Mitigating effect of EUK-207 on radiation-induced cognitive impairments

Raber, Jacob; Davis, Michaël I.; Pfankuch, Timothy; Rosenthal, Robert W.; Doctrow, Susan R.; Moulder, John E.

doi:10.1016/j.bbr.2016.10.038

Cited by 14 publications

(7 citation statements)

References 52 publications

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“…To probe the impact of ROS mitigation on H 2 O 2 -induced DNA damage and senescence-like phenotypes, we tested a synthetic SOD/catalase mimetic, EUK-207. This molecule possesses both SOD and catalase activity and scavenges ROS generated in the cytoplasm or organelles, including the mitochondria [17]. In addition, EUK-207 suppresses oxidative modifications of proteins, lipids, and nucleic acids [61].…”

Section: Discussionmentioning

confidence: 99%

“…EUK-207 suppresses oxidative stress, including in the mitochondria [13, 14], through transforming oxygen free radicals into oxygen via a superoxide dismutase-like activity, and hydrogen peroxide into oxygen and water by a catalase-like activity [13]. EUK-207 has been used successfully to suppress age-related [15, 16] and radiation-induced cognitive impairment in mice [17].…”

Section: Introductionmentioning

confidence: 99%

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ROS-Induced Activation of DNA Damage Responses Drives Senescence-Like State in Postmitotic Cochlear Cells: Implication for Hearing Preservation

et al. 2019

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In our aging society, age-related hearing loss (ARHL) has become a major socioeconomic issue. Reactive oxygen species (ROS) may be one of the main causal factors of age-related cochlear cell degeneration. We examined whether ROS-induced DNA damage response drives cochlear cell senescence and contributes to ARHL from the cellular up to the system level. Our results revealed that sublethal concentrations of hydrogen peroxide (H 2 O 2 ) exposure initiated a DNA damage response illustrated by increased γH2AX and 53BP1 expression and foci formation mainly in sensory hair cells, together with increased levels of p-Chk2 and p53. Interestingly, postmitotic cochlear cells exposed to H 2 O 2 displayed key hallmarks of senescent cells, including dramatically increased levels of p21, p38, and p-p38 expression, concomitant with decreased p19 and BubR1 expression and positive senescence-associated β-galactosidase labeling. Importantly, the synthetic superoxide dismutase/catalase mimetic EUK-207 attenuated H 2 O 2 -induced DNA damage and senescence phenotypes in cochlear cells in vitro. Furthermore, systemic administration of EUK-207 reduced age-related loss of hearing and hair cell degeneration in senescence-accelerated mouse-prone 8 (SAMP8) mice. Altogether, these findings highlight that ROS-induced DNA damage responses drive cochlear cell senescence and contribute to accelerated ARHL. EUK-207 and likely other antioxidants with similar mechanisms of action could potentially postpone cochlear aging and prevent ARHL in humans.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ROS-Induced Activation of DNA Damage Responses Drives Senescence-Like State in Postmitotic Cochlear Cells: Implication for Hearing Preservation

et al. 2019

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“…More recent studies were focused on the manganosalen EUK-207 due to both its ability to suppress oxidative stress and its greater biological stability. Thus, Raber et al [ 114 ] reported that this compound mitigated radiation-induced cognitive impairments without affecting cognition of sham-irradiated mice. Wang et al [ 22 , 115 ] used EUK-207 to treat hydrogen peroxide-induced DNA damage and senescence phenotype in senescence-accelerated mouse-prone 8 mice, reducing age-related loss of both hearing and hair cell degeneration.…”

Section: Therapeutic Effects Of Manganosalen Complexes In In Vivo mentioning

confidence: 99%

Pursuing the Elixir of Life: In Vivo Antioxidative Effects of Manganosalen Complexes

et al. 2020

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Manganosalen complexes are coordination compounds that possess a chelating salen-type ligand, a class of bis-Schiff bases obtained by condensation of salicylaldehyde and a diamine. They may act as catalytic antioxidants mimicking both the structure and the reactivity of the native antioxidant enzymes active site. Thus, manganosalen complexes have been shown to exhibit superoxide dismutase, catalase, and glutathione peroxidase activities, and they could potentially facilitate the scavenging of excess reactive oxygen species (ROS), thereby restoring the redox balance in damaged cells and organs. Initial catalytic studies compared the potency of these compounds as antioxidants in terms of rate constants of the chemical reactivity against ROS, giving catalytic values approaching and even exceeding that of the native antioxidative enzymes. Although most of these catalytic studies lack of biological relevance, subsequent in vitro studies have confirmed the efficiency of many manganosalen complexes in oxidative stress models. These synthetic catalytic scavengers, cheaper than natural antioxidants, have accordingly attracted intensive attention for the therapy of ROS-mediated injuries. The aim of this review is to focus on in vivo studies performed on manganosalen complexes and their activity on the treatment of several pathological disorders associated with oxidative damage. These disorders, ranging from the prevention of fetal malformations to the extension of lifespan, include neurodegenerative, inflammatory, and cardiovascular diseases; tissue injury; and other damages related to the liver, kidney, or lungs.

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“…More recent studies were focused on the manganosalen EUK-207, due to both its ability to supress oxidative stress and its greater biological stability. Thus, Raber et al [117] reported that this compound mitigated radiation-induced cognitive impairments without affecting cognition of shamirradiated mice. Wang et al [22,118] used EUK-207 to treat hydrogen peroxide induced DNA damage and senescence phenotype in senescence-accelerated mouse-prone 8 mice, reducing age-related loss of both hearing and hair cells degeneration.…”

Section: Neurodegenerative Diseases and Mental Disordersmentioning

confidence: 99%

Pursuing the Elixir of Life: In Vivo Antioxidative Effect of Manganosalen Complexes, a Review

Rouco¹,

Pedrido²,

Maneiro³

2020

Preprint

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Manganosalen complexes are coordination compounds that possess a chelating salen-type ligand, a class of bis-Schiff bases obtained by condensation of salicylaldehyde and a diamine. They may act as catalytic antioxidants mimicking both the structure and the reactivity of the native antioxidant enzymes active site. Thus, manganosalen complexes have shown to exhibit superoxide dismutase, catalase, and glutathione peroxidase activities, and they could potentially facilitate the scavenging of excess ROS, thereby restoring the redox balance in the damaged cells and organs. Initial catalytic studies compared the potency of these compounds as antioxidants in terms of rate constants of the chemical reactivity against ROS, giving catalytic values approaching and even exceeding that of the native antioxidative enzymes. Although most of these catalytic studies lack of biological relevance, subsequent in vitro studies have confirmed the efficiency of many manganosalen complexes in oxidative stress models. These synthetic catalytic scavengers, cheaper than natural antioxidants, have accordingly attracted intensive attention for the therapy of ROS-mediated injuries. The aim of this review is to focus on in vivo studies performed on manganosalen complexes and their activity on the treatment of several pathological disorders associated with oxidative damage. This disorders, ranging from the prevention of fetal malformations to the extension of lifespan, include neurodegenerative, inflammatory and cardiovascular diseases, tissue injury, and other damages related to liver, kidney or lungs.

show abstract

Mitigating effect of EUK-207 on radiation-induced cognitive impairments

Cited by 14 publications

References 52 publications

ROS-Induced Activation of DNA Damage Responses Drives Senescence-Like State in Postmitotic Cochlear Cells: Implication for Hearing Preservation

ROS-Induced Activation of DNA Damage Responses Drives Senescence-Like State in Postmitotic Cochlear Cells: Implication for Hearing Preservation

Pursuing the Elixir of Life: In Vivo Antioxidative Effects of Manganosalen Complexes

Pursuing the Elixir of Life: In Vivo Antioxidative Effect of Manganosalen Complexes, a Review

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