Therapeutic Manganese Related Agents

The first known therapeutic use of manganese was the treatment of psoriasis, in combination with vitamin Bi in 1966.30 Since that time, manganese salts, enzymes, related genes and synthetic antioxidants have been used to treat disorders involving arthritis, cancer, dermatitis, osteoporosis and ischemia/ reperfusion injury (lack/return of blood) as reviewed below. Other possible therapeutic targets associated with manganese drugs in the future may involve treatment of cardiovascular diseases, diabetes, epilepsy, acquired immuno deficiency syndrome (AIDS), peritoneal adhesions (scars of membrane surrounding the abdominal cavity) and inflammatory pain.

Initial research focused on the use of manganese-rich herbs and manganese salts in disorders associated with lower manganese status. But the purity, stability and/or poor reaction rates of simple complexes limit their usefulness. Investigations then focused on the role of SOD2 in pathologies as it became clear that oxidative stress is a common contributor to numerous disease states. However, the native form of the enzyme had major pitfalls for clinical applications, including insolubility, proteolytic digestion, defective transport into cells or the brain and immune reactivity.31 For example, a CuZn isoform of SOD (SOD1), Orgotein®, was tested in clinical trials. Early results showed positive effects in rheumatoid- and osteoar-thritis, and reduced side effects of chemotherapy and radiation therapy.11 However, adverse immunological events occurred, presumably due to the bovine source of the enzyme. Thus, Orgotein® was withdrawn from clinical use except in Spain. Since then lower molecular weight, synthetic forms called SOD mimetics (SODm) have been developed and used for therapeutic purposes.

The three general types of SODm-containing manganese are the Mn(III) metalloporphyrins, Mn(III) salens and Mn(II) (pentaazamacrocyclic ligands)-based complexes. A fourth type, nitroxide, is outside the scope of this chapter as it does not contain manganese. Metalloporphyrin complexes contain manganese instead of iron at the core. These compounds are very stable and are potent inhibitors of oxidative stress that results from lipid peroxidation.15 Mn(III) salens are free radical scavengers that remove superoxide, but also exhibit catalase activity. Salens investigated in pathologies related to oxidative stress include manganese N,N-bis(salicylidene)ethylenediamine chloride (EUK-8) and manganese 3-methoxy-N,N-bis(salicylidene)ethylenediamine chloride (EUK-134) (Figure 9.1). These dual-functioning SODm reduce oxidative injury from superoxide and H2O2 effectively.32 Protective effects of Mn salens have been reported in models of respiratory distress syndrome, neurodegenerative diseases, amyotrophic lateral sclerosis, cardiomyopathies (diseases of heart muscle) and ischemia/reperfusion.11 Yet a limitation of salen compounds is their non-selectivity for ROS, such that the relative influence of the specific types of ROS cannot be discerned.

A more selective type of SODm is the low molecular weight Mn(II) (penta-azamacrocyclic ligands)-based complex. An example of the non-peptide SOD mimetic is M40403, a bis (cyclo-hexylpyridine-substituted) macrocyclic ligand as shown in Figure 9.2.33 This artificial antioxidant is more potent than natural forms of other antioxidants, with enhanced pharmacokinetics and stability. Its advantage is its selectivity, in that it scavenges superoxide anions without removing other compounds of interest such as NO, H2O2 or hypochlorite.34

The disadvantage of native SOD2 is that the protein cannot bind to the surface of the endothelial cell. This adherence to the cell surface is important for the protective effect of SOD on the membrane-associated proteins (NOX). The NOX proteins produce superoxide and H2O2 as a defense mechanism, and for cell signaling in smooth muscle and endothelial cells.35 Thus, both inflammatory cells and vascular cells create superoxide ions that lead to oxidative damage. Recently a chimeric recombination superoxide dismutase was constructed as a fusion gene expressed in Escherichia coli that combines the best features of SOD2 and SOD3. The chimera SOD2/3 consists of the coding


Figure 9.1 SOD mimetic Mn(III) salens. In EUK 8, X is H; in EUK-134, X is OCH:

Figure 9.1 SOD mimetic Mn(III) salens. In EUK 8, X is H; in EUK-134, X is OCH:

Figure 9.2 SOD mimetic Mn(II) pentaazamacrocylic ligand M40403

sequence from SOD2 (with mitochondrial targeting signal deleted) coupled with the COOH-terminal tail from SOD3. The tail of SOD3 has the important attribute of binding to the endothelial cell surface.36

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