Changes in mouse brain metabolism following a convulsive dose of soman: A proton HRMAS NMR study

Fauvelle, F.; Dorandeu, Frédéric; Carpentier, Pierre; Foquin, Annie; Rabeson, H.; Graveron‐Demilly, D.; Arvers, P.; Testylier, Guy

doi:10.1016/j.tox.2009.10.026

Cited by 20 publications

(36 citation statements)

References 78 publications

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“…There they found a decrease in NAA levels in the piriform cortex, starting 4 h postintoxication and lasting for the 7 following days, similar to our results. The lowest value was obtained at 48 h. In concordance with our hypothesis, choline was increased during the first hours after the intoxication and eventually decreased by the 7th day after soman intoxication (28).…”

Section: Discussionsupporting

confidence: 86%

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Early in vivo MR spectroscopy findings in organophosphate‐induced brain damage—potential biomarkers for short‐term survival

Shrot¹,

Anaby²,

Krivoy³

et al. 2012

Magnetic Resonance in Med

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Organophosphates are highly toxic substances, which cause severe brain damage. The hallmark of the brain injury is major convulsions. The goal of this study was to assess the spatial and temporal MR changes in the brain of paraoxon intoxicated rats. T2-weighted MRI and ¹H-MR-spectroscopy were conducted before intoxication, 3 h, 24 h, and 8 days postintoxication. T2 prolongation mainly in the thalami and cortex was evident as early as 3 h after intoxication (4-6% increase in T2 values, P < 0.05). On spectroscopy, N-acetyl aspartate (NAA)/creatine and NAA/choline levels significantly decreased 3 h postintoxication (>20% decrease, P < 0.005), and 3 h lactate peak was evident in all intoxicated animals. On the 8th day, although very little T2 changes were evident, NAA/creatine and choline/creatine were significantly decreased (>15%, P < 0.05). Animals who succumbed had extensive cortical edema, significant higher lactate levels and a significant decrease in NAA/creatine and NAA/choline levels compared to animals which survived the experiment. Organophosphates-induced brain damage is obvious on MR data already 3 h postintoxication. In vivo spectroscopic changes are more sensitive for assessing long-term injury than T2-weighted MR imaging. Early spectroscopic findings might be used as biomarkers for the severity of the intoxication and might predict early survival.

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Section: Discussionsupporting

confidence: 86%

“…The lactate peak was in good correlation with overall mortality. In an ex vivo study of soman intoxicated rats, elevation of lactate levels was found only 24–72 h postintoxication (28). In a piglet model of hypoxic‐ischemic encephalopathy ratios of lactate/choline and lactate/NAA were significantly higher after 7 h compared to baseline.…”

Section: Discussionmentioning

confidence: 99%

Early in vivo MR spectroscopy findings in organophosphate‐induced brain damage—potential biomarkers for short‐term survival

Shrot¹,

Anaby²,

Krivoy³

et al. 2012

Magnetic Resonance in Med

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“…This leads to the last phase of the model, which is predominantly a noncholinergic phenomenon starting approximately 40 min after seizure onset with the presence of prolonged epileptiform activity. It is proposed that this excess influx of calcium is the ultimate cause of neuropathology following nerve agent exposure as it can hyperactivate enzymes such as lipases, proteases, endonucleases, kinases, or phosphatases that can cause damage to cell membranes, cytoskeleton, or organelle structure and function [41,42]. …”

Section: Discussionmentioning

confidence: 99%

Transcriptional analysis of rat piriform cortex following exposure to the organophosphonate anticholinesterase sarin and induction of seizures

Spradling¹,

Lumley²,

Robison³

et al. 2011

J Neuroinflammation

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BackgroundOrganophosphorus nerve agents irreversibly inhibit acetylcholinesterase, causing a toxic buildup of acetylcholine at muscarinic and nicotinic receptors. Current medical countermeasures to nerve agent intoxication increase survival if administered within a short period of time following exposure but may not fully prevent neurological damage. Therefore, there is a need to discover drug treatments that are effective when administered after the onset of seizures and secondary responses that lead to brain injury.MethodsTo determine potential therapeutic targets for such treatments, we analyzed gene expression changes in the rat piriform cortex following sarin (O-isopropyl methylphosphonofluoridate)-induced seizure. Male Sprague-Dawley rats were challenged with 1 × LD50 sarin and subsequently treated with atropine sulfate, 2-pyridine aldoxime methylchloride (2-PAM), and the anticonvulsant diazepam. Control animals received an equivalent volume of vehicle and drug treatments. The piriform cortex, a brain region particularly sensitive to neural damage from sarin-induced seizures, was extracted at 0.25, 1, 3, 6, and 24 h after seizure onset, and total RNA was processed for microarray analysis. Principal component analysis identified sarin-induced seizure occurrence and time point following seizure onset as major sources of variability within the dataset. Based on these variables, the dataset was filtered and analysis of variance was used to determine genes significantly changed in seizing animals at each time point. The calculated p-value and geometric fold change for each probeset identifier were subsequently used for gene ontology analysis to identify canonical pathways, biological functions, and networks of genes significantly affected by sarin-induced seizure over the 24-h time course.ResultsA multitude of biological functions and pathways were identified as being significantly altered following sarin-induced seizure. Inflammatory response and signaling pathways associated with inflammation were among the most significantly altered across the five time points examined.ConclusionsThis analysis of gene expression changes in the rat brain following sarin-induced seizure and the molecular pathways involved in sarin-induced neurodegeneration will facilitate the identification of potential therapeutic targets for the development of effective neuroprotectants to treat nerve agent exposure.

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“…Although the cell passage number has also been found to affect numerous of the cell line features, including growth in culture, viability and efflux protein expression (40), a certain passage range Metabolomics offers a platform for the development of scientific research (42). Pattern recognition and multivariate statistics are effective methods used to determine differences in cells, individuals and treatments (43,44). PCA and PLS-DA are two types of pattern recognition analyses.…”

Section: Discussionmentioning

confidence: 99%

1H nuclear magnetic resonance-based extracellular metabolomic analysis of multidrug resistant Tca8113 oral squamous carcinoma cells

et al. 2015

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Abstract.A major obstacle of successful chemotherapy is the development of multidrug resistance (MDR) in the cancer cells, which is difficult to reverse. Metabolomic analysis, an emerging approach that has been increasingly applied in various fields, is able to reflect the unique chemical fingerprints of specific cellular processes in an organism. The assessment of such metabolite changes can be used to identify novel therapeutic biomarkers. In the present study, 1 H nuclear magnetic resonance (NMR) spectroscopy was used to analyze the extracellular metabolomic spectrum of the Tca8113 oral squamous carcinoma cell line, in which MDR was induced using the carboplatin (CBP) and pingyangmycin (PYM) chemotherapy drugs in vitro. The data were analyzed using the principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) methods. The results demonstrated that the extracellular metabolomic spectrum of metabolites such as glutamate, glycerophosphoethanol amine, α-Glucose and β-Glucose for the drug-induced Tca8113 cells was significantly different from the parental Tca8113 cell line. A number of biochemicals were also significantly different between the groups based on their NMR spectra, with drug-resistant cells presenting relatively higher levels of acetate and lower levels of lactate. In addition, a significantly higher peak was observed at δ 3.35 ppm in the spectrum of the PYM-induced Tca8113 cells. Therefore, 1 H NMR-based metabolomic analysis has a high potential for monitoring the formation of MDR during clinical tumor chemotherapy in the future.

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Changes in mouse brain metabolism following a convulsive dose of soman: A proton HRMAS NMR study

Cited by 20 publications

References 78 publications

Early in vivo MR spectroscopy findings in organophosphate‐induced brain damage—potential biomarkers for short‐term survival

Early in vivo MR spectroscopy findings in organophosphate‐induced brain damage—potential biomarkers for short‐term survival

Transcriptional analysis of rat piriform cortex following exposure to the organophosphonate anticholinesterase sarin and induction of seizures

1H nuclear magnetic resonance-based extracellular metabolomic analysis of multidrug resistant Tca8113 oral squamous carcinoma cells

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