Mice deficient in L-12/15 lipoxygenase show increased vulnerability to 3-nitropropionic acid neurotoxicity

He, Yan; Akumuo, Rita; Yang, Yuan; Hewett, Sandra J.

doi:10.1016/j.neulet.2017.02.031

Cited by 10 publications

(4 citation statements)

References 55 publications

(61 reference statements)

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“…Cell SPM dysregulation has been implicated in neuroinflammation related to Alzheimer's disease, stroke, and age-related macular degeneration (17,18). Additionally, mice deficient in ALOX5 or ALOX15 have increased vulnerability in models of multiple sclerosis (MS) and Huntington's disease (43,44). Yet most SPM actions have been linked to their established antiinflammatory and proresolving activities.…”

Section: Resultsmentioning

confidence: 99%

Astrocyte-derived lipoxins A4 and B4 promote neuroprotection from acute and chronic injury

Livne‐Bar¹,

Wei²,

Liu³

et al. 2017

Journal of Clinical Investigation

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Section: Resultsmentioning

confidence: 99%

Astrocyte-derived lipoxins A4 and B4 promote neuroprotection from acute and chronic injury

Livne‐Bar¹,

Wei²,

Liu³

et al. 2017

Journal of Clinical Investigation

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“…In vivo cell death was analyzed histologically. Frozen brain sections (40 µm) were collected serially from the rostrocaudal extent of each brain (+1.54 to −0.18 relative to bregma) and stained with 0.5% thionin by submersion in multiple solutions (70% EtOH, 50% EtOH, ddH 2 O, thionin, ddH 2 O, ddH 2 O, 70% EtOH, 95% EtOH, 100% EtOH, 100% EtOH, 100% Xylene, 100% Xylene), as previously described [ 22 ]. Images were captured by scanning (Epson Perfection 3170, Epson, Long Beach, CA USA) at 2400 dpi.…”

Section: Methodsmentioning

confidence: 99%

Interleukin-1β Protects Neurons against Oxidant-Induced Injury via the Promotion of Astrocyte Glutathione Production

et al. 2018

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Interleukin-1β (IL-1β), a key cytokine that drives neuroinflammation in the Central Nervous System (CNS), is enhanced in many neurological diseases/disorders. Although IL-1β contributes to and/or sustains pathophysiological processes in the CNS, we recently demonstrated that IL-1β can protect cortical astrocytes from oxidant injury in a glutathione (GSH)-dependent manner. To test whether IL-1β could similarly protect neurons against oxidant stress, near pure neuronal cultures or mixed cortical cell cultures containing neurons and astrocytes were exposed to the organic peroxide, tert-butyl hydroperoxide (t-BOOH), following treatment with IL-1β or its vehicle. Neurons and astrocytes in mixed cultures, but not pure neurons, were significantly protected from the toxicity of t-BOOH following treatment with IL-1β in association with enhanced GSH production/release. IL-1β failed to increase the GSH levels or to provide protection against t-BOOH toxicity in chimeric mixed cultures consisting of IL-1R1+/+ neurons plated on top of IL-1R1−/− astrocytes. The attenuation of GSH release via block of multidrug resistance-associated protein 1 (MRP1) transport also abrogated the protective effect of IL-1β. These protective effects were not strictly an in vitro phenomenon as we found an increased striatal vulnerability to 3-nitropropionic acid-mediated oxidative stress in IL-1R1 null mice. Overall, our data indicate that IL-1β protects neurons against oxidant injury and that this likely occurs in a non-cell-autonomous manner that relies on an increase in astrocyte GSH production and release.

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“…As neurons are highly mitochondriadependent cells, they are particularly susceptible to mitochondrial toxicants (Schmidt et al 2017). Accordingly, some of the most notorious neurotoxicants, such as carbon monoxide, nitropropionic acid, rotenone and MPP + are mitochondrial respiratory chain inhibitors (He et al 2017;Leist et al 1997aLeist et al , c, 1998Levy 2017;Nicklas et al 1985;Nicotera and Leist 1997;Schildknecht et al 2017;Sherer et al 2007). One of the few adverse outcome pathways (AOP) fully endorsed by the OECD has mitochondrial dysfunction as the pivotal key event (Bal-Price et al 2018;Terron et al 2018).…”

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confidence: 99%

Development of a neurotoxicity assay that is tuned to detect mitochondrial toxicants

et al. 2019

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Many neurotoxicants affect energy metabolism in man, but currently available test methods may still fail to predict mito-and neurotoxicity. We addressed this issue using LUHMES cells, i.e., human neuronal precursors that easily differentiate into mature neurons. Within the NeuriTox assay, they have been used to screen for neurotoxicants. Our new approach is based on culturing the cells in either glucose or galactose (Glc-Gal-NeuriTox) as the main carbohydrate source during toxicity testing. Using this Glc-Gal-NeuriTox assay, 52 mitochondrial and non-mitochondrial toxicants were tested. The panel of chemicals comprised 11 inhibitors of mitochondrial respiratory chain complex I (cI), 4 inhibitors of cII, 8 of cIII, and 2 of cIV; 8 toxicants were included as they are assumed to be mitochondrial uncouplers. In galactose, cells became more dependent on mitochondrial function, which made them 2-3 orders of magnitude more sensitive to various mitotoxicants. Moreover, galactose enhanced the specific neurotoxicity (destruction of neurites) compared to a general cytotoxicity (plasma membrane lysis) of the toxicants. The Glc-Gal-NeuriTox assay worked particularly well for inhibitors of cI and cIII, while the toxicity of uncouplers and non-mitochondrial toxicants did not differ significantly upon glucose ↔ galactose exchange. As a secondary assay, we developed a method to quantify the inhibition of all mitochondrial respiratory chain functions/ complexes in LUHMES cells. The combination of the Glc-Gal-NeuriTox neurotoxicity screening assay with the mechanistic follow up of target site identification allowed both, a more sensitive detection of neurotoxicants and a sharper definition of the mode of action of mitochondrial toxicants. Keywords Neurotoxicity • Mitotoxicity • Metabolic reprogramming • High-throughput toxicity screening • High content imaging • Mechanistic safety assessment Abbreviations ADP Adenosine triphosphate AOP Adverse outcome pathway Asp l-Aspartate ATP Adenosine diphosphate cAMP N6,2′-O-Dibutyryladenosine 3′,5′-cyclic monophosphate cI-V MRC complex I-V CNS Central nervous system Cyt c Cytochrome c FAD(H 2) Flavin adenine dinucleotide (FAD: oxidized, FADH2: reduced) FCCP Carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone G6P Glucose-6-phosphate Gal1P Galactose-1-phosphate GALK Galactokinase GALT Galactose-1-phosphate uridylyltransferase GDNF Glial derived neurotrophic factor Glc1P Glucose-1-phosphate Hex Hexose, in this study either glucose or galactose HK Hexokinase Lac Lactate Mal Malate MoA Mode of action MPP 1-Methyl-4-phenylpyridinium Electronic supplementary material The online version of this article (

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Mice deficient in L-12/15 lipoxygenase show increased vulnerability to 3-nitropropionic acid neurotoxicity

Cited by 10 publications

References 55 publications

Astrocyte-derived lipoxins A4 and B4 promote neuroprotection from acute and chronic injury

Astrocyte-derived lipoxins A4 and B4 promote neuroprotection from acute and chronic injury

Interleukin-1β Protects Neurons against Oxidant-Induced Injury via the Promotion of Astrocyte Glutathione Production

Development of a neurotoxicity assay that is tuned to detect mitochondrial toxicants

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