CN1211178A - 抑制皮肤光老化的方法 - Google Patents

抑制皮肤光老化的方法 Download PDF

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CN1211178A
CN1211178A CN97191735A CN97191735A CN1211178A CN 1211178 A CN1211178 A CN 1211178A CN 97191735 A CN97191735 A CN 97191735A CN 97191735 A CN97191735 A CN 97191735A CN 1211178 A CN1211178 A CN 1211178A
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J·J·沃里斯
G·J·费希尔
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Abstract

通过在未损伤的皮肤暴露于UVB照射之前局部涂敷抑制剂来抑制皮肤由于上述暴露而光老化,所述抑制剂抑制下列各项中的至少一项:(a)皮肤中可由UVB照射诱导的MMP活性、(b)转录因子AP－1和NF－B中的一个或两者、和(c)GTP结合蛋白或参与构成AP－1和Jun或fos蛋白的活化和/或生成的激酶中的至少一种;并在皮肤暴露之前在皮肤上涂敷所述抑制剂,其量足以抑制可由UVB诱导的MMP的生成或活性、AP－1和NF－B中的一个或两者、或者GTP结合蛋白或参与构成AP－1的jun或fos蛋白的活化和/或生成、激酶中的至少一种。

Description

抑制皮肤光老化的方法
                      发明领域
本发明属于光保护领域。更具体地说，本发明涉及一种用基质金属蛋白酶(MMP)生成和/或活性的抑制剂来抑制未损伤皮肤的光老化。
                      背景技术
光老化一词是用来描述皮肤在阳光下反复暴露后其外观和功能的变化。阳光中的紫外线(UV)成分，尤其是中紫外(称UVB，波长在290-320nm)是光老化的主要诱导因素。目前尚不知引起光老化所需的UVB照射量。然而，反复暴露于能引起红斑和晒黑的强度的UVB下通常会伴随光老化。光老化在临床上的特征是皮肤粗糙、起皱、混杂色素沉着，呈病黄色、松弛、毛细管扩张、生痣、紫癜病和容易淤伤、萎缩、出现纤维化脱色素区域、最终为恶化前的和恶化的瘤。光老化一般出现在日常暴露于阳光的皮肤部位，如脸、耳、头皮的光秃区域、颈和手。
已有防止未老化的皮肤光老化和治疗已老化的皮肤的方法。防晒药(sunscreen)一般被用来防止日常暴露于阳光的皮肤部位光老化。防晒药是局部用制剂，它将UV吸收、反射或散射。有些是以不透明的颗粒物质如氧化锌、氧化钛、粘土和三氯化铁为基的。由于这些制剂是明显可见的，会堵塞毛孔，因此许多人认为这些不透明的助剂不符合化妆品要求。其他防晒药含化学物质，如对氨基苯甲酸(PABA)、羟苯甲酮、二羟苯宗、乙基己基-甲氧基肉桂酰胺和丁基甲氧基二苯甲酰甲烷，它们是透光和无色的，因为它们不吸收可见波长的光。虽然这些透光的防晒药可能更符合化妆品要求，但它们的使用期仍较短，并容易被洗掉或被汗水冲掉。此外，所有防晒药会抑制维生素D的生成。
M.M.Rieger在Cosmetic and Toiletries(1993)108:43-56中综述了活性氧组分(ROS)在UV诱致的皮肤老化中的作用。该文报道说，在皮肤上局部涂敷已知抗氧化剂可减少ROS在皮肤上的存在，从而减少光损伤。
视黄醛衍生物已被用来减缓光老化在太阳损伤的皮肤中的作用。美国专利No.4,877,805描述了对光损伤皮肤进行干扰治疗以减缓光老化的进行。该专利指出，在老化作用开始出现之前，并不是进行治疗的时机。在这个意义上说，本申请人知道，现有技术中尚无用视黄醛衍生物来防止未损伤皮肤的光老化的提示。
MMP是一族在结缔组织的生理和病理破坏中起主要作用的酶。已鉴定了其中的10多种酶。它们用数字(MMP-1、MMP-2等)以及常用名表示。它们似乎在若干结构和功能特性方面相同，而在组织底物特异性方面不同。它们包括将Ⅰ、Ⅱ、Ⅲ、Ⅶ、Ⅷ、Ⅸ型胶原和明胶降解的间质胶原酶(MMP-1)和PMN胶原酶(MMP-8)；将Ⅳ、Ⅴ、Ⅶ、Ⅹ、Ⅺ、明胶、弹性蛋白和纤连蛋白降解的72kDa(MMP-2)和92kDa(MMP-9)Ⅳ型胶原酶/明胶酶；将纤连蛋白、PG核心蛋白、Ⅳ、Ⅴ、Ⅸ和Ⅹ型胶原、层粘连蛋白和弹性蛋白降解的溶基质素-1(MMP-3)、溶基质素-2(MMP-10)和溶基质素-3(MMP-11)；将Ⅳ型胶原、明胶、层粘连蛋白、纤连蛋白和PG核心蛋白降解的PUMP-1(MMP-7)；和将弹性蛋白和纤连蛋白降解的金属弹性蛋白酶(MMP-12)。
MMP基因的表达由转录因子AP-1和NF-B诱导。见PAngel等，Cell(1987)49:729-739和H.Sato和M.Seiki,Oncogene(1993)8:395-405。AP-1和NF-B活性是以细胞因子(例如，白细胞介素IL-1、IL-6和TNFα)、生长因子(TGFα、bFGF)和外界环境影响(如氧化剂、热和紫外辐射)为媒介的。AP-1诱导与组成AP-1的jun蛋白(C-jun、jun-B和jun-D)和fos蛋白(C-fos、fos-B、fra-1和fra-2)的生成是以许多分子(例如RAC、CDC42、MEKK、JNKK、JNK、RAS、RAF、MEK和ERK)为媒介的。已知AP-1和NF-B在暴露于UV的哺乳动物细胞中活化。Y.Devary等，Science(1993)262:1442-1445。M.Wlaschek等在Photochemistry and Photobiology(1994)59(5):550-556中还报道说，成纤维细胞在UVA辐射下导致以IL-1和IL-6为媒介的MMP-1诱导，这些诱导可能对光老化中胶原的损失起作用。
此外，影响MMP基因表达的MMP抑制剂或转录因子也是已知的。PA.Hill等在Biochem J(1995)308:167-175中描述了二种MMP抑制剂，即CT1166和RO31-7467。M.R.Gowravaram等在J Med Chem(1995)38:2570-2581中描述了抑制MMP的一系列异羟肟酸酯的开发并述及了作为已知的MMP抑制剂的硫醇、膦酸酯、次膦酸酯、氨基膦酸酯和N-羧基烷基化合物。该文指出，MMP抑制剂包括一个螯合锌的部分和与MMP特异性囊的小集团结合的肽片段。J.Hodgson在Biotechnology(1995)13:554-557中综述了包括加拉定(Galardin)、巴替马司他(Batimastat)和马立马司他(Marimastat)在内的几个MMP抑制剂的临床使用状况。其他MMP抑制剂包括丁二酰亚胺(J.G.Conway等，J Exp Med(1995)182:449-457)、TIMP(C.Mauch等，Arch Dermatol Res(1994)287:107-114)和视黄醛衍生物(A.Fanjul等，EMBO Journal(1990)9(13)4443-4454；和C.Bailly等，J Investig Derm(1990)94(1):47-51)。
                     发明的公开
本发明是以申请人的以下发现为基础的：UVB照射可迅速地增强暴露的皮肤中的AP-1和NF-B并诱导MMP。由UVB照射产生的MMP活性的提高使皮肤中结缔组织蛋白降解。这些损伤若修复不完全的话，会导致在反复的UVB照射过程中积聚的日灼痕，还可引起光老化。
因此，申请人通过在皮肤暴露于UVB之前涂敷可由UVB诱导的MMP的抑制剂(其量足以抑制可由UVB诱导的MMP的诱导和/或活性)来防止由皮肤暴露于UVB引起的未损伤的皮肤的光老化。令人惊奇的是，这种情况在UVB剂量低于引起红斑的剂量时和在引起红斑的UVB剂量时发生。
本发明的另一方面是在用于防止未损伤的皮肤由于反复的UVB照射而光老化的药物的制造过程中使用可由UVB诱导的MMP诱导或活动的抑制剂。
                    图面的简单描述
图1是表示UVB诱导MMP生成的路径的流程图。
图2a-d、3a-b、4a-d和5a-e是下面的实施例中所述试验结果的图表。
                   本发明的实施方式
本发明用于抑制(即，减缓或防止)未损伤的皮肤的光老化，即，皮肤不出现光老化的效果。因而，应在皮肤(如日常暴露于阳光的头、颈、手和臂上的皮肤)出现光老化的警告迹象之前，在这些皮肤上进行本发明的治疗。由于在低于引起红斑的剂量的UVB下反复照射可导致光老化，本发明应在受到这些低剂量照射的皮肤上进行。在此方面，30-50mJ/cm2的UVB剂量在大多数白皮肤的人上会引起红斑。因此，本发明将防止受到低于此范围剂量(通常在约相当于数分钟阳光照射的5mJ/cm2以上)的皮肤光老化。
在本发明中，防止或抑制光老化的方法是：抑制可由UVB诱导的、由MMP引起的皮肤细胞外的基质的降解。它是通过在将暴露于阳光的皮肤上涂敷MMP抑制剂来实现的。在此方面，“MMP抑制剂”一词是指那些直接或间接抑制(即，减缓或消除)可由UVB诱导的MMP在这些皮肤中表达或抑制这些MMP的酶活性的药剂。“间接抑制”是指与转录因子Ap-1和NF-B中的一个或两个和/或与诱导皮肤中Jum和fos的三个激酶级联途径中所包含的一种或多种分子相结合，从而减少或消除可被UVB诱导的MMP的表达。
图1是可由UVB诱导的MMP表达途径的示意图。如图1所示，UVB照射产生活性氧中间体(ROI)，该中间体激活AP-1和NF-B的活性，而激活的AP-1和NF-B则诱导细胞因子和生长因子。细胞因子和生长因子与其受体的相互作用引发小的GTP结合的蛋白质RAC/CDC42和RAS。这些蛋白质将生成jun和fos蛋白质(jun和fos蛋白质构成AP-1)所必需的三个级联激酶活化。AP-1诱导某些MMP的表达。防止光老化的药剂可作用在MMP、转录因子AP-1和NF-B、和/或图1所示的三个激酶级联中所包含的一种或多种分子上。阿司匹林和E5510(T.Fujimori等在JPn J Pharmacol(1991)55(1):81-91中有叙述)抑制NF-B活化。法呢基转移酶抑制剂如B-581(A.M.Garcia等在J Biol Chem(1993)268(25):18415-18中有叙述)、BZA-5B(M.B.Dalton等在Cancer Res(1995)55(15):3295-3304中有叙述)、乙酸法呢酯和(α-羟基法呢基)磷酸作用在RAS上，抑制ERK级联活化；而牻牛儿基转移酶抑制剂和lisofylline抑制JNK级联活化。SB202190(J.C.Lee等在Natrue(1994)372:739-746中有叙述)和PD98059(D.T.Dudley等在PNAS(USA)(1995)92:7686-7689中有叙述)等化合物抑制上述级联中的特异性激酶。视黄醛衍生物(如美国专利No.4,877,805中公开的那些)和对AP-1拮抗作用具有特异性的解离的视黄醛衍生物(如Fanjul等在Nature(1994)372:104-110中所述的那些)、糖〔肾上腺〕皮质激素、和维生素D3针对AP-1。除视黄醇之外，其他视黄醛衍生物包括天然的和合成的维生素A(视黄醇)类似物、维生素A醛(视黄醛)、维生素A酸(视黄酸，包括全反式的和13-顺式的视黄酸)及EP379367A2中所述的其他化合物。最终，MMP可被BB2284(A.J.H.Gearing等在Natrue(1994)370:555-557中有叙述)、GI129471(G.M.McGeehan等在Natrue(1994)370:555-561中有叙述)、TIMP、加拉定、巴替马司他、马立马司他、异羟肟酸酯和其他已知的抑制剂所抑制。
最好将这些MMP抑制剂的一种或多种局部施用在将暴露于阳光下的皮肤上。对这些施用而言，通常将它们配制成乳液、凝胶、油膏、喷雾剂或洗剂。可用常用的符合药理学和化妆品要求的载体配制抑制剂。这些载体的例子在美国专利No.4,877,805和欧洲专利公报EP0586106A1中有叙述。如所指出的，在给定的制剂中可有一种或多种抑制剂。例如，可使用作用在二种或多种不同的与进行皮肤的MMP降解有关的分子上的抑制剂的组合物。所述制剂也可含添加剂，如润肤剂、皮肤渗透促进剂、色素和香料。此外，制剂可含可使抑制剂缓释至皮肤上的吸收剂颗粒(例如，聚合物珠)。抑制剂在制剂中的浓度(以重量计)通常为0.01-10％，更通常的为0.1-1％。一般在每平方厘米皮肤上涂敷约50mg制剂。
最好在未损伤的皮肤暴露于阳光之前施用抑制剂。施用计划(即，每日、每周等)将主要取决于抑制剂的寿命(例如，在皮肤中的代谢、半衰期)和它们作用的靶分子。此外，还受到洗海水澡、出汗和阳光照射程度的影响。通常，每日施用抑制剂。
下面通过实施例进一步描述本发明。但这些实施例并非是对本发明的限定。
                            实施例UVB诱导的光老化的分子基础的确定MMP的高UVB剂量诱导
MMP-1、MMP-3、MMP-9和MMP-2、mRNA、蛋白质和酶活性在UVB照射之后随时间的变化确定如下。
受验者为具有轻度至中度色素沉着的白种成人(男性和女性的数目大致相等)。照射后24小时，确定各受验者引起仅能感觉到的变红的UVB剂量(最小红斑剂量，即“MED”)。所有受验者的1MED范围为30-50mJ/cm2。用含4根F36T12 ERE-VHO UVB管的Ultralite Panelite灯照射受验者的臀部。照射强度用IL443光治疗辐射计和SED240/UVB/W光电探测器进行监测。在离光源48cm处的UVB输出为0.5mW/cm2。在照射后的第8、16、24、48和72小时，用角膜刀从各受验者的4个部位(一个是未照射的，3个是照射的)取出皮肤。将组织快速冷冻，用G.J.Fisher等在J Invest Dermatol(1991)96:699-707中所述的Northern印迹法分离和分析总RNA。带强度用PhosphorImager进行定量。将MMP转录本底值归一化成对照基因36B4的值。这些试验的结果见图2a(MMP-1)、2b(MMP-3)、2c(MMP-9)和2d(MMP-2)。结果为平均值±SEM(8、16、48和72小时的n=6，无UVB对照和24小时的n=17)，用归一化值相对于未照射的皮肤的倍数增长进行表示。图中出现的带是由若干个体复合而成的。
如图2a-d所示，MMP-1、MMP-3和MMP-9的诱导在16-24小时内达到最大(6-60倍)，在48-72小时内回复至接近基线。可探测出MMP-2mRNA，但照射后24小时，仅提高1.6倍。MMP-1和MMP-9的诱导和由2MED UVB激发的活性随时间的变化曲线与从它们的mRNA观察到的曲线平行。MMP-2和活性均未诱导。
用对MMP-3(溶基质素Ⅰ)特异性的探针对UVB处理过的皮肤进行Northern分析，结果与用全长MMP-3探针得到的结果相同(图2b)，而用对MMP-10(溶基质素Ⅱ)特异性的探针进行杂交，则无任何信号。这表明，在溶基质素中，UVB主要诱导溶基质素Ⅰ。MMP的低剂量UVB诱导
如上所述，受验者在剂量为0.01-2MED的UVB下暴露。照射后24小时，从处理过的和未处理过的部位得到整个厚度的皮肤试样(6mm圆柱体)。将试样在20mM Tris HCl(pH7.6)、5mM CaCl2中匀浆，并以3000×g离心10分钟。用上清液进行以下测定：用化学荧光检测，通过Western印迹法(100μg/泳道)测定MMP-1和MMP-9蛋白质，按C.L.Hu等的方法(Anal Biochem(1978)88:638-643)通过3H纤维性胶原(100μg/测定)的水解，和按M.S.Hibbs等的方法(J Biol Chem(1985)260:2493-2500)通过明胶的酶谱分析分别测定活性。所用的MMP-2和MMP-9抗体分别在Werb等的J Cell Biol(1989)109:877-889和G.Murphy等的Biochem J(1989)258:463-472中有叙述。这些试验的结果见图3a和3b。
在图3a中，MMP-2蛋白质值用空心柱表示，而MMP-2活性值用交叉阴影线柱表示。图3a插图分别是二个受验者的典型的Western印迹。较大的54kDa带是完整的MMP-2，较小的45kDa带是MMP-2的经蛋白水解处理过的活化型。
在图3b中，MMP-9蛋白质值用空心柱表示，而MMP-9活性值用交叉阴影线柱表示。图3b插图是典型的Western印迹(左边部分)和典型的酶谱(右边部分)。酶谱上的多条带是MMP-9的经蛋白水解处理过的活化型。
条带强度用激光光密度测定术进行定量。结果以n=10的平均值±SEM给出。
如图3a和3b所示，MMP-2和MMP-9蛋白质和活性的诱导是剂量依赖性的，因为MMP在蛋白质和活性中的变化均是彼此反映的。MMP-2被试验的所有UVB剂量诱导，而MMP-9被剂量≥0.1MED的剂量诱导。诱导在1MED达到最大，在0.1MED约为最大值的半值。0.1MED相当于夏日在阳光下照射2-3分钟，它不会引起任何感觉得到的皮肤变红。低剂量UVB诱导AP-1和NF-B
如上所述，照射受验者并取出组织试样。按G.J.Fisher等的方法(J Biol Chem(1994)269:20629-20635)制备核提取物。含～108细胞的活组织检体(约200mg湿重)平均产生500μg核提取蛋白。按G.J.Fisher等的方法(同上)用32P标记的含AP-1和NF-B相同的和突变的DNA结合序列的DMA探针进行电泳迁移移位试验(8μ核提取蛋白质)。用Santa Cruz生物技术得到针对超移位带抗体。Jun和fos抗体分别对所有jun和fos族蛋白具有很宽的反应性。NF-B抗体对p65/RelA具有特异性。这些试验的结果见图4a、4b、4c和4d(NS是指非特异性实施例)。这些图中的插图是典型的AP-1和NF-B阻滞的复合体。+Compet是指添加100倍过量的未标记的探针；Mut是指突变的32P探针。
图4a是结合在未照射过的和照射过的(2MED UVB照射后4小时)皮肤上的AP-1和NF-B。如图4a所示，二种转录因子与其DNA响应成分的结合是特异性的，其表现是与突变的标记探针的阻滞的复合体的损失。抗体移位表明，与UVB照射过的皮肤的提取物一起观察到的特异性的AP-1和NF-B的阻滞的复合体分别含jun和fos蛋白质和RelA蛋白质。
图4b和4c是分别在2MED UVB照射下的AP-1和NF-B结合的诱导过程。结果用n=9的平均值+SEM表示。如图所示，二种因子的诱导均在15分钟内发生。
图4d是AP-1(用空心柱表示)和NF-B(用交叉阴影线表示)诱导的剂量依赖性。DNA结合在照射后30分钟进行测定。如图所示，二种因子均在约0.1MED发生半最大诱导，在1MED发生最大诱导。这些因子诱导的UVB剂量依赖性与上述对MMP-2和MMP-9的报道值紧密对应，与这些转录因子在这二种MMP的UVB诱导的增加中的参与是一致的。抑制UVB诱导AP-1、MMP-2和MMP-9
按G.J.Fisher等的方法(J Invest Dermatol(1991)96:699-707)将0.1％全反式视黄酸(t-RA)和其载体(70％乙醇和30％丙二醇)或0.05％糖肾上腺皮质激素(GC)丙酸氯倍他索和其载体(2％丙二醇+2％去水山梨糖醇单油酸酯-去水山梨糖醇二油酸酯，在白矿脂中)在受验者上施用(300mg/6cm2皮肤)48小时。然后用2MED UVB照射处理过的皮肤部位。如上所述，照射后30分钟，将所得皮肤进行AP-1测定或照射后24小时进行MMP测定。AP-1测定和MMP-1和MMP-9测定按前述方法进行。为确定t-RA是否使UVB诱导的皮肤变红有变化，用0.1％t-RA和其载体处理受验者24小时。用10-80mJ/cm2UVB照射处理过的区域，24小时后，用Minolta色度仪确定皮肤红变程度。这些试验的结果见图5a、5b、5c和5e。
图5a是AP-1测定的结果。如图所示，用t-RA对皮肤进行预处理，使UVB诱导的AP-1DNA结合减少约70％。
图5b和5c是MMP-1和MMP-9测定的结果。如图所示，t-RA预处理使UVB诱导的MMP-1和MMP-9mRNA、蛋白质和活性下降50-80％。
图5d是t-RA预处理对皮肤红变的效果的试验。如图所示，虽然t-RA吸收与UVB范围重叠(t-RAmax=351nm)，t-RA并未减少UVB诱导的皮肤红变。这表明，在AP-1和MMP诱导中观察到的减少是特异性的而非由于UVB被t-RA吸收所致。
图5e是用GC预处理皮肤的效果。如图所示，GC预处理使MMP-1和MMP-9活性下降至与t-RA预处理的结果相似的程度。
在上述说明书中提及的文献据此作为参考文献而明确地引入本文中。

Claims (11)

1．抑制人的未损伤的皮肤由于暴露于紫外光B(UVB)照射而光雾化的方法，包括：提供至少一种以下物质的抑制剂：(a)皮肤中可由UVB照射诱导的MMP活性、(b)转录因子AP-1和NF-B中的一个或两者、和(c)GTP结合蛋白或参与构成AP-1的jun或fos蛋白的活化和/或生成的激酶中的至少一种；和在皮肤暴露之前在皮肤上施用所述抑制剂，其量足以抑制可由UVB诱导的MMP的生成或活性、AP-1和NF-B中的一个或两者、或者GTP结合蛋白或参与构成AP-1的jun或fos蛋白的活化和/或生成的激酶中的至少一种。
2．如权利要求1所述的方法，其特征在于，所述方法抑制由UVB剂量低于引起皮肤红变所需最小值的暴露诱导的光老化。
3．如权利要求2所述的方法，其特征在于，所述UVB剂量约在5mJ/CM2以上。
4．如权利要求1所述的方法，其特征在于，所述抑制剂抑制AP-1和NF-B中的至少一种的活性。
5．如权利要求1所述的方法，其特征在于，所述抑制剂抑制可由UVB诱导的MMP的活性。
6．如权利要求1所述的方法，其特征在于，所述抑制剂抑制GTP结合的蛋白、或者jun或fos蛋白的生成所必需的激酶。
7．如权利要求4所述的方法，其特征在于，所述抑制剂抑制AP-1，该抑制剂是视黄醛衍生物、糖肾上腺皮质激素或维生素D3。
8．如权利要求4所述的方法，其特征在于，所述抑制剂抑制NF-B，该抑制剂是糖肾上腺皮质激素、阿司匹林或E5510。
9．如权利要求5所述的方法，其特征在于，所述抑制剂是TIMP、加拉定、巴替马司他、马立马司他或异羟肟酸酯。
10．如权利要求6所述的方法，其特征在于，所述抑制剂是法呢基转移酶抑制剂、牻牛儿牻牛儿基转移酶抑制剂，SB202190或PD98059。
11．紫外线B照射诱导的基质金属蛋白酶的抑制剂在制造用于防止未损伤的人皮肤的光老化的药物中的应用。
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