Novel membrane localized iron chelators as inhibitors of iron-dependent lipid peroxidation

Braughler, J M; Burton, Philip S.; Chase, R L; Pregenzer, J F; Jacobsen, E. J.; Vandoornik, Frederick J.; Tustin, J. M.; Aver, Donald E.; Bundy, Gordon L.

doi:10.1016/0006-2952(88)90066-4

Cited by 167 publications

(149 citation statements)

References 20 publications

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“…In cultures ex- The neuroprotective activity of ubiquinone may be mediated by at least two independent mecha nisms: (i) an improvement of energy balance; and (ii) removal of free radicals and inhibition of lipid peroxidation. The latter mechanism is consistent with the neuroprotective activity of 21-aminoste roids (which inhibit oxygen free radical-induced lipid peroxidation) against glutamate receptor mediated neuronal toxicity (Braughler et al , 1987;4 FIG. 5.…”

Section: Discussionsupporting

confidence: 73%

Ubiquinone Protects Cultured Neurons against Spontaneous and Excitotoxin-Induced Degeneration

Favit

Nicoletti

Scapagnini

et al. 1992

J Cereb Blood Flow Metab

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Summary:Ubiquinone is an endogenous quinone with pharmacological actions mainly related to its antioxidant properties. Here we report that ubiquinone protects cul tured cerebellar granule cells against glutamate-induced neurotoxicity. In control cultures at 9 days of maturation in vitro (DIY), a 30-min exposure to 100 fLM glutamate induced neuronal degeneration, as reflected by the great percentage (>90%) of cells labeled with propidium iodide 24 h after the exposure. Glutamate-induced neuronal death was dramatically reduced in cultures treated daily with Ubiquinone since the second DIV. In these cultures, glutamate failed to induce a "delayed" increase in the An excessive activation of glutamate receptors has been implicated in the pathophysiology of neu ronal damage in acute and chronic degenerative dis eases of the central nervous system (CNS) (re viewed in Choi, 1988). The neurotoxic action of glu tamate is mostly mediated by an exaggerated activation of N-methyl-D-aspartate (NMDA) recep tors, which leads to a persistent perturbation of in tracellular Ca2+ homeostasis. The excessive rise in cytosolic free Ca2+ results in a sustained activation of a variety of Ca2 + -dependent enzymes, including neutral proteases, protein kinases, phospholipases, and endonucleases. These enzymes may trigger a cascade of intracellular reactions that are ultimately responsible for neuronal degeneration and death (Vaccarino et ai

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Section: Discussionsupporting

confidence: 73%

Ubiquinone Protects Cultured Neurons against Spontaneous and Excitotoxin-Induced Degeneration

Favit

Nicoletti

Scapagnini

et al. 1992

J Cereb Blood Flow Metab

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“…The 21-aminosteroid TM (U74006F), is a potent antioxidant and LP inhibitor, has been shown to be e ective in animal models of SCI, 19,20,23,40 ± 43 and is currently being examined in the NASCIS III clinical trial. 8 In vitro studies suggest that tirilazad exerts its antioxidant activity by multiple mechanisms including; increasing membrane stability, scavenging of lipid peroxyl radicals, reducing LP, induced arachidonic acid release, decreased formation or scavenging of hydroxyl radicals, and maintenance of the level of endogenous vitamin E. 11,21,22 In contrast to MP, it has no steroidal side e ects or peripheral vasodilator activity and is far more potent. 3,29,30 These characteristics make TM an interesting compound for possible treatment of CNS injury.…”

Section: Discussionmentioning

confidence: 99%

Effect of methylprednisolone, tirilazad mesylate and vitamin E on lipid peroxidation after experimental spinal cord injury

et al. 1999

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E ect of methylprednisolone (MP), tirilazad mesylate (TM) and vitamin E on lipid peroxidation (LP) was evaluated in an experimental model of spinal cord compression injury in anesthetized rats. Forty rats, divided randomly into four groups, were injured by compressing on the spinal cord at Th 3 for 1 min. Bolus injections of saline solution, MP (30 mg/kg bolus and 5.4 mg/kg/h), TM (10 mg/kg four times per day), or vitamin E (30 mg/ kg four times per day) were begun 1 h after the spinal cord injury (SCI). Twenty-four hours after treatment, the rats were killed, and malondialdehyde (MDA), a LP product, was measured in the spinal cord tissues. Rats treated with MP, TM and vitamin E had signi®cantly decreased MDA levels (P50.01) than rats in the control group. The lowest MDA levels were found in the TM group. These results suggest that MP, TM and vitamin E may have a protective e ect against SCI in rats by its antioxidant e ect.

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“…59 In a manner similar to vitamin E, U-74006F has been found to scavenge lipid peroxyl radical thereby inhibiting lipid radical chain reactions. 26 U-74006F also decreased hydroxyl radical formation from Fenton reactions like due to its ability to chelate redox-active iron. 2 3H-1,2-dithiole-3-thione: as noted earlier, the central nervous system is particularly vulnerable to oxidative stress due to many intrinsic factors.…”

Section: Nucleusmentioning

confidence: 93%

“…2,26 U-72099E has been shown to be more potent than methylprednisolone in protecting rat brain synaptosomes from lipid peroxidation-induced inhibition of 14 C-GABA uptake. 2,26 In addition, it equaled the ability of methylprednisolone to enhance the early neurological recovery of head injured mice. 2 The dose-response characteristics and capability of U-74006F to promote functional recovery in cats subjected to compression trauma of the upper lumbar (L-2) spinal cord have also been evaluated.…”

Section: Nucleusmentioning

confidence: 99%

Oxidative stress in spinal cord injury and antioxidant-based intervention

Jia

Zhu

Li³

et al. 2011

Spinal Cord

265

176

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Study design: Literature review. Objectives: Spinal cord injury (SCI) remains a major public health issue in developed countries as well as worldwide. The pathophysiology of SCI is characterized by an initial primary injury followed by secondary deterioration. Although the etiology and pathogenesis of SCI remain to be fully understood, it has been suggested that reactive oxygen species (ROS) and oxidative stress have a significant role in the pathophysiology of SCI. Thus, alleviating oxidative stress may be an effective strategy for therapeutic intervention of SCI. The aim of this review was to describe (i) the sources of ROS as well as the major antioxidant defenses with particular attention being paid to lipid peroxidation; (ii) the biomarkers of oxidative stress in SCI and (iii) the neuroprotective effects of various compounds with antioxidative properties in animal models of SCI. Methods: PubMed, one of the most comprehensive biomedical databases, was searched from 1976-2011. All relevant papers were read by title, abstract and full-length article. Results: Oxidative stress is considered a hallmark of injury of SCI. Thus, alleviating oxidative stress may be an effective way of therapeutic intervention of SCI. Two of these agents, the glucocorticoid steroid methylprednisolone and the non-glucocorticoid 21-aminosteroid tirilazad, have been shown to possess significant antioxidant activities and improve recovery of SCI patients in clinical trials. Other promising botanical compounds and their molecular targets and mechanisms of action with regard to potential protection against SCI were also described. These include carotenoids and phenolic compounds. Conclusion: ROS and oxidative stress have a significant role in the pathophysiology of SCI. Alleviating oxidative stress is be an effective strategy for therapeutic intervention of SCI. Extensive research over the past several decades has identified numerous bioactive compounds that have antioxidative stress benefits in animal models of SCI. Thus, continued studies on bioactive compounds with ROS-scavenging capacity may lead to the development of effective antioxidant-based modalities for treating SCI in human subjects.

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Novel membrane localized iron chelators as inhibitors of iron-dependent lipid peroxidation

Cited by 167 publications

References 20 publications

Ubiquinone Protects Cultured Neurons against Spontaneous and Excitotoxin-Induced Degeneration

Ubiquinone Protects Cultured Neurons against Spontaneous and Excitotoxin-Induced Degeneration

Effect of methylprednisolone, tirilazad mesylate and vitamin E on lipid peroxidation after experimental spinal cord injury

Oxidative stress in spinal cord injury and antioxidant-based intervention

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