Antioxidant properties of Neu2000 on mitochondrial free radicals and oxidative damage

Nishant P. Visavadiya; Melanie L. McEwen; Jignesh D. Pandya; Patrick G. Sullivan; Byoung Joo Gwag; Joe E. Springer

doi:10.1016/j.tiv.2012.12.011

Antioxidant properties of Neu2000 on mitochondrial free radicals and oxidative damage

Nishant P. Visavadiya, Melanie L. McEwen, Jignesh D. Pandya, Patrick G. Sullivan, Byoung Joo Gwag, Joe E. Springer

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

Abstract

Neu2000 [2-hydroxy-5-(2,3,5,6-tetrafluoro-4 trifluoromethylbenzylamino) benzoic acid] is a dual-acting neuroprotective agent that functions both as a noncompetitive N-methyl- d-aspartate (NMDA) receptor antagonist and a free radical scavenger. In the present study, we investigated the scavenging activity of Neu2000 on various classes of reactive oxygen species and reactive nitrogen species (ROS/RNS) as well as its efficacy for reducing free radicals and oxidative stress/damage induced in spinal cord mitochondrial preparations. Neu2000 exerted scavenging activity against superoxide, nitric oxide, and hydroxyl radicals, and efficiently scavenged peroxynitrite. In the mitochondrial studies, Neu2000 markedly inhibited ROS/RNS and hydrogen peroxide levels following antimycin treatment. In addition, Neu2000 effectively scavenged hydroxyl radicals generated by iron(III)-ascorbate, reduced protein carbonyl formation mediated by hydroxyl radicals and peroxynitrite, and prevented glutathione oxidation caused by tert-butyl hydroperoxide in isolated mitochondria. Interestingly, incubation of isolated mitochondria with Neu2000 followed by centrifugation and removal of the supernatant also resulted in a concentration-dependent decrease in lipid peroxidation. This observation suggests that Neu2000 enters mitochondria to target free radicals or indirectly affects mitochondrial function in a manner that promotes antioxidant activity. The results of the present study demonstrate that Neu2000 possesses potent in vitro antioxidant activity due, most likely, to its active phenoxy group.

Original language	English
Pages (from-to)	788-797
Number of pages	10
Journal	Toxicology in Vitro
Volume	27
Issue number	2
DOIs	https://doi.org/10.1016/j.tiv.2012.12.011
State	Published - Mar 2013

Bibliographical note

Funding Information:
This work was supported by a grant from the Kentucky Spinal Cord and Head Injury Research Trust (Grant 7-23 to J.E.S.), the Craig H. Neilsen Foundation (Grant 56879 to M.L.M. and Grant 124814 to J.E.S.), National Institutes of Health ( R01-NS062993 to P.G.S.), and an endowment from Cardinal Hill Rehabilitation Hospital (to J.E.S.).

Keywords

Antioxidant
Lipid peroxidation
Mitochondria
Neu2000
Reactive nitrogen species
Reactive oxygen species

ASJC Scopus subject areas

Toxicology

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10.1016/j.tiv.2012.12.011

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title = "Antioxidant properties of Neu2000 on mitochondrial free radicals and oxidative damage",

abstract = "Neu2000 [2-hydroxy-5-(2,3,5,6-tetrafluoro-4 trifluoromethylbenzylamino) benzoic acid] is a dual-acting neuroprotective agent that functions both as a noncompetitive N-methyl- d-aspartate (NMDA) receptor antagonist and a free radical scavenger. In the present study, we investigated the scavenging activity of Neu2000 on various classes of reactive oxygen species and reactive nitrogen species (ROS/RNS) as well as its efficacy for reducing free radicals and oxidative stress/damage induced in spinal cord mitochondrial preparations. Neu2000 exerted scavenging activity against superoxide, nitric oxide, and hydroxyl radicals, and efficiently scavenged peroxynitrite. In the mitochondrial studies, Neu2000 markedly inhibited ROS/RNS and hydrogen peroxide levels following antimycin treatment. In addition, Neu2000 effectively scavenged hydroxyl radicals generated by iron(III)-ascorbate, reduced protein carbonyl formation mediated by hydroxyl radicals and peroxynitrite, and prevented glutathione oxidation caused by tert-butyl hydroperoxide in isolated mitochondria. Interestingly, incubation of isolated mitochondria with Neu2000 followed by centrifugation and removal of the supernatant also resulted in a concentration-dependent decrease in lipid peroxidation. This observation suggests that Neu2000 enters mitochondria to target free radicals or indirectly affects mitochondrial function in a manner that promotes antioxidant activity. The results of the present study demonstrate that Neu2000 possesses potent in vitro antioxidant activity due, most likely, to its active phenoxy group.",

keywords = "Antioxidant, Lipid peroxidation, Mitochondria, Neu2000, Reactive nitrogen species, Reactive oxygen species",

author = "Visavadiya, {Nishant P.} and McEwen, {Melanie L.} and Pandya, {Jignesh D.} and Sullivan, {Patrick G.} and Gwag, {Byoung Joo} and Springer, {Joe E.}",

note = "Funding Information: This work was supported by a grant from the Kentucky Spinal Cord and Head Injury Research Trust (Grant 7-23 to J.E.S.), the Craig H. Neilsen Foundation (Grant 56879 to M.L.M. and Grant 124814 to J.E.S.), National Institutes of Health ( R01-NS062993 to P.G.S.), and an endowment from Cardinal Hill Rehabilitation Hospital (to J.E.S.).",

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doi = "10.1016/j.tiv.2012.12.011",

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AU - Visavadiya, Nishant P.

AU - McEwen, Melanie L.

AU - Pandya, Jignesh D.

AU - Sullivan, Patrick G.

AU - Gwag, Byoung Joo

AU - Springer, Joe E.

N1 - Funding Information: This work was supported by a grant from the Kentucky Spinal Cord and Head Injury Research Trust (Grant 7-23 to J.E.S.), the Craig H. Neilsen Foundation (Grant 56879 to M.L.M. and Grant 124814 to J.E.S.), National Institutes of Health ( R01-NS062993 to P.G.S.), and an endowment from Cardinal Hill Rehabilitation Hospital (to J.E.S.).

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N2 - Neu2000 [2-hydroxy-5-(2,3,5,6-tetrafluoro-4 trifluoromethylbenzylamino) benzoic acid] is a dual-acting neuroprotective agent that functions both as a noncompetitive N-methyl- d-aspartate (NMDA) receptor antagonist and a free radical scavenger. In the present study, we investigated the scavenging activity of Neu2000 on various classes of reactive oxygen species and reactive nitrogen species (ROS/RNS) as well as its efficacy for reducing free radicals and oxidative stress/damage induced in spinal cord mitochondrial preparations. Neu2000 exerted scavenging activity against superoxide, nitric oxide, and hydroxyl radicals, and efficiently scavenged peroxynitrite. In the mitochondrial studies, Neu2000 markedly inhibited ROS/RNS and hydrogen peroxide levels following antimycin treatment. In addition, Neu2000 effectively scavenged hydroxyl radicals generated by iron(III)-ascorbate, reduced protein carbonyl formation mediated by hydroxyl radicals and peroxynitrite, and prevented glutathione oxidation caused by tert-butyl hydroperoxide in isolated mitochondria. Interestingly, incubation of isolated mitochondria with Neu2000 followed by centrifugation and removal of the supernatant also resulted in a concentration-dependent decrease in lipid peroxidation. This observation suggests that Neu2000 enters mitochondria to target free radicals or indirectly affects mitochondrial function in a manner that promotes antioxidant activity. The results of the present study demonstrate that Neu2000 possesses potent in vitro antioxidant activity due, most likely, to its active phenoxy group.

AB - Neu2000 [2-hydroxy-5-(2,3,5,6-tetrafluoro-4 trifluoromethylbenzylamino) benzoic acid] is a dual-acting neuroprotective agent that functions both as a noncompetitive N-methyl- d-aspartate (NMDA) receptor antagonist and a free radical scavenger. In the present study, we investigated the scavenging activity of Neu2000 on various classes of reactive oxygen species and reactive nitrogen species (ROS/RNS) as well as its efficacy for reducing free radicals and oxidative stress/damage induced in spinal cord mitochondrial preparations. Neu2000 exerted scavenging activity against superoxide, nitric oxide, and hydroxyl radicals, and efficiently scavenged peroxynitrite. In the mitochondrial studies, Neu2000 markedly inhibited ROS/RNS and hydrogen peroxide levels following antimycin treatment. In addition, Neu2000 effectively scavenged hydroxyl radicals generated by iron(III)-ascorbate, reduced protein carbonyl formation mediated by hydroxyl radicals and peroxynitrite, and prevented glutathione oxidation caused by tert-butyl hydroperoxide in isolated mitochondria. Interestingly, incubation of isolated mitochondria with Neu2000 followed by centrifugation and removal of the supernatant also resulted in a concentration-dependent decrease in lipid peroxidation. This observation suggests that Neu2000 enters mitochondria to target free radicals or indirectly affects mitochondrial function in a manner that promotes antioxidant activity. The results of the present study demonstrate that Neu2000 possesses potent in vitro antioxidant activity due, most likely, to its active phenoxy group.

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KW - Mitochondria

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KW - Reactive nitrogen species

KW - Reactive oxygen species

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JO - Toxicology in Vitro

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IS - 2

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Antioxidant properties of Neu2000 on mitochondrial free radicals and oxidative damage

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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