Oxidative Stress Contributes to Status Epilepticus Associated Mortality

Pearson-Smith, Jennifer N.; Liang, Li‐Ping; Rowley, Shane; Day, Brian J.; Patel, Manisha

doi:10.1007/s11064-017-2273-1

Cited by 42 publications

(30 citation statements)

References 36 publications

(45 reference statements)

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“…We have previously shown the efficacy of AEOL10150 against oxidative/ nitrative stress and neurodegeneration induced by chemoconvulsant agents, kainate and pilocarpine when administered at a 5 mg/kg s.c. every 4 h dosing paradigm (Liang et al, 2016;Pearson et al, 2015). This same dosing paradigm resulted in significant protection against pilocarpineinduced mortality (Pearson-Smith et al, 2017). This, in conjunction with the pharmacokinetic data detailed above lead us to determine the therapeutic window of AEOL10150 against DFP-induced oxidative stress markers.…”

Section: Discussionmentioning

confidence: 91%

“…Treatments targeting oxidative stress may therefore hold promise as novel and efficacious neuroprotective countermeasures against OP toxicity. We have previously shown that oxidative stress contributes to neuronal loss, cognitive impairment and mortality caused by the nerve agent surrogate, pilocarpine (Pearson et al, 2015;Pearson-Smith et al, 2017). However, whether an authentic OP, such as Diisopropylflurorphoshate (DFP) also results in increased indices of oxidative stress and neuroinflammation is relatively poorly understood (Flannery et al, 2016;Zaja-Milatovic et al, 2009).…”

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confidence: 99%

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Neuroprotective Effects of AEOL10150 in a Rat Organophosphate Model

Liang

Pearson-Smith

Huang

et al. 2017

Toxicological Sciences

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Prolonged seizure activity or status epilepticus (SE) is one of the most critical manifestations of organophosphate exposure. Previous studies in our laboratory have demonstrated that oxidative stress is a critical mediator of SE-induced neuronal injury. The goal of this study was to determine if diisopropylflurorphoshate (DFP) exposure in rats resulted in oxidative stress and whether scavenging reactive oxygen species attenuated DFP-induced neurotoxicity. DFP treatment increased indices of oxidative stress in a time- and region- dependent manner. Neuronal loss measured by Fluoro-Jade B staining was significantly increased in the hippocampus, piriform cortex and amygdala following DFP. Similarly, levels of the proinflammatory cytokines, particularly TNF-α, IL-6, and KC/GRO were significantly increased in the piriform cortex and in the hippocampus following DFP treatment. The catalytic antioxidant AEOL10150, when treatment was initiated 5 min after DFP-induced SE, significantly attenuated indices of oxidative stress, neuroinflammation and neuronal damage. This study suggests that catalytic antioxidant treatment may be useful as a novel therapy to attenuate secondary neuronal injury following organophosphate exposure.

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Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 99%

Neuroprotective Effects of AEOL10150 in a Rat Organophosphate Model

Liang

Pearson-Smith

Huang

et al. 2017

Toxicological Sciences

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“…Markers of oxidative stress, such as iNOS, are modulated by chemoconvulsants, including DFP. 25,27,69,70 As fluctuating hormones and pharmacodynamic sex differences might dictate response to disease-modifying agents, we tested 1400W in female rats exposed to DFP. On the first day of treatment, 1400W suppressed seizures but not the epileptiform spikes in those females that had severe SE ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Sex as a biological variable in the rat model of diisopropylfluorophosphate‐induced long‐term neurotoxicity

Gage

Golden

Putra

et al. 2020

Annals of the New York Academy of Sciences

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Sex differences in response to neurotoxicant exposure that initiates epileptogenesis are understudied. We used telemetry-implanted male and female adult rats exposed to an organophosphate (OP) neurotoxicant, diisopropylflourophosphate (DFP), to test sex differences in the severity of status epilepticus (SE) and the development of spontaneous recurrent seizures (SRS). Females had significantly less severe SE and decreased epileptiform spikes compared with males, although females received a higher dose of DFP than males. The estrous stages had no impact on seizure susceptibility, but rats with severe SE had a significantly prolonged diestrus. A previously demonstrated disease-modifying agent, an inducible nitric oxide synthase inhibitor, 1400W, was tested in both sexes. None of the eight males treated with 1400W developed convulsive SRS during 4 weeks post-DFP exposure, while two of seven females developed convulsive SRS. Concerning gliosis and neurodegeneration, there were region-specific differences in the interaction between sex and SE severity. As SE severity influences epileptogenesis, and as females had significantly less severe SE, sex as a biological variable should be factored into the design of future OP nerve agent experiments while evaluating neurotoxicity and optimizing potential disease-modifying agents.

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“…Prolonged seizure activity such as SE is associated with increased oxidative stress leading to neuronal loss and interventions aimed at attenuating seizure-induced oxidative stress have been demonstrated to be neuroprotective [6] , [7] , [8] , [9] , [10] , [11] . AEOL 10150 is a small molecular weight, superoxide dismutase (SOD) mimetic with the capability to catalytically detoxify a broad range of reactive species including superoxide, hydrogen peroxide, lipid peroxides and peroxynitrite [12] .…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective effects of a catalytic antioxidant in a rat nerve agent model

et al. 2019

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Persistent inhibition of acetylcholinesterase resulting from exposure to nerve agents such as soman, is associated with prolonged seizure activity known as status epilepticus (SE). Without medical countermeasures, exposure to soman and resultant SE leads to high morbidity and mortality. Currently available therapeutics are effective in limiting mortality, however effects on morbidity are highly time-dependent and rely on the ability to suppress SE. We have previously demonstrated significant protection from secondary neuronal injury in surrogate nerve agent models by targeting oxidative stress. However, whether oxidative stress represents a relevant therapeutic target in genuine nerve agent toxicity is unknown. Here, we demonstrate that soman exposure results in robust region- and time-dependent oxidative stress. Targeting this oxidative stress in a post-exposure paradigm using a small molecular weight, broad spectrum catalytic antioxidant, was sufficient to attenuate brain and plasma oxidative stress, neuroinflammation and neurodegeneration. Thus, targeting of oxidative stress in a post-exposure paradigm can mitigate secondary neuronal injury following soman exposure.

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Oxidative Stress Contributes to Status Epilepticus Associated Mortality

Cited by 42 publications

References 36 publications

Neuroprotective Effects of AEOL10150 in a Rat Organophosphate Model

Neuroprotective Effects of AEOL10150 in a Rat Organophosphate Model

Sex as a biological variable in the rat model of diisopropylfluorophosphate‐induced long‐term neurotoxicity

Neuroprotective effects of a catalytic antioxidant in a rat nerve agent model

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