Effect of Glutathione Augmentation on Lipid Peroxidation after Spinal Cord Injury

Lucas, Jen Hill; Wheeler, Debra G.; Guan, Zhen; Suntres, Zacharias E.; Stokes, Bradford T.

doi:10.1089/08977150260139138

Cited by 43 publications

(37 citation statements)

References 47 publications

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“…Others have confirmed that MDA levels increase in the first 2 h [15]. An increase in LP that appears in the injured cord within the first hour has also been evidenced in terms of a depletion of endogenous antioxidants, including ascorbic acid [16], alpha-tocopherol (also known as vitamin E) [17], glutathione [18], and ubiquinol-9 and ubiqunol-10 [19]. More contemporary immunohistochemical and immunoblotting methods have been recently used, which reveals an impressive increase in the levels of the LP-derived aldehydic breakdown products 4-HNE [20][21][22][23] and acrolein [24,25].…”

Section: Increased Lipid Peroxidationmentioning

confidence: 92%

“…Although this tripartite LOO• antioxidant defense system (vit E, vitamin C, GSH) works fairly effectively in the absence of a major post-traumatic oxidative stress, studies have shown that each of these antioxidants is rapidly consumed during the early minutes and hours after SCI [16][17][18]. Thus, it has long been recognized that more effective pharmacological LOO• and LO• scavengers are needed than what endogenous biochemistry has provided.…”

Section: Overview Of Antioxidant Mechanistic Approachesmentioning

confidence: 99%

“…These include methylene blue [110], mexilitine [111], thiopental [112], β-glucan [113], N-acetylcysteine [114], γ-glutamylcysteine [18], polyethylene glycol [115], edaravone (MCI186), cyclosporine A [116], NIM811 [117,118], erythropoietin [119] and α-lipoic acid [120]. Although some of these are probably true chemical antioxidants (e.g., methylene blue, edaravone, α-lipoic acid), others may work indirectly by induction of endogenous antioxidant defenses (e.g., N-acetylcysteine, γ-glutamylcysteine), reduction of mitochondrial dysfunction, and its associated free radical leakage (e.g., cyclosporine A, NIM811) or by enhancement of cell membrane repair mechanisms (e.g., polyethylene glycol).…”

Section: Efficacy Of Miscellaneous Antioxidants In Sci Modelsmentioning

confidence: 99%

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Antioxidant Therapies for Acute Spinal Cord Injury

2011

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Summary:One of the most investigated molecular mechanisms involved in the secondary pathophysiology of acute spinal cord injury (SCI) is free radical-induced, iron-catalyzed lipid peroxidation (LP) and protein oxidative/nitrative damage to spinal neurons, glia, and microvascular cells. The reactive nitrogen species peroxynitrite and its highly reactive free radicals are key initiators of LP and protein nitration in the injured spinal cord, the biochemistry, and pathophysiology of which are first of all reviewed in this article. This is followed by a presentation of the antioxidant mechanistic approaches and pharmacological compounds that have been shown to have neuroprotective properties in preclinical SCI models. Two of these, which act by inhibition of LP, are high-dose treatment with the glucocorticoid steroid methylprednisolone (MP) and the nonglucocorticoid 21-aminosteroid tirilazad, have been demonstrated in the multicenter NASCIS clinical trials to produce at least a modest improvement in neurological recovery when administered within the first 8 hours after SCI. Although these results have provided considerable validation of oxidative damage as a clinically practical neuroprotective target, there is a need for the discovery of safer and more effective antioxidant compounds for acute SCI.

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Section: Increased Lipid Peroxidationmentioning

confidence: 92%

Section: Overview Of Antioxidant Mechanistic Approachesmentioning

confidence: 99%

Section: Efficacy Of Miscellaneous Antioxidants In Sci Modelsmentioning

confidence: 99%

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Antioxidant Therapies for Acute Spinal Cord Injury

2011

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“…14 Lucas,et al 14 examined the effects of glutathione treatment on lipid peroxidation after SCI in a rat contusion injury model. The results suggested that elevation of levels of glutathione by irrigation with d-glutamylcysteine conferred significant protection against lipid peroxidation after SCI, suggesting that glutathione augmentation may be an effective strategy for curtailment of lipid peroxidation-mediated damage in SCI.…”

Section: Ros and Oxidative Stress In Scimentioning

confidence: 99%

“…The results suggested that elevation of levels of glutathione by irrigation with d-glutamylcysteine conferred significant protection against lipid peroxidation after SCI, suggesting that glutathione augmentation may be an effective strategy for curtailment of lipid peroxidation-mediated damage in SCI. 14 Mutations in the gene for Cu,ZnSOD have been identified in familial amyotrophic lateral sclerosis (ALS), a disease characterized by damage and loss of neurons in both the brain and the spinal cord. 15 Transgenic mice overexpressing wide-type Cu,ZnSOD gene show resistance to SCI, indicating that Cu,ZnSOD has an important role in protecting against spinal neuron death.…”

Section: Ros and Oxidative Stress In Scimentioning

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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Effects of axon degeneration on oligodendrocyte lineage cells: Dorsal rhizotomy evokes a repair response while axon degeneration rostral to spinal contusion induces both repair and apoptosis

Sun

Lin

McTigue

et al. 2010

Glia

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Wallerian degeneration in the dorsal columns (DC) after spinal cord injury (SCI) is associated with microglial activation and prolonged oligodendrocyte (OL) apoptosis that may contribute to demyelination and dysfunction after SCI. But, there is an increase in OL lineage cells after SCI that may represent a reparative response, and there is evidence for remyelination after SCI. To assess the role of axonal degeneration per se in OL apoptosis and proliferation, we cut the L2-S2 dorsal roots producing massive axonal degeneration and microglial activation in the DC, and found no evidence of OL loss or apoptosis. Rather, the numbers of OL-lineage cells positive for NG2 and APC (CC1) increased, and BrdU studies suggested new OL formation. We then tested contusion SCI (cSCI) that results in comparable degeneration in the DC rostral to the injury, microglial activation, and apoptosis of DC OLs by 8 days. NG2+ cell proliferation and oligodendrogenesis was seen as after rhizotomy. The net result of this combination of proliferation and apoptosis was a reduction in DC OLs, confirming earlier studies. Using an antibody to oxidized nucleic acids, we found rapid and prolonged RNA oxidation in OLs rostral to cSCI, but no evidence of oxidative stress in DC OLs after rhizotomy. These results suggest that signals associated with axonal degeneration are sufficient to induce OL proliferation, and that secondary injury processes associated with the central SCI, including oxidative stress, rather than axonal degeneration per se, are responsible for OL apoptosis.

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Effect of Glutathione Augmentation on Lipid Peroxidation after Spinal Cord Injury

Cited by 43 publications

References 47 publications

Antioxidant Therapies for Acute Spinal Cord Injury

Antioxidant Therapies for Acute Spinal Cord Injury

Oxidative stress in spinal cord injury and antioxidant-based intervention

Effects of axon degeneration on oligodendrocyte lineage cells: Dorsal rhizotomy evokes a repair response while axon degeneration rostral to spinal contusion induces both repair and apoptosis

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