Synthetic superoxide dismutase/catalase mimetics reduce oxidative stress and prolong survival in a mouse amyotrophic lateral sclerosis model

Jung, Cheolwha; Rong, Yongqi; Doctrow, Susan R.; Baudry, Michel; Malfroy, Bernard; Xu, Zuoshang

doi:10.1016/s0304-3940(01)01784-0

Cited by 167 publications

(93 citation statements)

References 15 publications

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“…Along with Mn porphyrins, Mn salen derivatives attenuated lung inflammation in a porcine model of LPS-induced acute respiratory syndrome (260), supposedly through decreasing oxidative stress, which in turn suppresses NF-kB activation and pro-inflammatory gene expression (260). A mild effect on the survival of the G93A mouse in an amyotrophic lateral sclerosis model (eight low copies model) was observed with EUK-134 and EUK-8 (33 mg=kg, 3 times per week for the duration of the study), the former being more effective (164). The effect of Mn salens in neurodegenerative disorders was summarized in a review by Patel (133).…”

Section: Mn Salens In Suppressing Oxidative-stress Injuries In Vivomentioning

confidence: 99%

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

Batinić‐Haberle

Rebouças

Spasojević

2010

Antioxidants & Redox Signaling

459

689

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Oxidative stress has become widely viewed as an underlying condition in a number of diseases, such as ischemia-reperfusion disorders, central nervous system disorders, cardiovascular conditions, cancer, and diabetes. Thus, natural and synthetic antioxidants have been actively sought. Superoxide dismutase is a first line of defense against oxidative stress under physiological and pathological conditions. Therefore, the development of therapeutics aimed at mimicking superoxide dismutase was a natural maneuver. Metalloporphyrins, as well as Mn cyclic polyamines, Mn salen derivatives and nitroxides were all originally developed as SOD mimics. The same thermodynamic and electrostatic properties that make them potent SOD mimics may allow them to reduce other reactive species such as peroxynitrite, peroxynitrite-derived CO 3 _ À , peroxyl radical, and less efficiently H 2 O 2 . By doing so SOD mimics can decrease both primary and secondary oxidative events, the latter arising from the inhibition of cellular transcriptional activity. To better judge the therapeutic potential and the advantage of one over the other type of compound, comparative studies of different classes of drugs in the same cellular and=or animal models are needed. We here provide a comprehensive overview of the chemical properties and some in vivo effects observed with various classes of compounds with a special emphasis on porphyrin-based compounds. Antioxid. Redox Signal. 13, 877-918.

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Section: Mn Salens In Suppressing Oxidative-stress Injuries In Vivomentioning

confidence: 99%

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

Batinić‐Haberle

Rebouças

Spasojević

2010

Antioxidants & Redox Signaling

459

689

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“…This antioxidant has been successfully used to prevent cell death in several neuropathological models. [20][21][22] We carried out 12 h cultures of complete E13 spinal cords in the presence of increasing concentrations of EUK-134 and compared its effects with the effect of 150 mM Z-VAD-FMK, a broad-spectrum caspase inhibitor, known to inhibit neuronal death. In agreement with our observations in fresh developing spinal cords, we found high ROS levels in the motoneuronal region of spinal cord sections ( Figure 4, left panel), as detected by the ROS Figure 2 Expression pattern of antioxidant enzymes in developing spinal cord.…”

Section: Antioxidant Euk-134 Rescues Motoneurons From Death In Thoracmentioning

confidence: 99%

“…21 It protects neurons from dying in models of stroke and amyotrophic lateral sclerosis, 22 and increases the life expectancy of Sod2 mutant mice. 20 When EUK-134 was added to the cultures, we observed a decrease in the number of cells under oxidative stress and of those dying (detected by TUNEL technique or AO staining).…”

Section: Ros As Inducers Of Motoneuron Deathmentioning

confidence: 99%

Motoneuronal death during spinal cord development is mediated by oxidative stress

et al. 2005

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The involvement of reactive oxygen species (ROS) in neuronal death has been determined in culture, and in association with several neurodegenerative disorders. We examined whether ROS participate in the cell death observed during spinal cord development. We found that the general pattern of high ROS levels, gene expression for some antioxidant enzymes, and motoneuron death correlated positively along spinal cord development. 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. The number of motoneurons was higher in spinal cords treated with the antioxidant than in those treated with caspase inhibitors. In general, the increase in motoneuron survival did not correlate with the reduction in cells undergoing DNA degradation in the motoneuronal region. These results suggest that ROS are signaling molecules controlling caspase-dependent and caspaseindependent programmed motoneuron death, and support the hypothesis that this mechanism is abnormally turned on in some neurodegenerative disorders and aging.

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“…However, the role of oxidative stress in this gain of function remains unclear. Administration of SOD͞catalase mimetic compounds prevented the accumulation of some oxidative damage byproducts in FALS SOD transgenic mice but had very limited effects on disease onset and survival times (9).…”

Section: A Myotrophic Lateral Sclerosis (Als) Also Known As Loumentioning

confidence: 99%

Phenotypic effects of familial amyotrophic lateral sclerosis mutant Sod alleles in transgenic Drosophila

Mockett

Radyuk

Benes

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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A subset of patients suffering from familial amyotrophic lateral sclerosis (FALS) exhibit point mutations in the gene encoding Cu-Zn superoxide dismutase [superoxide:superoxide oxidoreductase, EC 1.15.1.1 (SOD)]. The human wild-type and five FALS Sod mutant transgenes were introduced into the fruit fly, Drosophila melanogaster, in a Cu-Zn Sod null background. Sod null flies had dramatically decreased life span, glutathione and methionine content, fertility, locomotor activity, and resistance to hyperoxic stress, compared with wild-type controls. All of these phenotypic manifestations were rescued fully by a single human wild-type allele, expressing 5-10% of wild-type SOD activity. Full recovery of wild-type life span was also observed when human mutant and wild-type alleles were placed together in the fly Sod null background. The FALS Sod mutations alone caused a recessive phenotype, usually involving low or undetectable levels of SOD activity, in which: (i) full restoration of the wild-type phenotype was observed among young adults, and (ii) older adults exhibited a sudden increase in oxidative stress, accompanied by physiological impairment of abrupt onset, and followed by premature death. Thus, the minimal SOD activity associated with the FALS Sod mutations appears to determine longevity, not by chronically increasing oxidative stress, but by limiting the time in which a viable redox environment can be maintained. However, the dominant gain of function by mutant SOD, which occurs in human patients and in the transgenic mouse model of FALS, is not observed in Drosophila.

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Synthetic superoxide dismutase/catalase mimetics reduce oxidative stress and prolong survival in a mouse amyotrophic lateral sclerosis model

Cited by 167 publications

References 15 publications

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

Motoneuronal death during spinal cord development is mediated by oxidative stress

Phenotypic effects of familial amyotrophic lateral sclerosis mutant Sod alleles in transgenic Drosophila

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