Glatiramer Acetate in Treatment of Multiple Sclerosis: A Toolbox of Random Co-Polymers for Targeting Inflammatory Mechanisms of both the Innate and Adaptive Immune System?

Abstract

Multiple sclerosis is a disease of the central nervous system, resulting in the demyelination of neurons, causing mild to severe symptoms. Several anti-inflammatory treatments now play a significant role in ameliorating the disease. Glatiramer acetate (GA) is a formulation of random polypeptide copolymers for the treatment of relapsing-remitting MS by limiting the frequency of attacks. While evidence suggests the influence of GA on inflammatory responses, the targeted molecular mechanisms remain poorly understood. Here, we review the multiple pharmacological modes-of-actions of glatiramer acetate in treatment of multiple sclerosis. We discuss in particular a newly discovered interaction between the leukocyte-expressed integrin αMβ2 (also called Mac-1, complement receptor 3, or CD11b/CD18) and perspectives on the GA co-polymers as an influence on the function of the innate immune system.

The random co-polymer glatiramer acetate rapidly kills primary human leukocytes through sialic-acid-dependent cell membrane damage

“…While this treatment may appear as a more powerful tool to dampen inflammation, it also contains the risk of adverse side effects such as infections. The remarkable safety of GA treatment and its well-documented effects in MS treatment heightens the interest in this formulation and other similar polymers devised for immunotherapy (2). The link between GA as a nanomedicine and its lysis of leukocytes is likely to aid the improved design of a class of polymers with such immunomodulatory effects.…”

“…More recently, cellular compartments and molecular mechanisms of the innate immune response has also been considered as targets for GA (2)(3)(4)(5).…”

“…The copolymers are composed of four amino acids, i.e., L-glutamate, L-lysine, L-alanine, and L-tyrosine in molar ratios of 1.4 (Glu): 3.4 (Ala): 4.2 (Lys): 1 (Tyr) (2). The M r varies from 5,000-9,000, corresponding to ∼45-80 residues with an experimentally mean M r of 8,030 and a narrow standard deviation of only 170 (6).…”

“…Considering these properties, treatment with GA theoretically could generate more than 10 30 different amino acid sequences (2,7). At physiological pH, the amphipathic co-polymers would carry an average net charge of ~+3 as judged from the molar ratios of glutamate and lysine.…”

Positive and Negative Aspects of Copaxone ( Glatiramer acetate) Action on TC, TG HbA1c and Iron Levels in The Sera of Iraqi Women with Multiple Sclerosis in Baghdad

“…Multiple sclerosis is a chronic autoimmune neurodegenerative disease of the central nervous system (CNS) [1,2]. Indeed, this disease causes chronic neurological features, particularly in "young and middle" age adults [3]. Anyway, multiple sclerosis is characterized as an inflammatory disease associated with inflammation, demyelination and destruction of oligodendrocytes and axons [1,4].…”