SuperOxide Dismutase/Catalase Mimetics

Introduction

This page is a review of the scientific evidence for health benefits from the oral use of chemicals which mimic the action of superoxide dismutase (SOD) and catalase, both major mammalian cellular enzymes which scavenge reactive oxygen species (ROS). Currently there are several such chemicals under investigation by various companies, but this review will focus on those that were first developed and investigated by Eukarion, which has since been acquired by Proteome Systems. Because of their Eukarion background, these chemicals have code names: EUK-8, EUK-134 and EUK-189, EUK-207. They are referred to as "synthetic catalytic scavengers (SCS)" and Eukarion has described their operation. (This page was no longer available online since the Eukarion site was allowed to lapse after the acquisition of Eukarion by Proteome Systems; it has been captured for local use from the Internet WayBack Machine.) "EUK-189 ... has SOD and catalase activities equivalent to those of EUK-134 but is more lipophilic, based on solvent partitioning. The catalytic activities and lipophilicities of the three compounds are compared in Table 1."R The properties of EUK-207 have not yet been fully described and contrasted with those of EUK-134 and EUK-189. Because EUK-189 is not orally bioavailable, Proteome Systems have slated EUK-189 for topical use, EUK-207 for injectable use and a new variant, EUK-418 (description not yet available), for oral use.

Safety and Interactions

  1. "At µmolar levels, catalytic antioxidants appear non-toxic and protect a wide variety of different types of cultured cells against the toxicity of ROS."R
  2. Note: The numbers within [] refer to the references within the available full paper of this major review.
    "The beneficial effects of catalytic antioxidants have been demonstrated in several in vivo model systems (Table 3), including models of lung fibrosis [38,39], chronic obstructive lung diseases [40], asthma [41], acute respiratory distress syndrome [42], bronchopulmonary dysplasia [43], pleurisy [44], shock [45-50], myocardial infarction [51,52], liver failure [53,54], ischemia-reperfusion [55,56], colitis [57,58], diabetes [59], transplantation [60], arthritis [61], amyotrophic lateral sclerosis [62,63], migraine [64,65], neurodegenerative diseases [66], stroke [67-70], spinal cord injury [71,72], pain [73] and dementia [74]. The efficacy of Catalytic antioxidants Catalytic antioxidants demonstrated in an incredible diversity of model systems highlights the extensive involvement of ROS in common animal models of human disease."R

Proven Benefits

  1. "[C]ell treatment with the catalytic ROS scavengers EUK-134 and EUK-189 attenuates Met signaling to ERKs and inhibits the anchorage-independent growth of F10 cells [mouse melanoma], consistent with a critical role for oxygen species in HGF [hepatocyte growth factor] signaling and in aggressive cell behavior. Finally, genetic manipulation of the Rac-ROS cascade at different levels demonstrated its crucial role in the pro-metastatic activity of c-Met in vivo. ... evidence that ROS directly contribute to Met-dependent metastatic growth opens a novel perspective in the complex correlation between oxygen radicals and malignancy, and suggest new possibilities of antioxidant-based therapeutic intervention, complementary to the search for Met-inhibitory compounds."R
  2. "[S]ystemic administration of EUK-189 decreases paraquat-mediated SNpc dopaminergic neuronal cell death [a model for Parkinson disease (PD)], in vivo [in adult mice]. ... our data provide direct evidence that systemic administration of bioavailable synthetic SOD/catalase mimetics protects against selective paraquat-mediated dopaminergic neuronal cell death through mechanisms involving the elimination of oxidative damage and the modulation of signal transduction pathways. Given the potential for exposure to this herbicide to increase the risk for the development of PD and the recent establishment of its systemic administration as a viable model for the disease, this has obvious therapeutic implications."R
  3. "ROS were reduced in spinal cords cultured in the presence of a synthetic superoxide dismutase and catalase mimetic, with a concomitant reduction in cell death and an increase in the number of motoneurons."R
  4. "Alzheimer disease is characterized by cerebral Abeta deposition, which we have recently discovered occurs also in the lens as cataracts in Alzheimer disease patients. Here we report the presence of significantly increased cataracts in the lenses of an Abeta-transgenic mouse model for Alzheimer disease and their amelioration upon treatment with EUK-189, a synthetic SOD/catalase mimetic. These data support an oxidative etiology for AD-associated lens cataracts and their potential to be treated preventatively with antioxidants."R
  5. "[C]hronic systemic administration of a superoxide dismutase (SOD)/catalase mimetic (EUK-189), delivered over a 1 month period via osmotic pump, prevents heat stress-induced liver injury by dramatically decreasing oxidative damage in aged animals. Widespread liver injury was present in old but not young vehicle-treated rats in response to a 2 day heating protocol. However, SOD/catalase mimetic treatment markedly decreased the hyperthermia-induced liver injury associated in old animals. The reversal of damage with EUK-189 was associated with an improvement in intracellular redox status and a striking reduction in hepatocellular lipid peroxidation."R
  6. "Cell death in the AER [apical ectodermal ridge] of [C57BL/6J mice] embryos concurrently exposed to ethanol and EUK-134 was notably reduced compared with that in embryos from ethanol-treated dams. Additionally, the antioxidant treatment reduced the incidence of forelimb malformations to 35.9%. This work illustrates that antioxidants can significantly improve the adverse developmental outcome that results from ethanol exposure in utero, diminishing the incidence and severity of major malformations that result from exposure to this important human teratogen."R
  7. "Treatment [in C. elegans] with SOD mimetics [EUK-8 and EUK-134] elevated in vivo SOD activity levels, particularly in mitochondria, where up to 5-fold increases in SOD activity were recorded. Treatment with exogenous SOD mimetics did not affect endogenous protein SOD levels. Where life span was reduced by the superoxide generators paraquat and plumbagin, EUK-8 treatment increased life span in a dose-dependent fashion."R
  8. "The protection conferred by EUK-134 [on primary human keratinocytes] resulted in a significant increase in cell survival following UVB irradiation."R
  9. "[In] perfused isolated hearts [aged female Sprague-Dawley rats]... subjected to global ischemia (25 min) followed by reperfusion (40 min), ... EUK-8 and estrogen improved cardiac recovery... Given the controversy surrounding hormone replacement therapy, EUK-8 may be an alternative to estrogen in protecting those [females] at risk for myocardial ischemia in the aging population."R
  10. "Pre-treatment [of lipopolysaccharide (LPS)-activated microglia in vitro] with superoxide dismutase (SOD)/catalase, or SOD/catalase mimetics EUK-189 - more potently than the enzymes] significantly reduced COX-2 expression and PGE2 production. These findings suggest a potential therapeutic intervention strategy for the treatment of inflammation-mediated neurodegenerative diseases."R
  11. "We propose that EUK-134 reduces renal I/R [ischemia/reperfusion] injury [in rats] not only via reduction of oxidative stress, but also by reducing nitrosative stress caused by renal I/R."R
  12. "[I]n SOD2 null mice ... we observed a striking pattern of neuronal cell death as a result of mitochondrial oxidative stress, and were able to significantly reduce the loss of neurons via antioxidant [EUK-189] treatment ... in vivo. Our results have important implications for the successful implementation of rational antioxidant therapy in age-related neurodegenerative disease in which neuronal cell loss is linked to mitochondrial dysfunction and oxidative stress.."R
  13. "Here we demonstrate that the [synthetic superoxide dismutase/ catalase] mimetics, Euk-134 and Euk-8, confer resistance to the oxidative stress-inducing agent, paraquat and to thermal stress [in C. elegans]. The protective effects of the compounds are apparent with treatments either during development or during adulthood and are independent of an insulin/IGF-I-like signalling pathway also known to affect thermal and oxidative stress resistance. Worms exposed to the compounds do not induce a cellular stress response and no detrimental effects are observed."R
  14. "Here we report a dramatic loss of learning and memory function from 8 to 11 months of age in mice, associated with marked increases in several markers of brain oxidative stress. Chronic systemic administration of two synthetic catalytic scavengers of reactive oxygen species, Eukarion experimental compounds EUK-189 and EUK-207, from 8 to 11 months almost completely reversed cognitive deficits and increase in oxidative stress taking place during this time period in brain. ... These results further support the role of reactive oxygen species in age-related learning impairment and suggest potential clinical applications for synthetic catalytic scavengers of reactive oxygen species."R
  15. "Treatment of rats with EUK-8 (0.3 or 1 mg/kg bolus injection followed by an infusion of 0.3 or 1 mg/kg/h) attenuated the renal and liver injury and dysfunction in a dose-related fashion. In addition, the higher dose of EUK-8 attenuated the delayed hypotension caused by endotoxin in the rat. ... We propose that small molecules, which have the catalytic activity of both superoxide dismutase and catalase, may represent a novel therapeutic approach for the therapy of endotoxic shock."R
  16. After induced "Hemorrhage (sufficient to lower mean arterial blood pressure to 45 mmHg for 90 min), ... Treatment of rats on resuscitation with EUK-8 (3 mg/kg i.v. bolus followed by 3 mg/kg/h i.v. infusion) significantly attenuated liver injury, renal dysfunction and pancreatic injury caused by hemorrhage and resuscitation. Administration of EUK-134 (3 mg/kg i.v. bolus followed by 3 mg/kg/h) reduced the liver injury and renal dysfunction (but not the pancreatic injury) caused by hemorrhagic shock. However, neither EUK-8 nor EUK-134 reduced the delayed circulatory failure associated with hemorrhagic shock. Thus, we propose that an enhanced formation of ROS contributes to the MOF in hemorrhagic shock, and that membrane-permeable SOD-mimetics with catalase activity, such as EUK-8 or EUK-134, may represent a novel therapeutic approach for the therapy of hemorrhagic shock."R
  17. "We show that treatment of sod2 nullizygous mice with synthetic superoxide dismutase (SOD)-catalase mimetics [EUK-8, EUK-134, and EUK-189] extends their lifespan by threefold, rescues the spongiform encephalopathy, and attenuates mitochondrial defects. This class of antioxidant compounds has been shown previously to extend lifespan in the nematode Caenorhabditis elegans (Melov et al., 2000). These new findings in mice suggest novel therapeutic approaches to neurodegenerative diseases associated with oxidative stress such as Friedreich ataxia, spongiform encephalopathies, and Alzheimer's and Parkinson's diseases, in which chronic oxidative damage to the brain has been implicated." From the full paper: "The percentage of mice surviving beyond 3 weeks of age was greater with EUK-189 treatment (80%), compared with 54% and 49% for EUK-8 and EUK-134, respectively"R
  18. "Pretreatment with 20 microM EUK-134 or 0.5 microM EUK-189 significantly attenuated STS [staurosporine]-induced neurotoxicity"R
  19. "[T]hese results show that synthetic superoxide dismutase-catalase mimetics such as EUK-134 can protect ischemically injured rat kidneys from ischemia-reperfusion syndrome when administered just before reperfusion."R
  20. "We conclude that EUK-8 prevents many of the manifestations of [lipopolysaccharide]-induced adult respiratory distress syndrome in pigs by detoxifying reactive oxygen metabolites without affecting the release of other important proinflammatory mediators."R

Potential Benefits

  1. "These results suggest that Sod2 [mitochondrial manganese superoxide dismutase] protects the aging brain against hAPP/Abeta [human amyloid precursor protein]-induced impairments. Whereas reductions in Sod2 would be expected to trigger or exacerbate neuronal and vascular pathology in AD, increasing Sod2 activity might be of therapeutic benefit. "R
  2. "Overall, combined with a recent study from our laboratory showing increased hepatic GSH-to-GSSG ratios (indicative of a more reduced hepatic environment) in old rats following a month of EUK-189 treatmentR, these results strongly support the view that chronic low-dose supplementation with a SOD/catalase mimetic enhances antioxidant capacity and improves redox status in old animals."R
  3. "These data demonstrate that overexpression of MnSOD or treatment with SOD mimics can result in antioxidant or prooxidant effects in [human prostate cancer] cells, depending on the presence of other antioxidants and prooxidants. MnSOD also has redox regulatory effects on cell growth and gene expression. These findings suggest that MnSOD and SOD mimics have the potential for cancer prevention or treatment."R
  4. "Treatment of wild-type worms [C. Elegans with EUK-8 or EUK-134] increased their mean life-span by a mean of 44 percent, and treatment of prematurely aging worms resulted in normalization of their life-span (a 67 percent increase). It appears that oxidative stress is a major determinant of life-span and that it can be counteracted by pharmacological intervention." "the lifespan of C. elegans can also be extended by the administration of synthetic superoxide dismutase/catalase mimetics. These compounds also appear to confer resistance to oxidative damage, since they protect against paraquat treatment. The protective effects of these compounds are apparent with treatment during either development or adulthood. These findings have demonstrated that pharmacological intervention in the aging process is possible and that these compounds can provide important information about the underlying mechanisms."R1,R2
  5. "Many previous antioxidant therapies have been disappointing, but newly characterized SOD mimetics are being shown to protect against oxidant-related lung disorders in animal models."R
  6. "[S]tructural modification of the prototype EUK-8 yields compounds with enhanced catalase activity and, in turn, biological effectiveness. This supports the concept that salen-manganese complexes represent a class of SOD and, in particular, catalase mimetics potentially useful against ROS-associated diseases."R
  7. "This paper describes the pharmacological approach to understand the molecular components of inflammation and oxidative stress on the activation of microglial cells and neuronal cell viability [key components of the pathology of Alzheimer's disease (AD)] ... we explore the effects of a series of salen-manganese complexes, EUK-8, -134 and -189, which are known to possess both superoxide and catalase activity. These compounds are able to protect cells from insults produced by hydrogen peroxide or peroxynitrite. ... Together, these data support a pivotal role for oxidative stress and inflammation as key mediators of the pathological cascade in AD and provide some ideas about possible therapeutic targets."R
  8. "We treated mice expressing human mutant SOD1 G93A [one cause of Amyotrophic lateral sclerosis(ALS)] with EUK-8 and EUK-134, two synthetic SOD/catalase mimetics that have shown efficacy in several animal models of human diseases. These treatments reduced levels of oxidative stress and prolonged survival. The results suggest that oxidative stress plays an active role in ALS and illustrate the potential for treatment strategies aimed specifically against ROS."R
  9. "[I]n primary DAergic [dopaminergic] neuron cultures ... Pretreatment of cultures with 0.5 microM EUK-134 completely prevented [neurotoxicity of] MPP(+)- [1-methyl-4-phenylpyridinium] or 6-OHDA [6-hydroxydopamine]-induced nitration of tyrosine residues in TH [tyrosine hydroxylase - the enzyme which converts tyrosine into dopamine]. Taken together, these results support the idea that reactive oxygen species (ROS) are critically involved in MPP(+)- and 6-OHDA-induced neurotoxicity and suggest a potential therapeutic role for synthetic catalytic scavengers of ROS, such as EUK-134, in the treatment of PD [Parkinson's disease]."R
  10. "[I]n the rat limbic system as a result of seizure activity elicited by systemic kainic acid (KA) administration... These results ... suggest that synthetic superoxide dismutase/catalase mimetics such as EUK-134 might be used to prevent excitotoxic neuronal injury."R
  11. "This study is an evaluation of the effectiveness of salen-manganese complexes, a class of synthetic SOD/catalase mimetics, in a rat focal ischemia model involving middle cerebral artery occlusion. We focus on EUK-134, a newly reported salen-manganese complex demonstrated here to have greater catalase and cytoprotective activities and equivalent SOD activity compared with the previously described prototype EUK-8. The administration of EUK-134 at 3 hr after middle cerebral artery occlusion significantly reduced brain infarct size, with the highest dose apparently preventing further infarct growth. EUK-8 was also protective but substantially less effective. These findings support a key role for ROS in the cascade of brain injury after stroke, even well after the onset of ischemia. The enhanced activity of EUK-134 suggests that, in particular, hydrogen peroxide contributes significantly to this injury. Overall, this study suggests that synthetic SOD/catalase mimetics might serve as novel, multifunctional therapeutic agents for stroke."R

Negative or Null Results and Limitations

  1. "[I]n the absence of a superoxide generator, treatment with EUK-8 or EUK-134 did not increase life span, even at doses that were optimal for protection against pro-oxidants. Thus, an elevation of SOD activity levels sufficient to increase life span when it is limited by superoxide generators does not retard aging in the absence of superoxide generators. This suggests that C. elegans life span is not normally limited by levels of superoxide and its derivatives."R
  2. "The superoxide dismutase mimetic EUK-8 has been reported to extend lifespan in the nematode Caenorhabditis elegans. However, in five trials administering EUK-8 in liquid culture with E. coli, and two trials using defined liquid medium, we observed no increase in C. elegans lifespan. Instead we saw a dose-dependent reduction of lifespan and fertility. We conclude that extension of C. elegans lifespan by EUK-8 may only occur under very particular culture conditions."R

Additional Reading and Reviews

  1. "Metal-containing catalytic antioxidants have emerged as a novel class of potential therapeutic agents that scavenge a wide range of reactive oxygen species. ... Cardiovascular, neurodegenerative and inflammatory lung disorders are all potentially important targets for catalytic antioxidant therapy."R
  2. "One key antioxidant enzyme implicated in the regulation of ROS-mediated tissue damage is extracellular superoxide dismutase (EC-SOD). EC-SOD is found in the extracellular matrix of tissues and is ideally situated to prevent cell and tissue damage initiated by extracellularly produced ROS. In addition, EC-SOD is likely to play an important role in mediating nitric oxide-induced signaling events, since the reaction of superoxide and nitric oxide can interfere with nitric oxide signaling. This review will discuss the regulation of EC-SOD and its role in a variety of oxidant-mediated diseases."R
  3. "Manganese-salen superoxide dismutase mimics interfere with the mitochondrial electron transport chain by acting as antimetabolites and thus effect "calorie restriction," leading to extended lifespan."R
  4. "Superoxide dismutase specific activity levels were measured in cytoplasmic fractions of liver, brain, and heart of 2 rodent and 12 primate species. These species had maximum life-span potentials ranging from 3.5 to 95 years. Liver, brain, and heart had similar specific activity levels for a given species, but the levels for different species varied over 2-fold, with man having the highest level. No general correlation was found in the levels with life-span. However, the ratio of superoxide dismutase specific activity to specific metabolic rate of the tissue or of the whole adult organism was found to increase with increasing maximum lifespan potential for all the species."R
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