**1. Introduction**

154 Rheumatoid Arthritis – Treatment

Zwerina J, Hayer S, Tohidast-Akrad M, Bergmeister H, Redlich K, Feige U, et al. Single and

erosion, and cartilage destruction. Arthritis Rheum. 2004;50(1):277-90.

combined inhibition of tumor necrosis factor, interleukin-1, and RANKL pathways in tumor necrosis factor-induced arthritis: effects on synovial inflammation, bone

> Enkorten is a new potential drug for the treatment of rheumatoid arthritis**,** with an immunomodulatory and anti-inflammatory effect. It is a combination of two peptide components of endogenous origin: methionine-enkephalin of 5 mg and tridecactide of 1 mg (Picture 1 and 2). According to the chemical structures, these components correspond to amino acid sequences of the neuropeptide precursor proopiomelanocortin.


Picture 1. Chemical characteristics of tridecactide


Picture 2. Chemical characteristics of met-enkephalin

The holder of effects of the tested combination is alpha 1-13 corticotrophin–tridecactide (ACTH 1-13), composed of 13 amino acids, identical to the amino acid sequence of the alpha-melanostimulating hormone (-MSH), but without the acetyl and amide ending. Some studies suggest that -MSH is synthesized in the pituitary, other parts of the CNS, the placenta, and some endocrine organs – especially the adrenal, the skin and the gastrointestinal tract (Star et al, 1995; Catania et al, 2000). The presence of this neuropeptide in the mucous membrane of the gastrointestinal tract and keratinocytes of the skin suggests

<sup>\*</sup> Jasna Kusturica, Maida Todić-Rakanović, Mirjana Mijanović, Fahir Bečić, Asija Začiragić,

Selma Škrbo, Lejla Burnazović-Ristić, Aida Kulo and Svjetlana Loga-Zec

*Medical Faculty University of Sarajevo Institute of Pharmacology, Clinical Pharmacology and Toxicology, Bosnia and Herzegovina*

Enkorten – A Potential Drug for the Treatment of Rheumatoid Arthritis 157

inflammatory response of T cells through the activation of regulatory physiological

Until recently it was thought that the immune/inflammatory reaction develops exclusively in the periphery. Today it is known that the nervous, endocrine and immune systems are interconnected, and that they communicate by signals that are transmitted through neuropeptides. In this way, central neurogenic influences can either enhance or modulate the peripheral response, so by analogy the treatment of inflammatory reactions could be improved by the influence of the proinflammatory signals in the central nervous system. Thus, Catania et al. (1999) suggest that one of these strategies could be based on the action of

In the past several years, particular attention has been given to the anti-inflammatory effects of this peptide, as a result of the introduction of -MSH and related peptides in clinical practice for the treatment of inflammatory diseases (Getting, 2006). Undoubtedly, -MSH, administered systemically or locally, expresses strong anti-inflammatory effects. Antiinflammatory effects of this peptide are mediated by direct effects on cells of the immune system, as well as by indirect effects that are achieved by changing the function of non-

Three basic mechanisms of -MSH anti-inflammatory action can be distinguished: direct effects through melanocortin receptors on cells in the periphery (monocytes/macrophages and neutrophils); effects on glial cells; and descendent anti-inflammatory effects through melanocortin receptors on neurons (Lipton et al, 2000). These mechanisms of action correspond to the concept of neuroimmunomodulation in which nerves, endocrine and immune systems are independent networks that mutually communicate through soluble

Multiple anti-inflammatory effects that -MSH has have been identified in various *in vitro* systems of cell cultures. Studies of anti-inflammatory effects of -MSH on cellular level were primarily concentrated on the issue whether and to what degree -MSH suppresses the production of pro-inflammatory cytokines. In this respect, several studies have shown that treatment with -MSH results in significant downregulation of pro-inflammatory cytokines such as IL-1, IL-2, IL-4, IL-6, IL-13 and TNF-, as well as chemokines such as IL8, Gro and interferon (IFN) (Brzoska et al, 2008). Furthermore, chemotaxis induced by IL8 in the cells of human neutrophils and monocytes has been suppressed under the influence of -MSH (Manna et al, 2006), which indicates that the function of these types of phagocytic cells during the inflammatory response is blocked by the peptide via multiple effector pathways. Contrary to the inhibitory effects of -MSH on the production and activity of proinflammatory mediators, it has been found that -MSH induces IL-10, a cytokine with a potent anti-inflammatory activity. Specifically, in monocytes of human peripheral blood and cultivated human monocytes, -MSH increases the production and expression of IL-10 (Bhardway et al, 1996). Since IL-10 reduces the production of pro-inflammatory cytokines in

resident immune cells of peripheral tissues (Luger and Brzoska, 2007).

macrophages, its upregulation could result in anti-inflammatory influences.

Studies on different cell types of human skin, including pigment cells, fibroblastic cells and dermal microvascular endothelial cells, as well as rat mast cells, showed that -MSH is able to suppress the expression of several intracellular adhesion molecules (interstitial adhesion molecule-1 - ICAM-1 and P-selectin) induced by proinflammatory stimuli such as IFN-, LPS and TNF-Böhm et al, 2005; Hill et al, 2006; Sarkar et al, 2003). Finally, the inhibition of adhesion and transmigration of inflammatory cells may contribute to the anti-

mediators such as cytokines and neuropeptides.

mechanisms (Štambuk et al, 1997).


that it is a component of natural immunity (Catania et al, 2000a). The supposed connection between alpha-MSH and immune processes is confirmed by the clinical data on changes of its plasma level under certain pathological conditions (Lipton and Catania, 1997; Lipton et al, 2000). An increased concentration of -MSH has been recorded in patients with an acute myocardial infarction who received thrombolytic therapy, probably as an endogenous antiinflammatory response. This peptide has been identified in the synovial fluid of patients with rheumatoid arthritis (Star et al, 1995) and it is believed that the inflammation and joint destruction in this disease occur due to imbalances of production of proinflammatory and anti-inflammatory cytokines such as -MSH. A higher concentration of -MSH has been found in patients suffering from arthropathy accompanied by heavy inflammation (Lipton et al, 2000). Since -MSH is a natural modulator peptide, its concentration is subject to intensive control to avoid excessive inhibition of the immune response. It is assumed that the increased concentration of peptides leads to downregulation of receptors in cells, which could explain the biphasic curve of the anti-inflammatory effects -MSH (Catania et al, 2000).

The other component contained in the drug is met-enkephalin, which belongs to a group of endogenous opioid peptides, widely distributed in the CNS. All opioid peptides contain one or more copies of the simplest opioid peptides: methionine-enkefalin (tyrosine-glycineglycine-phenylalanine-methionine) and leucine-enkephalin (tyrosine-glycine-glycinephenylalanine-leucine) (Janković, 1991). They participate in, and modulate neurotransmission. Opioid peptides also act as growth factors that control proliferation and differentiation of cells and may participate in the process of wound healing, tissue regeneration and immune response. Enkephalins show antidepressant, antianxiety and anticonvulsive effects. They are produced in the adrenal and the hypothalamus. Metenkephalin belongs to a group of enkephalins that are involved in transmitting signals in the nervous system, intestines, endocrine glands, bronchial tree, lymphatic and other tissues (Štambuk et al, 1996). The highest concentrations are present in the core of adrenal, hypothalamus, autonomic ganglia and the gastrointestinal tract (Janković, 1991).

Met-enkephalin as an inhibitory peptide modulates the proliferation and migration of cells, as well as the organization of tissues during development, homeostatic cell renewal, wound healing, angiogenesis, and in malignant neoplasms (Zagon et al, 2000). Physiologically, enkephalins have a signalling function in the nervous system, intestine, endocrine glands, bronchial tree, cardiovascular system, lymphatic and other tissues, and participate in the regulation of haematopoiesis (Štambuk et al, 1996). It is assumed that they participate in maintaining homeostasis of the organism exposed to stress (Mulabegović et Rakanović-Todić, 2008).
