Changes in purine levels associated with cellular brain injury in gerbils experimentally infected with Neospora caninum

Tonin, Alexandre A.; Silva, Aleksandro S. Da; Thomé, Gustavo R.; Schirmbeck, Gabriel Henrique; Cardoso, Valesca Veiga; Casali, Émerson André; Toscan, Gustavo; Vogel, Fernanda Silveira Flores; Flores, Mariana M.; Fighera, Rafael A.; Lopes, Sonia T.A.

doi:10.1016/j.rvsc.2014.03.004

Cited by 6 publications

(5 citation statements)

References 28 publications

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“…Alternatively, reduced ATP might be attributed to parasite salvage of host cytosolic ATP, which affects the host cell’s metabolism leading to alterations in the ATP concentration in the medium. In agreement with our finding, a recent study reported an association between low level of purine and early phase of experimental N. caninum infection in gerbils [14]. …”

Section: Discussionsupporting

confidence: 94%

Metabolic footprinting of extracellular metabolites of brain endothelium infected with Neospora caninum in vitro

et al. 2014

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BackgroundThe survival of the intracellular protozoan parasite Neospora caninum depends on its ability to adapt to changing metabolic conditions of the host cell. Thus, defining cellular and metabolic changes in affected target tissues may aid in delineating pathogenetic mechanism. We undertook this study to assess the metabolic response of human brain microvascular endothelial cells (HBMECs) to N. caninum infection in vitro.MethodsHBMECs were exposed to N. caninum infection and the cytotoxic effects of infection were analyzed by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazoliumbromidin (MTT) assay and lactate dehydrogenase (LDH) release assay. Metabolic footprinting of the extracellular metabolites of parasite-infected and non-infected culture supernatant was determined by using targeted (Randox RX Imola clinical chemistry analyser) and unbiased RS (Raman microspectroscopy) approaches.ResultsThe MTT assay did not reveal any cytotoxic effect of N. caninum challenge on host cell viability. Measurement of LDH activity showed that N. caninum significantly induced loss of cell membrane integrity in a time-dependent and dose-dependent manner compared to control cells. Targeted biochemical analysis revealed that beta hydroxybutyrate, pyruvate, ATP, total protein, non-esterified fatty acids, and triglycerides are significantly different in infected cells compared to controls. RS-based footprinting with principal component analysis (PCA) were able to correctly distinguish extracellular metabolites obtained from infected and control cultures, and revealed infection-related spectral signatures at 865 cm−1, 984 cm−1, 1046 cm−1, and 1420 cm−1, which are attributed to variations in the content of lipids and nucleic acids in infected cultures.ConclusionsThe changing pattern of extracellular metabolites suggests that HBMECs are target of metabolic alterations in N. caninum infection, which seem to reflect the changing metabolic state of infected cells and constitute a level of information exchange that host and parasite use to coordinate activities.

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Section: Discussionsupporting

confidence: 94%

Metabolic footprinting of extracellular metabolites of brain endothelium infected with Neospora caninum in vitro

et al. 2014

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“…Our study demonstrates a dramatic elevation in purine metabolites, specifically members of the xanthine/hypoxanthine pathway, in the amniotic fluid, 6 hours after insult. It is known that purines are released in the face of inflammation and infection as well as during pathological conditions such as hypoxia/ischemia, stroke or trauma [ 27 – 29 ]. Purines and their metabolites are not only harbingers of inflammation, but are signaling molecules that control neural stem cell function and neurogenesis [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Exposure to intrauterine inflammation alters metabolomic profiles in the amniotic fluid, fetal and neonatal brain in the mouse

et al. 2017

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IntroductionExposure to prenatal inflammation is associated with diverse adverse neurobehavioral outcomes in exposed offspring. The mechanism by which inflammation negatively impacts the developing brain is poorly understood. Metabolomic profiling provides an opportunity to identify specific metabolites, and novel pathways, which may reveal mechanisms by which exposure to intrauterine inflammation promotes fetal and neonatal brain injury. Therefore, we investigated whether exposure to intrauterine inflammation altered the metabolome of the amniotic fluid, fetal and neonatal brain. Additionally, we explored whether changes in the metabolomic profile from exposure to prenatal inflammation occurs in a sex-specific manner in the neonatal brain.MethodsCD-1, timed pregnant mice received an intrauterine injection of lipopolysaccharide (50 μg/dam) or saline on embryonic day 15. Six and 48 hours later mice were sacrificed and amniotic fluid, and fetal brains were collected (n = 8/group). Postnatal brains were collected on day of life 1 (n = 6/group/sex). Global biochemical profiles were determined using ultra performance liquid chromatography/tandem mass spectrometry (Metabolon Inc.). Statistical analyses were performed by comparing samples from lipopolysaccharide and saline treated animals at each time point. For the P1 brains, analyses were stratified by sex.Results/ConclusionsExposure to intrauterine inflammation induced unique, temporally regulated changes in the metabolic profiles of amniotic fluid, fetal brain and postnatal brain. Six hours after exposure to intrauterine inflammation, the amniotic fluid and the fetal brain metabolomes were dramatically altered with significant enhancements of amino acid and purine metabolites. The amniotic fluid had enhanced levels of several members of the (hypo) xanthine pathway and this compound was validated as a potential biomarker. By 48 hours, the number of altered biochemicals in both the fetal brain and the amniotic fluid had declined, yet unique profiles existed. Neonatal pups exposed to intrauterine inflammation have significant alterations in their lipid metabolites, in particular, fatty acids. These sex-specific metabolic changes within the newborn brain offer an explanation regarding the sexual dimorphism of certain psychiatric and neurobehavioral disorders associated with exposure to prenatal inflammation.

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“…These clinical signs were anorexia and decreasing body condition and occurred from five to seventeen days after inoculation. Other clinical signs of acute neosporosis, commonly reported in adult gerbils (RAMAMOORTHY et YANG et al, 2009;TONIN et al, 2014), were not reported in the neonate gerbils, indicating differences in the clinical course in neonate and adult animals. Mortality (spontaneous death or euthanasia in extremis) of neonate gerbils occurred from the eighth to seventeenth days.…”

Section: Resultsmentioning

confidence: 91%

Oral infection of neonate gerbils by Neospora caninum tachyzoites

et al. 2015

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Changes in purine levels associated with cellular brain injury in gerbils experimentally infected with Neospora caninum

Cited by 6 publications

References 28 publications

Metabolic footprinting of extracellular metabolites of brain endothelium infected with Neospora caninum in vitro

Metabolic footprinting of extracellular metabolites of brain endothelium infected with Neospora caninum in vitro

Exposure to intrauterine inflammation alters metabolomic profiles in the amniotic fluid, fetal and neonatal brain in the mouse

Oral infection of neonate gerbils by Neospora caninum tachyzoites

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