Glatiramer acetate (GA), also known as copolymer-1 (COP-1), is a random mixture of synthetic polypeptides composed of four amino acids (L-glutamic acid, L-lysine, L-alanine, and L-tyrosine) in a residue molar ratio 4.2:3.4:1.4:1.0, with an average molecular mass of 4700-11,000 Da. These amino acids resemble myelin basic protein (MBP), and Glatiramer acetate has been shown to be effective in preventing and suppressing experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis [1,2].
In vitro studies have shown that Glatiramer acetate competes with myelin peptides from binding to major histocompatibility (MHC) molecules and is able to displace MBP peptides from antigen presenting cells (APC) [3]. Glatiramer acetate inhibits MHC II assisted activation of myelin specific T cells [4]. Glatiramer acetate -treated (1-10 µg/ml) dendritic cells were able to shift the phenotype of naive T cells towards TH2 like T cells. In addition Glatiramer acetate inhibited the secretion of IL-12 and TNF-α by human dendritic cells and macrophages [5]. In addition to competition for binding to MHC molecules and thus inhibiting the T cell response to several myelin antigens, Glatiramer acetate is proposed to act as an antagonist to MBP/MHC at MBP-specific T cell receptors (TCR). It was demonstrated to operate as an "altered peptide ligand" to the 82-100 epitope of MBP [6].
Glatiramer acetate (250 µg/mouse, i.c.v.) and Glatiramer acetate (10, 2.5 mg/kg; s.c.) in Y-maze reversed memory impairment (LPS 100 µg/kg, i.p.). In passive-avoidance task, Glatiramer acetate (2.5, 10 mg/kg; s.c.) reversed LPS-induced impairment and the mice showed significantly longer latency times during the retention trial [7]. 2 mg/mouse of Glatiramer acetate prevented the manifestation of EAE altogether, the doses of 200 and 500 µg of Glatiramer acetate were considered suboptimal in preventing EAE, 250 µg/mouse (equivalent to 10 mg/kg) [8].
References:
[1]. Schrempf W, Ziemssen T. Glatiramer acetate: mechanisms of action in multiple sclerosis. Autoimmunity reviews. 2007 Aug 1;6(7):469-75.
[2]. Habisch HJ, SchwalenstÖcker B, Danzeisen R, Neuhaus O, Hartung HP, Ludolph A. Limited effects of glatiramer acetate in the high-copy number hSOD1-G93A mouse model of ALS. Experimental neurology. 2007 Aug 1;206(2):288-95.
[3]. Fridkis-Hareli M, Teitelbaum D, Gurevich E, Pecht I, Brautbar C, Kwon OJ, Brenner T, Arnon R, Sela M. Direct binding of myelin basic protein and synthetic copolymer 1 to class II major histocompatibility complex molecules on living antigen-presenting cells--specificity and promiscuity. Proceedings of the National Academy of Sciences. 1994 May 24;91(11):4872-6.
[4]. Gran B, Tranquill LR, Chen M, Bielekova B, Zhou W, Dhib-Jalbut S, Martin R. Mechanisms of immunomodulation by glatiramer acetate. Neurology. 2000 Dec 12;55(11):1704-14.
[5]. Vieira PL, Heystek HC, Wormmeester J, Wierenga EA, Kapsenberg ML. Glatiramer acetate (copolymer-1, copaxone) promotes Th2 cell development and increased IL-10 production through modulation of dendritic cells. The Journal of Immunology. 2003 May 1;170(9):4483-8.
[6]. Aharoni R, Teitelbaum D, Arnon R, Sela M. Copolymer 1 acts against the immunodominant epitope 82-100 of myelin basic protein by T cell receptor antagonism in addition to major histocompatibility complex blocking. Proceedings of the National Academy of Sciences. 1999 Jan 19;96(2):634-9.
[7]. Mohammadi F, Rahimian R, Fakhraei N, Rezayat SM, Javadi‐Paydar M, Dehpour AR, Afshari K, Ejtemaei Mehr S. Effect of glatiramer acetate on short‐term memory impairment induced by lipopolysaccharide in male mice. Fundamental & Clinical Pharmacology. 2016 Aug;30(4):347-56.
[8]. Giuliani F, Metz LM, Wilson T, Fan Y, Bar-Or A, Yong VW. Additive effect of the combination of glatiramer acetate and minocycline in a model of MS. Journal of neuroimmunology. 2005 Jan 1;158(1-2):213-21.
醋酸格拉替雷(Glatiramer acetate,GA),也称为copolymer-1(COP-1),是一种随机混合的合成多肽,由四种氨基酸(L-谷氨酸、L-赖氨酸、L-丙氨酸和L-酪氨酸)按照残基摩尔比例4.2:3.4:1.4:1.0组成,平均分子量为4700-11000 Da。这些氨基酸类似于髓鞘基础蛋白(MBP),并已经证明,醋酸格拉替雷在预防和抑制实验性自身免疫性脑脊髓炎(EAE),多发性硬化的动物模型方面非常有效[1,2]。
体外研究表明,醋酸格拉替雷可以与髓鞘肽竞争结合主要组织相容性(MHC)分子,并且能够从抗原呈递细胞(APC)中取代MBP肽[3]。醋酸格拉替雷抑制MHC II辅助激活髓鞘特异性T细胞[4]。处理醋酸格拉替雷(1-10µg/ml)的树突状细胞能够将原生T细胞的表型转变为类似于TH2的T细胞。此外,醋酸格拉替雷还抑制人类树突状细胞和巨噬细胞分泌IL-12和TNF-α [5]。除了通过竞争结合MHC分子从而抑制T细胞对多种髓鞘抗原的反应,醋酸格拉替雷还被认为在MBP特异性T细胞受体(TCR)中作为MBP/MHC的拮抗剂。它被证明是MBP 82-100表位的"改变肽配体"[6]。
醋酸格拉替雷(250 µg/只,i.c.v.)和醋酸格拉替雷(10, 2.5 mg/kg；s.c.)在Y型迷宫任务中逆转了LPS(100 µg/kg,i.p.)引起的记忆障碍。在被动避免任务中,醋酸格拉替雷(2.5,10 mg/kg；s.c.)逆转了LPS诱导的障碍,小鼠在保持试验期间显示出明显较长的潜伏期 [7]。2 mg/只的醋酸格拉替雷完全预防了EAE的表现,而200和500 µg的剂量被认为是预防EAE的亚优剂量,每只小鼠250 µg(相当于10 mg/kg)[8]。