Radical Trapping and Inhibition of Iron‐Dependent CNS Damage by Cyclic Nitrone Spin Traps

Thomas, Craig E.; Ohlweiler, David F.; Taylor, Vicki L.; Schmidt, Christopher J.

doi:10.1046/j.1471-4159.1997.68031173.x

Cited by 40 publications

(21 citation statements)

References 44 publications

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“…PBN concentrates in the mitochondria, where it reacts with ROS and forms stable adducts, and thereby maintains normal levels of energy metabolites. The protective effects of PBN have been described in experimental models of brain ischemia/reperfusion (Phillis and Clough-Helfman, 1990; Carney and Floyd,1991; Gido et al, 1997; Fetcher et al, 1997), excitotoxicity (Cheng and Sun,1994; Lancelot et al, 1997; Milatovic et al, 2002; Zaja-Milatovic et al, 2008), inhibition of NOS induction (Krishna et al, 1996; Miyajima and Kotake, 1997) and in different models of seizures (He et al, 1997; Thomas et al, 1997). Thus, these agents have been proven to rescue neurons in multiple experimental injury models.…”

Section: Discussionmentioning

confidence: 99%

Protection of DFP-induced oxidative damage and neurodegeneration by antioxidants and NMDA receptor antagonist

Zaja‐Milatovic

Gupta

Aschner

et al. 2009

Toxicology and Applied Pharmacology

103

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Prophylactic agents acutely administered in response to anticholinesterases intoxication can prevent toxic symptoms, including fasciculations, seizures, convulsions and death. However, anticholinesterases also have long-term unknown pathophysiological effects, making rational prophylaxis/treatment problematic. Increasing evidence suggests that in addition to excessive cholinergic stimulation, organophosphate compounds such as diisopropylphosphorofluoridate (DFP) induce activation of glutamatergic neurons, generation of reactive oxygen (ROS) and nitrogen species (RNS), leading to neurodegeneration. The present study investigated multiple affectors of DFP exposure critical to cerebral oxidative damage and whether antioxidants and NMDA receptor antagonist memantine provide neuroprotection by preventing DFP-induced biochemical and morphometric changes in rat brain. Rats treated acutely with DFP (1.25 mg/kg, s.c.) developed onset of toxicity signs within 7-15 min that progressed to maximal severity of seizures and fasciculations within 60 min. At this time point, DFP caused significant (p<0.01) increases in biomarkers of ROS (F 2 -isoprostanes, F 2 -IsoPs; and F 4 -neuroprostanes, F 4 -NeuroPs), RNS (citrulline), and declines in high-energy phosphates (HEP) in rat cerebrum. At the same time, quantitative morphometric analysis of pyramidal neurons of the hippocampal CA1 region revealed significant (p<0.01) reductions in dendritic lengths and spine density. When rats were pretreated with the antioxidants N-tert-butyl-α-phenylnitrone (PBN, 200 mg/kg, i.p.), or vitamin E (100 mg/kg, i.p./day for 3 days), or memantine (18 mg/kg, i.p.), significant attenuations in DFP-induced increases in F 2 -IsoPs, F 4 -NeuroPs, citrulline, and depletion of HEP were noted. Furthermore, attenuation in oxidative damage following antioxidants or memantine pretreatment was accompanied by rescue from dendritic degeneration of pyramidal neurons in the CA1 hippocampal area. These findings closely associated DFP-induced lipid peroxidation with dendritic degeneration of pyramidal neurons in the CA1 hippocampal area and point to possible interventions to limit oxidative injury and dendritic degeneration induced by anticholinesterase neurotoxicity.

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Section: Discussionmentioning

confidence: 99%

Protection of DFP-induced oxidative damage and neurodegeneration by antioxidants and NMDA receptor antagonist

Zaja‐Milatovic

Gupta

Aschner

et al. 2009

Toxicology and Applied Pharmacology

103

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“…It is generally assumed that nitrones that are active in in vivo models exert their effect by scavenging deleterious free radicals. Although PBN has been characterized as an antioxidant [20][21][22][23], the antioxidant potential of S-PBN and NXY-059 has not been reported. It is important to note that when PBN and NXY-059 were tested in the same transient middle cerebral artery occlusion focal stroke rat model, NXY-059 was much more efficacious [5].…”

Section: -Sulfophenyl-n-tert-butylmentioning

confidence: 99%

Comparison of the radical trapping ability of PBN, S-PBN and NXY-059

Maples¹,

Ma²,

Zhang³

2001

Free Radical Research

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The nitrones alpha-phenyl-N-tert-butyl nitrone (PBN), sodium 2-sulfophenyl-N-tert-butyl nitrone (S-PBN) and disodium 2,4-disulfophenyl-N-tert-butyl nitrone (NXY-059) are neuroprotective in a variety of rodent models. The objective of the current studies was to compare the ability of PBN, S-PBN, and NXY-059 to form radical adducts and to prevent salicylate oxidation in an aqueous system. For the electron spin resonance (ESR) studies, hydroxyl radicals were generated with ultraviolet (UV) light and hydrogen peroxide. Secondary radicals were then produced by the addition of methanol, ethanol, isopropanol, dimethylsulfoxide, tetrahydrofuran or 1,4-dioxane. In addition, competition spin trapping studies were performed using PBN-alpha-(13) C and either S-PBN or NXY-059. In the salicylate studies, PBN, S-PBN and NXY-059 were compared to a variety of other antioxidants and reference compounds (cysteine, glutathione, ascorbate, uric acid, Tempo, Trolox, and Tirilizad) for their ability to prevent 2,3- and 2,5-dihydroxybenzoic acid formation induced by hydroxyl radical generating systems. All 3 nitrones trapped carbon- and oxygen-centered radicals to produce ESR-detectable radical adducts. Each nitrone also prevented salicylate oxidation, with PBN being the most effective. The ability of these 3 nitrones to prevent salicylate oxidation resembled that of most of the other compounds tested.

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“…We tested the efficacy of the spin trapping agent, PBN and the antioxidant tocopherol. Protective effects of these agents are described in experimental models of brain ischemia/reperfusion (Phillis and Clough-Helfman, 1990;Carney and Floyd,1991;Gido et al, 1997;Fetcher et al, 1997), excitotoxicity (Cheng and Sun,1994;Lancelot et al, 1997;Milatovic et al, 2002), inhibition of nitric oxide synthase induction (Krishna et al, 1996;Miyajima and Kotake, 1995), and in different models of seizures (He et al, 1997;Thomas et al, 1997). Additional findings also corroborate that PBN effectively prevents neurodegeneration in Parkinson's (Fallon et al, 1997;Frederiksson et al, 1997;Sack et al, 1996), Alzheimer's disease and anticholinesterase neurotoxicity (Sack et al, 1996;Gupta et al, 2001a;Gupta et al, 2001b).…”

Section: Discusionmentioning

confidence: 77%

Pharmacologic suppression of oxidative damage and dendritic degeneration following kainic acid-induced excitotoxicity in mouse cerebrum

et al. 2008

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Intense seizure activity associated with status epilepticus and excitatory amino acid (EAA) imbalance initiates oxidative damage and neuronal injury in CA1 of the ventral hippocampus. We tested the hypothesis that dendritic degeneration of pyramidal neurons in the CA1 hippocampal area resulting from seizure-induced neurotoxicity is modulated by cerebral oxidative damage. Kainic acid (KA, 1 nmol/5 μl) was injected intracerebroventricularly to C57Bl/6 mice. F 2 -isoprostanes (F 2 -IsoPs) and F 4 -neuroprostanes (F 4 -NeuroPs) were used as surrogate measures of in vivo oxidative stress and biomarkers of lipid peroxidation. Nitric oxide synthase (NOS) activity was quantified by evaluating citrulline level and pyramidal neuron dendrites and spines were evaluated using rapid Golgi stains and a Neurolucida system. KA produced severe seizures in mice immediately after its administration and a significant (p<0.001) increase in F 2 -IsoPs, F 4 -NeuroPs and citrulline levels were seen 30 min following treatment. At the same time, hippocampal pyramidal neurons showed significant (p<0.001) reduction in dendritic length and spine density. In contrast, no significant change in neuronal dendrite and spine density or F 2 -IsoP, F 4 -NeuroPs and citrulline levels were found in mice pretreated with Vitamin E (α-tocopherol, 100 mg/kg, ip) for 3 days, or with N-tert-butyl-α-phenylnitrone (PBN, 200 mg/kg, ip) or ibuprofen (inhibitors of cyclooxygenase, COX, 14 μg/ml of drinking water) for 2 weeks prior to KA treatment. These findings indicate novel interactions among free radical-induced generation of F 2 -IsoPs and F 4 -NeuroPs, nitric oxide and dendritic degeneration, closely associate oxidative damage to neuronal membranes with degeneration of the dendritic system, and point to possible interventions to limit severe damage in acute neurological disorders.

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Radical Trapping and Inhibition of Iron‐Dependent CNS Damage by Cyclic Nitrone Spin Traps

Cited by 40 publications

References 44 publications

Protection of DFP-induced oxidative damage and neurodegeneration by antioxidants and NMDA receptor antagonist

Protection of DFP-induced oxidative damage and neurodegeneration by antioxidants and NMDA receptor antagonist

Comparison of the radical trapping ability of PBN, S-PBN and NXY-059

Pharmacologic suppression of oxidative damage and dendritic degeneration following kainic acid-induced excitotoxicity in mouse cerebrum

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