-03 | 生长激素在制备用于诱导神经保护作用的药剂中的应用 |
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US (1) | US7304029B1 (zh) |
EP (1) | EP1109572A4 (zh) |
JP (1) | JP2002524402A (zh) |
CN (1) | CN1261158C (zh) |
AU (1) | AU757907B2 (zh) |
BR (1) | BR9913457A (zh) |
CA (1) | CA2343214A1 (zh) |
WO (1) | WO2000013650A2 (zh) |
Families Citing this family (22)
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EP1109572A4 (en) | 1998-09-03 | 2004-11-24 | Neuronz Ltd | NEUROPROTECTION |
US7112570B2 (en) | 2000-08-24 | 2006-09-26 | Neuren Pharmaceuticals, Ltd. | GPE analogs |
AU2001289160A1 (en) * | 2000-08-24 | 2002-03-04 | Neuronz Ltd. | Gpe analogs |
US7714020B2 (en) | 2001-05-24 | 2010-05-11 | Neuren Pharmaceuticals Limited | Treatment of non-convulsive seizures in brain injury using G-2-methyl-prolyl glutamate |
US7605177B2 (en) | 2001-05-24 | 2009-10-20 | Neuren Pharmaceuticals Limited | Effects of glycyl-2 methyl prolyl glutamate on neurodegeneration |
EP1401808B1 (en) * | 2001-05-24 | 2009-07-08 | Neuren Pharmaceuticals Limited | Gpe analogs and peptidomimetics |
EP1423509A2 (en) | 2001-08-30 | 2004-06-02 | Stem Cell Therapeutics Inc. | Differentiation of neural stem cells and therapeutic use thereof |
EP1430114B1 (en) * | 2001-09-14 | 2012-01-18 | Stem Cell Therapeutics Inc. | Prolactin induced increase in neural stem cell numbers and therapeutical use thereof |
AR036402A1 (es) * | 2001-09-18 | 2004-09-08 | Stem Cell Therapeutics Inc | Efecto de la hormona de crecimiento y de igf-1 sobre celulas madre neuronales. |
AU2002340465A1 (en) * | 2001-11-09 | 2003-05-19 | Neuronz Biosciences, Inc. | Cyclo(prolyl-glycine) and methods of use to treat neural disorders |
AU2003250705A1 (en) | 2002-07-31 | 2004-02-16 | Stem Cell Therapeutics Inc. | Method of enhancing neural stem cell proliferation, differentiation, and survival using pituitary adenylate cyclase activating polypeptide (pacap) |
MXPA05009850A (es) * | 2003-03-14 | 2005-12-06 | Merck Sharp & Dohme | Metodo para tratar el deterioro cognitivo leve y para prevenir o atrasar la enfermedad de alzheimer. |
AU2003229222B2 (en) * | 2003-05-29 | 2009-11-12 | Theratechnologies Inc. | GRF analog compositions and their use |
US7476653B2 (en) * | 2003-06-18 | 2009-01-13 | Tranzyme Pharma, Inc. | Macrocyclic modulators of the ghrelin receptor |
BR0318426A (pt) * | 2003-07-29 | 2006-08-01 | Ares Trading Sa | uso de hormÈnio de crescimento humano em atrofia multissistêmica |
DE60336934D1 (de) | 2003-10-03 | 2011-06-09 | Veijlen N V | Verwendung von igf-1-serumspiegel-erhöhenden indolessigsäure-derivaten zur herstellung eines arzneimittels zur behandlung von verschiedenen krankheiten |
JP2005239712A (ja) * | 2004-01-30 | 2005-09-08 | Kaken Pharmaceut Co Ltd | 神経突起伸展剤 |
CA2556266A1 (en) | 2004-02-13 | 2005-08-25 | Stem Cell Therapeutics Corp. | Use of luteinizing hormone (lh), and chorionic gonadotropin (hcg) for proliferation of neural stem cells and neurogenesis |
US7534765B2 (en) | 2005-09-27 | 2009-05-19 | Stem Cell Therapeutics Corp. | Pregnancy-induced oligodendrocyte precursor cell proliferation regulated by prolactin |
BRPI0812768A2 (pt) * | 2007-06-08 | 2014-12-02 | Massachusetts Inst Technology | Igf para o tratamento de síndrome de rett e transtornos sinápticos. |
US20140357558A1 (en) * | 2011-06-24 | 2014-12-04 | Cold Spring Harbor Laboratory | Compositions and methods for treatment of spinal muscular atrophy |
JP6879297B2 (ja) * | 2016-04-13 | 2021-06-02 | 味の素株式会社 | 加齢に伴う身体機能低下もしくは身体機能障害、または加齢に伴う精神機能低下もしくは精神機能障害の抑制または改善用組成物 |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
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US4939124A (en) | 1988-01-26 | 1990-07-03 | Laboratorios Serono S.A. | Treatment and diagnosis of dementia |
US5057494A (en) * | 1988-08-03 | 1991-10-15 | Ethicon, Inc. | Method for preventing tissue damage after an ischemic episode |
JP2820698B2 (ja) * | 1988-08-31 | 1998-11-05 | 第一製薬株式会社 | 脳機能改善剤 |
AU6909091A (en) * | 1989-12-05 | 1991-06-26 | Ramsey Foundation | Neurologic agents for nasal administration to the brain |
JPH04506240A (ja) * | 1990-03-21 | 1992-10-29 | ヴッヅ,ロバート ジェイムス | 床排水施設支持具 |
US5750376A (en) * | 1991-07-08 | 1998-05-12 | Neurospheres Holdings Ltd. | In vitro growth and proliferation of genetically modified multipotent neural stem cells and their progeny |
WO1993008828A1 (en) * | 1991-11-08 | 1993-05-13 | Syntex-Synergen Neuroscience Joint Venture | Methods for the treatment of neuronal damage associated with ischemia, hypoxia or neurodegeneration |
CA2159738A1 (en) * | 1993-04-13 | 1994-10-27 | Eugene O. Major | Use of neuro-derived fetal cell lines for transplantation therapy |
SE9303068D0 (sv) | 1993-09-21 | 1993-09-21 | Kabi Pharmacia Ab | New use |
US5837234A (en) * | 1995-06-07 | 1998-11-17 | Cytotherapeutics, Inc. | Bioartificial organ containing cells encapsulated in a permselective polyether suflfone membrane |
AU7719596A (en) * | 1995-11-07 | 1997-05-29 | Baylor College Of Medicine | Adenovirus-mediated production of bioactive proteins by mammalian cells and animals |
EP0917566B1 (de) * | 1996-06-11 | 2004-09-22 | Roche Diagnostics GmbH | Rekombinante blutgerinnungsproteasen |
ATE258804T1 (de) * | 1996-10-16 | 2004-02-15 | Regeneron Pharma | Verfahren zur verabreichung von wachstumsfaktoren |
ES2146530B1 (es) * | 1997-12-26 | 2001-04-16 | Consejo Superior Investigacion | Utilizacion del factor de crecimiento igf-i en la fabricacion de composiciones utiles en el tratamiento de la ataxia cerebelar. |
EP1109572A4 (en) | 1998-09-03 | 2004-11-24 | Neuronz Ltd | NEUROPROTECTION |
EP1423509A2 (en) | 2001-08-30 | 2004-06-02 | Stem Cell Therapeutics Inc. | Differentiation of neural stem cells and therapeutic use thereof |
AR036402A1 (es) | 2001-09-18 | 2004-09-08 | Stem Cell Therapeutics Inc | Efecto de la hormona de crecimiento y de igf-1 sobre celulas madre neuronales. |
-
1999
- 1999-09-03 EP EP99946457A patent/EP1109572A4/en not_active Withdrawn
- 1999-09-03 CA CA002343214A patent/CA2343214A1/en not_active Abandoned
- 1999-09-03 AU AU58859/99A patent/AU757907B2/en not_active Ceased
- 1999-09-03 CN CNB998106135A patent/CN1261158C/zh not_active Expired - Fee Related
- 1999-09-03 US US09/786,982 patent/US7304029B1/en not_active Expired - Fee Related
- 1999-09-03 WO PCT/NZ1999/000147 patent/WO2000013650A2/en active IP Right Grant
- 1999-09-03 JP JP2000568459A patent/JP2002524402A/ja not_active Abandoned
- 1999-09-03 BR BR9913457-8A patent/BR9913457A/pt not_active IP Right Cessation
Also Published As
Publication number | Publication date |
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AU757907B2 (en) | 2003-03-13 |
BR9913457A (pt) | 2001-10-16 |
CA2343214A1 (en) | 2000-03-16 |
EP1109572A2 (en) | 2001-06-27 |
WO2000013650A2 (en) | 2000-03-16 |
JP2002524402A (ja) | 2002-08-06 |
WO2000013650A3 (en) | 2000-06-02 |
AU5885999A (en) | 2000-03-27 |
EP1109572A4 (en) | 2004-11-24 |
US7304029B1 (en) | 2007-12-04 |
CN1316908A (zh) | 2001-10-10 |
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