Edward D Hall

University of Kentucky, Lexington, KY, United States

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Publications (45)168.36 Total impact

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    ABSTRACT: The importance of free radical-induced oxidative damage after traumatic brain injury (TBI) has been well documented. Despite multiple clinical trials with radical-scavenging antioxidants that are neuroprotective in TBI models, none is approved for acute TBI patients. As an alternative antioxidant target, Nrf2 is a transcription factor that activates expression of antioxidant and cytoprotective genes by binding to antioxidant response elements (ARE) within DNA. Previous research has shown that neuronal mitochondria are susceptible to oxidative damage post-TBI, and thus the current study investigates whether Nrf2-ARE activation protects mitochondrial function when activated post-TBI. It was hypothesized that administration of carnosic acid (CA) would reduce oxidative damage biomarkers in brain tissue and also preserve cortical mitochondrial respiratory function post-TBI. A mouse controlled cortical impact (CCI) model was employed with a 1.0mm cortical deformation injury. Administration of CA at 15minutes post-TBI reduced cortical lipid peroxidation, protein nitration, and cytoskeletal breakdown markers in a dose-dependent manner at 48hours post-injury. Moreover, CA preserved mitochondrial respiratory function compared to vehicle animals. This was accompanied by decreased oxidative damage to mitochondrial proteins, suggesting the mechanistic connection of the two effects. Lastly, delaying the initial administration of CA up to 8hours post-TBI was still capable of reducing cytoskeletal breakdown, thereby demonstrating a clinically relevant therapeutic window for this approach. This study demonstrates that pharmacological Nrf2-ARE induction is capable of neuroprotective efficacy when administered after TBI. Copyright © 2014. Published by Elsevier Inc.
    Experimental neurology. 11/2014;
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    ABSTRACT: The pathophysiological importance of oxidative damage after traumatic brain injury (TBI) has been extensively demonstrated. The transcription factor Nrf2 mediates antioxidant and cytoprotective genes by binding to antioxidant response elements (ARE) present in nuclear DNA. In this study, we characterized the time-course of Nrf2-ARE-mediated expression in cortex and hippocampus using a unilateral controlled cortical impact (CCI) model of focal-TBI. Ipsilateral hippocampal and cortical tissue was collected for Western-blot protein analysis (n=6/group) or quantitative RT-PCR for mRNA (n=3/group) at 3, 6, 12, 24, 48, 72 hours or 1-week post-injury. Multiple genes mediated by Nrf2-ARE were altered post-TBI. Specifically, Nrf2 mRNA increased significantly post-TBI at 48, 72 hours in cortex and at 48, 72 hours and 1-week in hippocampus with a coincident increase in glial fibrillary acidic protein (GFAP) mRNA thereby implying this response is likely occurring in astrocytes. Presumably linked to Nrf2 activation, heme-oxygenase-1 (HO-1), NADPH-quinone-oxidoreductase 1 (NQO1), glutathione reductase (GR) and catalase mRNA overlap throughout the post-injury time course. This study demonstrates the first evidence of such changes during the first week after focal TBI and that increases in expression of some Nrf2-ARE-mediated cytoprotective genes are not observed until 24-48 hours post-injury. Unfortunately, this does not precede, but rather coincides with, the occurrence of lipid peroxidative damage. This is the first known comparison between the time course of peroxidative damage and that of Nrf2-ARE activation during the first week post-TBI. These results underscore the necessity to discover pharmacological agents to accelerate and amplify Nrf2-ARE-mediated expression early post-TBI.
    Journal of neurotrauma 03/2014; · 4.25 Impact Factor
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    ABSTRACT: Phenelzine (PZ) is a scavenger of the lipid peroxidation (LP)-derived reactive aldehyde 4-hydroxynonenal (4-HNE) due to its hydrazine functional group, which can covalently react with 4-HNE. In this study, we first examined the ability of PZ to prevent the respiratory depressant effects of 4-HNE on normal isolated brain cortical mitochondria. Second, in rats subjected to controlled cortical impact traumatic brain injury (CCI-TBI), we evaluated PZ (10 mg/kg subcutaneously at 15 minutes after CCI-TBI) to attenuate 3-hour post-TBI mitochondrial respiratory dysfunction, and in separate animals, to improve cortical tissue sparing at 14 days. While 4-HNE exposure inhibited mitochondrial complex I and II respiration in a concentration-dependent manner, pretreatment with equimolar concentrations of PZ antagonized these effects. Western blot analysis demonstrated a PZ decrease in 4-HNE in mitochondrial proteins. Mitochondria isolated from peri-contusional brain tissue of CCI-TBI rats treated with vehicle at 15 minutes after injury showed a 37% decrease in the respiratory control ratio (RCR) relative to noninjured mitochondria. In PZ-treated rats, RCR suppression was prevented (P<0.05 versus vehicle). In another cohort, PZ administration increased spared cortical tissue from 86% to 97% (P<0.03). These results suggest that PZ's neuroprotective effect is due to mitochondrial protection by scavenging of LP-derived 4-HNE.Journal of Cerebral Blood Flow & Metabolism advance online publication, 16 January 2013; doi:10.1038/jcbfm.2012.211.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 01/2013; · 5.46 Impact Factor
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    ABSTRACT: The transcription factor NF-E2-related factor 2 (Nrf2) mediates transcription of antioxidant/cytoprotective genes by binding to the antioxidant response element (ARE) within DNA. Upregulation of these genes constitutes a pleiotropic cytoprotective-defense pathway which has been shown to produce neuroprotection in numerous models by decreasing lipid peroxidation (LP) as measured by the neurotoxic LP by-product 4-hyrdoxynonenal (4-HNE). As neuronal mitochondria have previously been shown to be susceptible to insult-induced LP-mediated oxidative damage, we sought to mechanistically investigate whether Nrf2-ARE activation in vivo could protect mitochondria from subsequent 4-HNE exposure ex vivo. Young adult male CF-1 mice were administered one of two known Nrf2-ARE activators as single I.P. doses - sulforaphane (SFP; 5.0mg/kg) or carnosic acid (CA; 1.0mg/kg) - or their respective vehicles 48hours prior to Ficoll isolation of rat cerebral cortical mitochondria. Purified mitochondria were then exposed ex vivo to 4-HNE for 15minutes at 37°C which we showed to cause a concentration-related inhibition of mitochondrial respiration together with covalent binding of 4-HNE to mitochondrial proteins. We chose a 30µM concentration of 4-HNE, which produced an approximate 50% inhibition of complex I or complex II-driven respiration, to assess whether prior in vivo the Nrf2-ARE activating compounds would increase the resistance of the isolated cortical mitochondria to 4-HNE's mito-toxic effects. Administration of either compound significantly increased (p<0.05) expression of heme oxygenase-1 mRNA in cortical tissue 48hours post-administration, verifying that both compounds were capable of inducing the Nrf2-ARE pathway. Moreover, the prior in vivo administration of sulforaphane (SFP) and carnosic acid (CA) significantly (p<0.05) attenuated 4-HNE-induced inhibition of mitochondrial respiration for complex I while only carnosic acid acted to protect complex II. Furthermore, both CA and SFP significantly (p<0.05) reduced the amount of 4-HNE bound to mitochondria proteins as determined by Western blot. These results demonstrate the capability of Nrf2-ARE induction in vivo to protect from 4-HNE toxicity to cortical mitochondria ex vivo. Ongoing studies will determine the therapeutic efficacy of Nrf2-ARE activators to attenuate traumatic brain injury induced pathophysiology.
    Free Radical Biology and Medicine 12/2012; · 5.27 Impact Factor
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    ABSTRACT: The efficacy of the amphipathic ketoamide calpain inhibitor SNJ-1945 in attenuating calpain-mediated degradation of the neuronal cytoskeletal protein α-spectrin was examined in the controlled cortical impact (CCI) traumatic brain injury (TBI) model in male CF-1 mice. Using a single early (15 min after CCI-TBI) i.p. bolus administration of SNJ-1945 (6.25, 12.5, 25 or 50-mg/kg), we identified the most effective dose on α-spectrin degradation in the cortical tissue of mice at its 24 hr peak after severe CCI-TBI. We then investigated the effects of a pharmacokinetically-optimized regimen by examining multiple treatment paradigms that varied in dose and duration of treatment. Finally, using the most effective treatment regimen, the therapeutic window of α-spectrin degradation attenuation was assessed by delaying treatment from 15 min to 1 or 3 hr post-injury. The effect of SNJ-1945 on α-spectrin degradation exhibited a U-shaped dose-response curve when treatment was initiated 15 min post-TBI. The most effective 12.5 mg/kg dose of SNJ-1945 significantly reduced α-spectrin degradation by ~60% in cortical tissue. Repeated dosing of SNJ-1945 beginning with a 12.5 mg/kg dose did not achieve a more robust effect compared to a single bolus treatment, and the required treatment initiation was less than 1 hr. Although calpain has been firmly established to play a major role in posttraumatic secondary neurodegeneration, these data suggest that even brain and cell-permeable calpain inhibitors, when administered alone, do not possess sufficient cytoskeletal protective efficacy or a clinically practical therapeutic window after severe TBI. © 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry, J. Neurochem. (2012) 10.1111/jnc.12118.
    Journal of Neurochemistry 12/2012; · 3.97 Impact Factor
  • Edward D Hall, Juan A Wang, Darren M Miller
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    ABSTRACT: We have previously shown the pathophysiological importance of the reactive nitrogen species peroxynitrite (PN) formed from the reaction of nitric oxide (•NO) and superoxide (O(2)(•-)) radicals and its involvement in lipid peroxidation (LP) and protein nitration damage in brain tissue following traumatic brain injury (TBI). Nitric oxide is produced by at least three isoforms of the enzyme nitric oxide synthase (NOS) including: endothelial NOS (eNOS) in the CNS vasculature, neuronal NOS (nNOS), and inducible NOS (iNOS) in macrophages/microglia. In view of the requirement of •NO synthesis for PN formation, we sought to address the time course of NOS expression (mRNA by real time quantitative PCR and protein by western blot) after TBI in comparison with the time course of PN-mediated protein nitration (3-nitrotyrosine, 3-NT) in ipsilateral cortex (CTX) and hippocampus (HIPP) between 3hours and 1week post-injury using a controlled cortical impact (CCI) mouse model of TBI in young adult CF-1 mice. Protein nitration showed a progressive posttraumatic increase that became significant in CTX at 24hours and then peaked at 72hours in both CTX and HIPP. During the increase in PN-derived 3-NT, there was no increase in either CTX or HIPP eNOS mRNA levels, whereas eNOS protein levels were significantly (p<0.05) increased at 48 and 72hours in both brain regions. There was a significant decrease in HIPP, but not CTX nNOS mRNA; however, nNOS protein did not change except for a significant increase in CTX at 1week. There was significantly increased CTX and HIPP iNOS mRNA levels at 24, 48, and 72hours (p<.05) post-injury. In contrast, no change was seen in CTX or HIPP iNOS protein at any timepoint. Taken together, eNOS protein expression and iNOS mRNA appear to bear a coincident temporal relationship to the time course of PN-mediated protein nitrative damage after CCI-TBI suggesting that both constitutive and inducible NOS isoforms contribute •NO for PN formation and 3-NT protein modification after TBI.
    Experimental Neurology 08/2012; 238(2):176-182. · 4.65 Impact Factor
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    Mona Bains, Edward D Hall
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    ABSTRACT: Free radical formation and oxidative damage have been extensively investigated and validated as important contributors to the pathophysiology of acute central nervous system injury. The generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is an early event following injury occurring within minutes of mechanical impact. A key component in this event is peroxynitrite-induced lipid peroxidation. As discussed in this review, peroxynitrite formation and lipid peroxidation irreversibly damages neuronal membrane lipids and protein function, which results in subsequent disruptions in ion homeostasis, glutamate-mediated excitotoxicity, mitochondrial respiratory failure and microvascular damage. Antioxidant approaches include the inhibition and/or scavenging of superoxide, peroxynitrite, or carbonyl compounds, the inhibition of lipid peroxidation and the targeting of the endogenous antioxidant defense system. This review covers the preclinical and clinical literature supporting the role of ROS and RNS and their derived oxygen free radicals in the secondary injury response following acute traumatic brain injury (TBI) and spinal cord injury (SCI) and reviews the past and current trends in the development of antioxidant therapeutic strategies. Combinatorial treatment with the suggested mechanistically complementary antioxidants will also be discussed as a promising neuroprotective approach in TBI and SCI therapeutic research. This article is part of a Special Issue entitled: Antioxidants and antioxidant treatment in disease.
    Biochimica et Biophysica Acta 11/2011; 1822(5):675-84. · 4.66 Impact Factor
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    ABSTRACT: Free radical-induced lipid peroxidation (LP) is critical in the evolution of secondary injury following traumatic brain injury (TBI). Previous studies in our laboratory demonstrated that U-83836E, a potent LP inhibitor, can reduce post-TBI LP along with an improved maintenance of mouse cortical mitochondrial bioenergetics and calcium (Ca(2+)) buffering following severe (1.0 mm; 3.5 m/s) controlled cortical impact TBI (CCI-TBI). Based upon this preservation of a major Ca(2+) homeostatic mechanism, we have now performed dose-response and therapeutic window analyses of the ability of U-83836E to reduce post-traumatic calpain-mediated cytoskeletal (α-spectrin) proteolysis in ipsilateral cortical homogenates at its 24 h post-TBI peak. In the dose-response analysis, mice were treated with a single i.v. dose of vehicle or U-83836E (0.1, 0.3, 1.3, 3.0, 10.0 or 30.0 mg/kg) at 15 min after injury. U-83836E produced a dose-related attenuation of α-spectrin degradation with the maximal decrease being achieved at 3.0 mg/kg. Next, the therapeutic window was tested by delaying the single 3 mg/kg i.v. dose from 15 min post-injury out to 1, 3, 6 or 12 h. No reduction in α-spectrin degradation was observed when the treatment delay was 1 h or longer. However, in a third experiment, we re-examined the window with repeated U-83836E dosing (3.0 mg/kg i.v. followed by 10 mg/kg i.p. maintenance doses at 1 and 3 h after the initial i.v. dose) which significantly reduced 24 h α-α-spectrin degradation even when treatment initiation was withheld until 12 h post-TBI. These results demonstrate the relationship between post-TBI LP, disruptions in neuronal Ca(2+) homeostasis and calpain-mediated cytoskeletal damage.
    Journal of Neurochemistry 03/2011; 117(3):579-88. · 3.97 Impact Factor
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    Edward D Hall, Stephen M Onifer
    Journal of the American Society for Experimental NeuroTherapeutics 03/2011; 8(2):149-51. · 5.38 Impact Factor
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    Edward D Hall
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    ABSTRACT: 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.
    Journal of the American Society for Experimental NeuroTherapeutics 03/2011; 8(2):152-67. · 5.38 Impact Factor
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    ABSTRACT: Mitochondrial dysfunction plays a pivotal role in secondary cell death mechanisms following traumatic brain injury (TBI). Several reports have demonstrated that inhibition of the mitochondrial permeability transition pore with the immunosuppressant drug cyclosporine A (CsA) is efficacious. Accordingly, CsA is being moved forward into late-stage clinical trials for the treatment of moderate and severe TBI. However, several unknowns exist concerning the optimal therapeutic window for administering CsA at the proposed dosages to be used in human studies. The present study utilized a moderate (1.75 mm) unilateral controlled cortical impact model of TBI to determine the most efficacious therapeutic window for initiating CsA therapy. Rats were administered an IP dose of CsA (20 mg/kg) or vehicle at 1, 3, 4, 5, 6, and 8 h post-injury. Immediately following the initial IP dose, osmotic mini-pumps were implanted at these time points to deliver 10 mg/kg/d of CsA or vehicle. Seventy-two hours following the initiation of treatment the pumps were removed to stop CsA administration. Quantitative analysis of cortical tissue sparing 7 days post-injury revealed that CsA treatment initiated at any of the post-injury initiation times out to 8 h resulted in significantly less cortical damage compared to animals receiving vehicle treatment. However, earlier treatment begun in the first 3 h was significantly more protective than that begun at 4 and 8 h. Treatment initiated at 1 h post-injury (∼68% decrease) was not significantly different than that seen at 3 h (∼46% decrease), but resulted in significantly greater cortical tissue sparing compared to CsA treatment initiated at least 4 h post-injury (28% decrease). Together these results illustrate the importance of initiating therapeutic interventions such as CsA as soon as possible following TBI, preferably within 4 h post-injury, to achieve the best possible neuroprotective effect. However, the drug appears to retain some protective efficacy even when initiated as late as 8 h post-injury.
    Journal of neurotrauma 02/2011; 28(2):311-8. · 4.25 Impact Factor
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    ABSTRACT: The cytoskeletal and neuronal protective effects of early treatment with the blood-brain barrier- and cell-permeable calpain inhibitor MDL-28170 was examined in the controlled cortical impact (CCI) traumatic brain injury (TBI) model in male CF-1 mice. This was preceded by a dose-response and pharmacodynamic evaluation of IV or IP doses of MDL-28170 with regard to ex vivo inhibition of calpain 2 activity in harvested brain homogenates. From these data, we tested the effects of an optimized MDL-28170 dosing regimen on calpain-mediated degradation of the neuronal cytoskeletal protein α-spectrin in cortical or hippocampal tissue of mice 24 h after CCI-TBI (1.0 mm depth, 3.5 m/sec velocity). With treatment initiated at 15 min post-TBI, α-spectrin degradation was significantly reduced by 40% in hippocampus and 44% in cortex. This effect was still observed with a 1-h but not a 3-h post-TBI delay. The cytoskeletal protection is most likely taking place in neurons surrounding the area of mainly necrotic degeneration, since MDL-28170 did not reduce hemispheric lesion volume as measured by the aminocupric silver staining method. This lack of effect on lesion volume has been seen with other calpain inhibitors, which suggests that pharmacological calpain inhibition by itself, while able to reduce axonal injury, may not be able to produce a measurable reduction in lesion volume. This is in contrast to certain other neuroprotective mechanistic approaches such as the mitochondrial protectant cyclosporine A, which produces at least a partial decrease in lesion volume in the same model. Accordingly, the combination of a calpain inhibitor with a compound such as cyclosporine A may be needed to achieve the optimal degree of post-TBI neuroprotection.
    Journal of neurotrauma 12/2010; 27(12):2233-43. · 4.25 Impact Factor
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    ABSTRACT: Mitochondrial dysfunction after traumatic brain injury (TBI) is manifested by increased levels of oxidative damage, loss of respiratory functions and diminished ability to buffer cytosolic calcium. This study investigated the detrimental effects of lipid peroxyl radicals (LOO(*)) and lipid peroxidation (LP) in brain mitochondria after TBI by examining the protective effects of U-83836E, a potent and selective scavenger of LOO(*) radicals. Male CF1 mice were subjected to severe controlled cortical impact TBI (CCI-TBI) and treated with either vehicle or U-83836E initiated i.v. at 15 min post-injury. Calcium (Ca(++)) buffering capacity and respiratory function were measured in isolated cortical mitochondrial samples taken from the ipsilateral hemisphere at 3 and 12 h post-TBI, respectively. In vehicle-treated injured mice, the cortical mitochondrial Ca(++) buffering capacity was reduced by 60% at 3 h post-injury (p < 0.001) and the respiratory control ratio was decreased by 27% at 12 h post-TBI, relative to sham, non-injured mice. U-83836E treatment significantly (p < 0.05) preserved Ca(++) buffering capacity and attenuated the reduction in respiratory control ratio values. Consistent with the functional effects of U-83836E being as a result of an attenuation of mitochondrial oxidative damage, the compound significantly (p < 0.001) reduced LP-generated 4-hydroxynonenal levels in both cortical homogenates and mitochondria at both 3 and 12 h post-TBI. Unexpectedly, U-83836E also reduced peroxynitrite-generated 3-nitrotyrosine in parallel with the reduction in 4-hydroxynonenal. The results demonstrate that LOO(*) radicals contribute to secondary brain mitochondrial dysfunction after TBI by propagating LP and protein nitrative damage in cellular and mitochondrial membranes.
    Journal of Neurochemistry 07/2010; 114(1):271-80. · 3.97 Impact Factor
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    ABSTRACT: Mitochondrial bioenergetic dysfunction in traumatic spinal cord and brain injury is associated with post-traumatic free radical-mediated oxidative damage to proteins and lipids. Lipid peroxidation by-products, such as 4-hydroxy-2-nonenal and acrolein, can form adducts with proteins and exacerbate the effects of direct free radical-induced protein oxidation. The aim of the present investigation was to determine and compare the direct contribution of 4-hydroxy-2-nonenal and acrolein to spinal cord and brain mitochondrial dysfunction. Ficoll gradient-isolated mitochondria from normal rat spinal cords and brains were treated with carefully selected doses of 4-hydroxy-2-nonenal or acrolein, followed by measurement of complex I- and complex II-driven respiratory rates. Both compounds were potent inhibitors of mitochondrial respiration in a dose-dependent manner. 4-Hydroxy-2-nonenal significantly compromised spinal cord mitochondrial respiration at a 0.1-muM concentration, whereas 10-fold greater concentrations produced a similar effect in brain. Acrolein was more potent than 4-hydroxy-2-nonenal, significantly decreasing spinal cord and brain mitochondrial respiration at 0.01 muM and 0.1 muM concentrations, respectively. The results of this study show that 4-hydroxy-2-nonenal and acrolein can directly and differentially impair spinal cord and brain mitochondrial function, and that the targets for the toxic effects of aldehydes appear to include pyruvate dehydrogenase and complex I-associated proteins. Furthermore, they suggest that protein modification by these lipid peroxidation products may directly contribute to post-traumatic mitochondrial damage, with spinal cord mitochondria showing a greater sensitivity than those in brain.
    Journal of neurotrauma 04/2010; 27(7):1311-20. · 4.25 Impact Factor
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    ABSTRACT: Free radical-induced oxidative damage reactions, and membrane lipid peroxidation (LP), in particular, are among the best validated secondary injury mechanisms in preclinical traumatic brain injury (TBI) models. In addition to the disruption of the membrane phospholipid architecture, LP results in the formation of cytotoxic aldehyde-containing products that bind to cellular proteins and impair their normal functions. This article reviews the progress of the past three decades in regard to the preclinical discovery and attempted clinical development of antioxidant drugs designed to inhibit free radical-induced LP and its neurotoxic consequences via different mechanisms including the O(2)(*-) scavenger superoxide dismutase and the lipid peroxidation inhibitor tirilazad. In addition, various other antioxidant agents that have been shown to have efficacy in preclinical TBI models are briefly presented, such as the LP inhibitors U83836E, resveratrol, curcumin, OPC-14177, and lipoic acid; the iron chelator deferoxamine and the nitroxide-containing antioxidants, such as alpha-phenyl-tert-butyl nitrone and tempol. A relatively new antioxidant mechanistic strategy for acute TBI is aimed at the scavenging of aldehydic LP byproducts that are highly neurotoxic with "carbonyl scavenging" compounds. Finally, it is proposed that the most effective approach to interrupt posttraumatic oxidative brain damage after TBI might involve the combined treatment with mechanistically complementary antioxidants that simultaneously scavenge LP-initiating free radicals, inhibit LP propagation, and lastly remove neurotoxic LP byproducts.
    Journal of the American Society for Experimental NeuroTherapeutics 01/2010; 7(1):51-61. · 5.38 Impact Factor
  • Edward D Hall, Jeffrey M Bosken
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    ABSTRACT: One of the most completely validated processes involved in secondary tissue damage following acute brain or spinal cord injury and in many chronic neurodegenerative diseases has to do with the pathological formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). These are generated by multiple mechanisms and give rise to highly reactive oxygen radicals that can damage neuronal, glial, and microvascular elements. Particular interest has centered upon oxygen radical-induced, iron-catalyzed lipid peroxidation (LP) as the principal mechanism of neuronal injury associated with oxygen radicals. Thus, there has been a growing interest in monitoring increased oxygen radical levels as an index of oxidative stress, as well as measuring markers of LP-associated oxidative injury in in vitro and in vivo model systems and neurological patient samples. Accordingly, the purpose of this unit is to provide a variety of methods for the measurement of hydroxyl radical formation and/or LP in nervous tissue or biofluids.
    Current protocols in neuroscience / editorial board, Jacqueline N. Crawley ... [et al.] 08/2009; Chapter 7:Unit 7.17.1-51.
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    Yiqin Xiong, Indrapal N Singh, Edward D Hall
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    ABSTRACT: Peroxynitrite (PN)-mediated mitochondrial dysfunction has been implicated in the secondary injury process after traumatic spinal cord injury (SCI). This study investigated the detrimental effects of the PN donor SIN-1 (3-morpholinosydnonimine) on isolated healthy spinal cord mitochondria and the protective effects of tempol, a catalytic scavenger of PN-derived radicals. A 5 min exposure of the mitochondria to SIN-1 caused a dose-dependent decrease in the respiratory control ratio (RCR) that was accompanied by significant increases in complex I-driven states II and IV respiration rates and decreases in states III and V. These impairments occurred together with an increase in mitochondrial protein 3-nitrotyrosine (3-NT), but not in lipid peroxidation (LP)-related 4-hydroxynonenal (4-HNE). Tempol significantly antagonized the respiratory effects of SIN-1 in parallel with an attenuation of 3-NT levels. These results show that the exogenous PN donor, SIN-1, rapidly causes mitochondrial oxidative damage and complex I dysfunction identical to traumatic spinal cord mitochondrial impairment and that this is mainly due to tyrosine nitration. Consistent with that, the protection of mitochondrial respiratory function by tempol is associated with a decrease in 3-NT levels in mitochondrial proteins also similar to the previously reported antioxidant actions of tempol in traumatically-injured spinal cord mitochondria.
    Free Radical Research 07/2009; 43(6):604-12. · 3.28 Impact Factor
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    ABSTRACT: The reactive nitrogen species peroxynitrite (PN) has been suggested to be an important mediator of the secondary oxidative damage that occurs following acute spinal cord injury (SCI). The PN decomposition products nitrogen dioxide (*NO(2)), hydroxyl radical (*OH), and carbonate radical (*CO(3)) are highly reactive with cellular lipids and proteins. In this immunohistochemical study, we examined the temporal (3, 24, and 72 h, and 1 and 2 weeks) and spatial relationships of PN-mediated oxidative damage in the contusion-injured rat thoracic spinal cord (IH device, 200 kdyn, T10) using 3-nitrotyrosine (3-NT), a marker for protein nitration by PN-derived *NO(2) and 4-hydroxynonenal (4-HNE), an indicator of lipid peroxidation (LP) initiated by any of the PN radicals. Minimal 3-NT or 4-HNE immunostaining was seen in sham, non-injured spinal cords. In contrast, both markers showed a substantial increase at 3 h post-injury at the epicenter, that extended throughout the gray matter and into the surrounding white matter. At 24 and 72 h, the oxidative damage expanded circumferentially to involve all but a small rim of white matter tissue at the injury site, and longitudinally as much as 6-9 mm in the rostral and caudal directions. The staining was observed in neuronal soma, axons, and microvessels. At all time points except 3 h, there was no significant difference in the mean rostral or caudal extent of 3-NT and 4-HNE staining. By 1, and more so at 2 weeks, the longitudinal extent of the oxidative damage staining was greatly decreased. The spatial and temporal overlap of 3-NT and 4-HNE staining supports the concept that PN is involved in both damage produced by lipid peroxidation and protein nitration, and that antioxidant agents that target PN or PN-derived radicals should be effective neuroprotectants for acute SCI if administered during the first post-injury hours.
    Journal of neurotrauma 06/2009; 26(8):1369-78. · 4.25 Impact Factor
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    Edward D Hall, Richard J Traystman
    Frontiers of neurology and neuroscience 02/2009; 25:10-33.
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    Yiqin Xiong, Edward D Hall
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    ABSTRACT: Evidence suggests that the reactive oxygen species peroxynitrite (PN) is an important player in the pathophysiology of acute spinal cord injury (SCI). In the present study, we examined the ability of tempol, a catalytic scavenger of PN-derived free radicals, to alleviate oxidative damage, mitochondrial dysfunction and cytoskeletal degradation following a severe contusion (200 kdyn force) SCI in female Sprague-Dawley rats. PN-mediated oxidative damage in spinal cord tissue, including protein nitration, protein oxidation and lipid peroxidation was significantly reduced by acute tempol treatment (300 mg/kg, i.p. within 5 min post-injury). Injury-induced mitochondrial respiratory dysfunction, measured after 24 h in isolated mitochondria, was partially reversed by tempol along with an attenuation of oxidative damage to mitochondrial proteins. Mitochondrial dysfunction disrupts intracellular Ca(2+) homeostasis contributing to calpain-mediated axonal cytoskeletal protein (alpha-spectrin, 280 kD) degradation. Increased levels of alpha-spectrin breakdown proteins (SBDP 145 kD and 150 kD) were significantly decreased at 24 h in tempol-treated rats indicative of spinal axonal protection. However, a therapeutic window analysis showed that the axonal cytoskeletal protective effects require tempol dosing within the first hour after injury. Nevertheless, these findings are the first to support the concept that PN is an important neuroprotective target in early secondary SCI, and that there is a mechanistic link between PN-mediated oxidative compromise of spinal cord mitochondrial function, loss of intracellular Ca(2+) homeostasis and calpain-mediated proteolytic axonal damage.
    Experimental Neurology 01/2009; 216(1):105-14. · 4.65 Impact Factor

Publication Stats

2k Citations
168.36 Total Impact Points

Institutions

  • 2003–2013
    • University of Kentucky
      • • Department of Anatomy & Neurobiology
      • • Spinal Cord and Brain Injury Research Center
      Lexington, KY, United States
  • 2001
    • Pfizer Inc.
      • Pfizer Global Research & Development
      New York City, New York, United States